Adverse reactions to injectable soft tissue fillers

CONTINUING MEDICAL EDUCATION Adverse reactions to injectable soft tissue fillers Luis Requena, MD,a Celia Requena, MD,b Lise Christensen, MD,c Ute S...
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CONTINUING

MEDICAL EDUCATION

Adverse reactions to injectable soft tissue fillers Luis Requena, MD,a Celia Requena, MD,b Lise Christensen, MD,c Ute S. Zimmermann, MD,d Heinz Kutzner, MD,e and Lorenzo Cerroni, MDf Madrid and Valencia, Spain; Copenhagen, Denmark; Paris, France; Friedrichshafen, Germany; and Graz, Austria In recent years, injections with filler agents are often used for wrinkle-treatment and soft tissue augmentation by dermatologists and plastic surgeons. Unfortunately, the ideal filler has not yet been discovered and all of them may induce adverse reactions. Quickly biodegradable or resorbable agents may induce severe complications, but they will normally disappear spontaneously in a few months. Slowly biodegradable or nonresorbable fillers may give rise to severe reactions that show little or no tendency to spontaneous improvement. They may appear several years after the injection, when the patient does not remember which product was injected, and treatment is often insufficient. In this review, we discuss the most commonly used fillers, their most frequent adverse reactions as well as the characteristic histopathologic findings that allow the identification of the injected filler agent. In conclusion, histopathologic study remains as the gold standard technique to identify the responsible filler. ( J Am Acad Dermatol 2011;64:1-34.) Learning objectives: After completing this learning activity, participants should be able to recognize the most frequent adverse reactions induced by cosmetic fillers, identify their histopathologic characteristics so that they can be distinguished from each other, and advise their patients with adverse reactions about the different nature of these according to the filler for subsequent successful treatment. Key words: adverse reactions; bovine collagen; calcium hydroxylapatite; dextranomers; fillers; histopathology; hyaluronic acid; paraffin; polyacrylamide; polyalkylimide; poly-L-lactic acid; polymethylmethacrylate; polyvinylhydroxide; polyvinylpyrrolidone; silicone.

uring the last few decades, cosmetic dermatology has been growing with many different techniques for ‘‘rejuvenation.’’ Among them, injection techniques with filler agents are often used for wrinkle treatment and soft tissue augmentation. The treatment of age wrinkles, correction of atrophic scars or small cutaneous defects, and cosmetic soft tissue augmentation of different parts of the body are currently common parts of daily practice for many dermatologists and plastic surgeons. The ideal injectable material for wrinkle treatment or soft tissue augmentation should offer good aesthetic results and have a long-lasting effect. It should also be safe, biocompatible, and stable at the

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implantation site, with minimal complications and no risk of migration.1,2 Unfortunately, the ideal filler has not yet been discovered, although available agents are numerous and varied. Some of them seem to be less risky than others, but all of them can induce adverse reactions. Agents that degrade within months—such as collagen, hyaluronic acid, and agarose gel—may induce severe complications, but these will in general disappear spontaneously in a variable period of time. All other fillers can give rise to severe adverse reactions, and these show little or no tendency to spontaneous improvement. They may appear several years after the injections, when the patient does not remember which product was

From the Departments of Dermatology, Fundaci on Jimenez Dıaz,a Universidad Aut onoma, Madrid, and the Instituto Valenciano de Oncologıa,b Valencia, Spain; Department of Pathology,c Bispebjerg Hospital, University Hospital, Copenhagen, Denmark; Centre de Pathologie Cutanee de la Roquette,d Paris, France; Dermatopathologische Gemeinschaftspraxis,e Friedrichshafen, Germany; and the Department of Dermatology, University of Graz, Graz, Austria.f Robert T. Brodell, MD, JAAD CME Planner, has disclosed the following financial relationship: Medicis - Advisory Board/Honoraria. All other authors, editors, planners, editorial and education staff

involved with this CME activity and all content validation/peer reviewers of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Reprints not available from the authors. Correspondence to: Luis Requena, MD, Department of Dermatology, Fundaci on Jimenez Dıaz, Avda. Reyes Cat olicos 2, 28040-Madrid, Spain. E-mail: [email protected]. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.02.064

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injected, and treatment is often ineffective. Someassignment of the culpability of the filler or fillers times, surgical excision of the injected agent is the causing the adverse reaction. only therapeutic possibility, resulting in poorer cosmetic results than those which were attempted to BOVINE COLLAGEN correct by filler in the first place. Key points In this review, we will discuss the most commonly d Bovine collagen is a resorbable filler; the used fillers and their most frequent adverse reactions. duration of the effect from an injection of Special attention will be fobovine collagen procused on the characteristic ducts is usually less CAPSULE SUMMARY histopathologic findings that than 6 months d Histopathologically, boallow the identification of the All cosmetic fillers may induce adverse specific filler agent. This is vine collagen fibers are reactions. Complications secondary to necessary because only a much thicker than hubiodegradable or resorbable fillers will dermatopathologic examinaman collagen, have a disappear spontaneously in a few tion can identify precisely homogeneous appearmonths, but nonresorbable fillers may which filler is involved and ance nearly devoid of give rise to severe permanent reactions. therefore determine the type spaces between them, of adverse inflammatory reHistopathologic study of the cutaneous with fewer fibroblasts, action for optimal treatment. lesions is the criterion standard and fail to refract polarIn litigation cases, dermatotechnique to identify the responsible ized light d Skin tests are required pathologic evaluations of filler of the adverse reaction, because the skin specimens have been particles of each filler have specific before the injection of used as proof of association microscopic characteristics. bovine collagen products d Rare hypersensitive rebetween a filler and the paTreatment of cutaneous adverse tient’s subsequent skin reacactions to bovine collareactions to permanent fillers is often tion. This can be determined gen include foreign ineffective, and surgical excision of the because each filler has spebody granulomas and injected agent is typically the only cific histopathologic feapalisading granulomas therapeutic possibility. tures. This is particularly important in cases where a Bovine collagen has been number of different fillers have been injected in the used as injectable filler in human subjects for same site, or where the patients had not been nearly 30 years. Originally, this collagen was correctly informed concerning the procedure and injected into the dermis and subcutaneous tissue filler used. to correct depressed acne scars, viral pockmarks, Some authors have proposed a grading sysand lipoatrophy,4 but shortly thereafter the product tem classification of foreign body reactions was popularized for correcting deep nasolabial induced by injected fillers into four categories3: folds (Fig 1), age-related rhytides,5 and soft tissue grade I, slight reaction with a few inflammatory cells; augmentation, especially lip enhancement.6 The grade II, clear inflammatory reaction with one or two duration of the effect from an injection of bovine giant cells; grade III, fibrous tissue with inflammatory collagen is usually less than 6 months. However, cells, lymphocytes, and giant cells; and grade IV, variations in longevity are frequent depending on granuloma with encapsulated implants and clear collagen gel subtype, amount injected, mechanical foreign body reaction. stress at the treatment site, location, and individual In our experience, however, this classification response.7 system is difficult to apply in a specific case because Animal studies using bovine collagen8 and huthe intensity of the inflammatory response in foreign man histopathologic studies of bovine collagen body granulomas varies from one histopathologic implants in aging human facial skin5 have revealed section to another—or even within different areas of recipient collagen production that gradually rethe same section. places the injected collagen after implantation. Table I lists the most common fillers that are Ultrastructural studies identified fibroblasts within currently used. They have been classified into two the implant with dilated rough endoplasmic reticumain categories, namely transitory biodegradable or lum, which was indicative of active collagen secretresorbable within months and years respectively, ing cells,5 and direct immunofluorescent studies and permanent or nonresorbable. The trademark have also shown the deposition of type III collagen of each filler is also included for a more easy by the host during the bovine collagen resorption.9 d

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Table I. The most common injectable fillers for soft tissue augmentation Category

Resorbable within months

Chemical composition

Trade name*

Bovine collagen

Zyderm and Zyplast

Human-derived collagen

Autologen, Cosmoderm, Cosmoplast, and Cymetra Hylaform, Restylane, Juv ederm, Perlane, and Macrolane Matridex and Reviderm intra

Hyaluronic acid Resorbable within years

Permanent

Hyaluronic acid plus dextranomer microparticles Poly-L-lactic acid microspheres plus sodium carboxymethylcellulose, nonpyrogenic mannitol, and sterile water Calcium hydroxylapatite plus carboxymethylcellulose and glycerine Paraffin Silicone oil Silicone gel Silicone elastomer particles plus polyvinylpyrrolidone Polymethylmethacrylate microspheres and bovine collagen Hydroxyethylmethacrylate/ethylmethacrylate fragments and hyaluronic acid Polyacrylamide hydrogel

Polyalkylimide gel Polyvinylhydroxide microspheres plus polyacrylamide gel

Sculptra and New-Fill

Radiance and Radiesse

Silikon 1000 and Silskin MDX 4-4011 and Dow Corning Bioplastique Artecoll, Arteplast, and Artefill Dermalive and Dermadeep Aquamid, Interfall, OutLine, Royamid, Formacryl, Argiform, Amazingel, Bio-Formacryl, and Kosmogel Bio-Alcamid Evolution

*Trade names are owned by their respective manufacturers as noted in the manuscript.

Histopathologically, bovine collagen can be differentiated from human collagen because bundles of bovine collagen are much thicker and have a homogeneous appearance nearly devoid of spaces between them and with fewer fibroblasts,10 which by the colloidal iron stain have been shown to secrete glycosaminoglycans between the fibrils of the implant.11 Furthermore, human collagen is birefringent under polarized light and stains green with Masson trichrome stain, whereas bovine collagen fails to refract polarized light and stains with a pale gray-violet color with Masson trichrome stain.7,11 Early dermal implants induce a characteristic subepidermal response that consists of edema and fibroplasia of the papillary dermis.11 Within a few weeks, a perivascular lymphohistiocytic infiltrate is observed around the periphery of the implant. Invasion of the implant by neoformed host vessels is not seen.11 The inflammatory response around the implant is usually more dense when the bovine collagen is injected in the reticular dermis or partially infiltrates the subcutaneous fat, but panniculitis is not observed when the implant is confined to the dermis.11

Fig 1. Granulomatous reaction after bovine collagen injections in the nasolabial folds.

Zyderm I (Inamed, Santa Barbara, CA) was the first bovine collagen introduced in the market as injectable filler and is composed of a phosphatebuffered saline solution of 35 mg/mL of collagen with 0.3% lidocaine. Zyderm I was followed by Zyderm II (Inamed), a concentration of 65 mg/mL of collagen with 0.3% lidocaine, and by Zyplast (Inamed), which was developed to provide a longer-lasting effect by cross-linking collagen fibrils with glutaraldehyde. Zyplast is more resistant to

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proteolytic degradation and is less immunogenic.12 In addition, Zyplast has a lower viscosity than Zyderm I and Zyderm II and this makes it applicable for deeper contour defects. Skin tests are required before injection of these products, because 3% of the population develops a delayed hypersensitivity response. This is characterized by local erythema, swelling, and induration occurring 48 to 72 hours following intradermal injection of a 0.1-mL aliquot of collagen injectable in the volar forearm, indicating a preexisting allergy to bovine collagen.13-17 Some authors even recommend a second skin test either 2 or 4 weeks after a negative first test before initiating therapy, because 2% of patients will develop hypersensitivity after repeat exposure despite initial nonreactivity.18-20 Because most treatment-associated allergic reactions to bovine collagen occur shortly after the first treatment, double testing greatly reduces the frequency of this hypersensitivity side effect.21 Additional rare hypersensitive reactions include the formation of foreign body granulomas,7,22-25 palisading granulomas resembling granuloma annulare at the test site injections26,27 (one of these patients had a history of granuloma annulare and the reaction at the site injection might also be caused by Koebner phenomenon27), and cyst or abscess formation.28 Rare examples of disseminated and recurrent sarcoid-like granulomatous panniculitis caused by bovine collagen injection have also been described.29 Some authors differentiated a palisading granuloma (Fig 2), occurring mainly 2 or 3 months after injection and located in the mid to reticular dermis, from a diffusely organized granuloma, which was more frequent within the first 2 weeks and located in the reticular dermis and the subcutaneous tissue.30 Hypersensitivity reactions are associated with antiebovine collagen antibodies,12,31,32 which do not cross-react with human collagen.14,15,28 Allergic reactions to bovine collagen may be treated with topical, intralesional, or a brief course of systemic corticosteroids, and there are also reports of patients who have been successfully treated with oral cyclosporine33 or topical tacrolimus.34,35 Zyderm I is used for correction of superficial wrinkles, whereas Zyderm II is more effective in moderate to deep wrinkles, and both of them should be injected in the superficial dermis. In contrast, Zyplast works best when placed at the mid-dermis and is more valuable in treating deeper lines, such as nasolabial folds, deep acne scars, and lip augmentation through injection in the vermillion border. A slight degree of overcorrection (10%-20%) is sought when injecting bovine collagen, but

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persistent whiteness at the injection site and elevation can be observed with excessive overcorrection or when the injected material is placed too superficially.36-38 Other rare adverse localized effects at the site of the injection consist of ‘‘sterile’’ abscess formation39 (‘‘sterile’’ meaning negative culture), which is histopathologically characterized by numerous neutrophils, lymphocytes, plasma cells, and multinucleated giant cells surrounding particles of injected collagen, cellular debris, and hemorrhage. The inflammatory reaction is either confined to the implant or it can extend to the adjacent tissue, which appears richly vascularized. More uncommon side effects include bruising, the reactivation of herpetic infection, verified bacterial infection, and local necrosis. This is mostly seen with Zyplast injected at the glabellar area because of vascular interruption at the treatment site, and injections of Zyplast should therefore be avoided in this region.39 There have also been two reports of irreversible unilateral or bilateral vision loss after bovine collagen injection, probably resulting from an occlusive event involving the retinal artery.12,40 Rare systemic complications reported after injections of bovine collagen include flulike symptoms, paresthesias or difficulty breathing,41 and severe anaphylactic shock.42 Although some initial studies proposed that there may be a triggering effect of dermatomyositis in patients with injected bovine collagen,43 retrospective studies have found no evidence that bovine collagen induce connective tissue disease in human subjects.31,32,44-47

HUMAN-DERIVED BIOENGINEERED COLLAGEN IMPLANTS Key points d

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Human-based collagen implants have been investigated in recent years to avoid the hypersensitivity adverse reactions to bovine collagen No skin tests for hypersensitive reactions are required for any of these human-derived collagen products

To avoid hypersensitive adverse reactions to bovine collagen, human-based collagen implants have been produced in recent years. Autologen (Collagenesis, Beverly, MA) is an injectable autologous human tissue matrix primarily composed of intact collagen fibrils that are processed from the patient’s own skin and harvested during elective surgery.48,49 Human collagen implants are also obtained from human donor tissues that undergo extensive screening for infectious disease and the

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Fig 2. Histopathologic features of granulomatous reaction to bovine collagen. A, Scanning power showing palisading granulomas in the subcutaneous tissue. B, Higher magnification showing well circumscribed palisading granulomas. C, Bovine collagen at the center of the granulomas reveals a homogeneous eosinophilic appearance. D, Bovine collagen fibers are much thicker than those of human collagen and they have a homogeneous appearance nearly devoid of spaces between them and with fewer fibroblasts. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400. Photographs courtesy of Mark Jacobson, MD, New York, NY.)

material is irradiated before use. Dermal fibroblasts harvested from bioengineered human skin cells produce types I and III human collagen and extracellular matrix proteins. As the counterpart of the bovine collagen products, human-derived collagen implants have been named Cosmoderm I (Inamed), which contains 35 mg/cc human-based collagen dispersed in a phosphate-based saline solution and 0.3% lidocaine, Cosmoderm II (Inamed)—which contains about twice the collagen concentration of Cosmoderm I—and Cosmoplast (Inamed), which has the same ingredients as Cosmoderm I but is cross-linked by glutaraldehyde, making it more resistant to degradation and allowing for deeper placement of the injectable material.50,51 Cymetra (LifeCell, Branchburg, NJ) is another human-derived collagen containing micronized cadaveric-derived collagen.52 The cosmetic effect lasts about 4 to 7 months, depending on the area of treatment, injection technique, and amount of injected collagen.53 No skin test for hypersensitive reactions are required for any of these human-derived collagen products. Local adverse reactions include bruising,

erythema, and swelling at the site of injection. However, there also are few reported cases of granulomatous reaction at the site of the injection48 or at the skin test after injection of acellular human collagen.53

HYALURONIC ACID Key points d

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Hyaluronic acid gel is used as a resorbable filler; the longevity of the injected gel is about 6 months Hyaluronic acid has no organ or species specificity, and therefore in theory there is no risk of an allergic reaction Very few adverse hypersensitivity reactions secondary to injections of hyaluronic acid used as filler have been reported; histopathologically, they consisted of a granulomatous foreign body reaction, with abundant multinucleated giant cells surrounding an extracellular basophilic amorphous material, which was the injected hyaluronic acid gel

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Hyaluronic acid is one of the components of the normal skin forming part of the extracellular matrix of the dermis and providing support for other tissues. Chemically, hyaluronic acid is a glycosaminoglycan polysaccharide composed of alternating residues of the monosaccharide d-glucuronic acid and N-acetyl-d-glucosamine, both normally present in the human body.54 It is produced by dermal fibroblasts, synovial cells, endothelial cells, smooth muscle cells, adventitial cells, and oocytes, and is released into the surrounding extracellular space. Here, it functions as a hygroscopic material because it is capable of capturing large amounts of water, as seen in wound healing55,56 and in the lubrication of joints.57 Hyaluronic acid also acts as an important free radical scavenger,58 and it may indirectly stimulate some neocollagenogenesis after injection through mechanical stretching of the dermis and subsequent activation of dermal fibroblasts.59 Injections of hyaluronic acid gel are used for filling out wrinkles of the face, for soft tissue augmentation, and for the correction of all types of defects, such as scars and facial lipoatrophy. For the majority of patients, the longevity of the injected hyaluronic acid lasts for about 6 months, although slight variations occur depending on quantity, anatomy, and individual characteristics. There are two sources for industrial production of the hyaluronic acid used as a gel filler agent for soft tissue augmentation: an animal hyaluronic acid produced from rooster combs (Hylaform [Biomatrix, Ridgefield, NJ), and a nonanimal stabilized hyaluronic acid produced by bacterial fermentation from specific strains of streptococci (Restylane [Medicis Aesthetics, Scottsdale, AZ], Juv ederm [Allergan, Santa Barbara, CA], Perlane [Medicis Aesthetics], and Macrolane [QMed, Uppsala, Sweden]). Both types contain a small amount of protein, and a stabilization process modifies the hyaluronic acid molecule. Hyaluronic acid has no organ or species specificity, and therefore in theory there is no risk of an allergic reaction if exogenous hyaluronic acid is injected into the skin.60 Therefore, no skin testing is necessary before injecting hyaluronic acid because it is biodegradable. In fact, in spite of its frequent use for cosmetic reasons, there are very few descriptions of hypersensitivity reactions secondary to injections of hyaluronic acid used as a filler into the skin61-77 (Fig 3), and although Micheels78 described circulating antibodies against hyaluronic acid in patients after several injections, these findings could not be confirmed by other investigators.79 It may also be possible that the described hypersensitivity reactions are caused by

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Fig 3. Granulomatous reaction on the right side of the upper lip 2 months after the injection of hyaluronic acid (arrows indicate swollen areas of the upper lip).

impurities from the bacterial fermentation process, such as contaminating DNA, rather than to hyaluronic acid.71 Manna et al80 showed up to four times the quantity of protein in certain lots of Restylane as compared to the same volume of preparation of certain lots of Hylaform. Filion and Phillips81 further confirmed these findings when they studied low molecular weight fragments obtained from different preparations of hyaluronic acid. They revealed that some of these preparations stimulated the synthesis of interleukin-12 and tumor necrosis factorea in human monocytes, and that treatment of these preparations with deoxyribonuclease reduced the induction of proinflammatory cytokines by these cells. These findings might explain the rare reports of delayed hypersensitivity reactions in patients treated with hyaluronic acid gel injections.61-77 Histopathologically, a granulomatous foreign body reaction involves the dermis, with abundant multinucleated giant cells surrounding an extracellular basophilic amorphous material (Fig 4), the injected hyaluronic acid gel.82-85 Scant amounts of hyaluronic acid may be also seen within multinucleated giant cells. The hyaluronic acid stains positively for Alcian blue at a pH of 2.7 and is negative when examined under polarized light.85 A prominent eosinophilic granulomatous reaction has been described at the site of hyaluronic acid injections,77 and in another case,66 the adverse reaction to the injected hyaluronic acid for lip augmentation showed a granulomatous foreign body reaction surrounding a bluish amorphous material intermingled with numerous polymorphonuclear leukocytes. A suppurative granuloma developed, and bacterial infection could not be ruled out. Intralesional hyaluronidase injections are the treatment of choice when local hypersensitivity reactions are to be reversed.86-89 Severe systemic hypersensitivity reactions secondary to injections of hyaluronic acid fillers are even more

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Fig 4. Histopathologic features of a granulomatous reaction to hyaluronic acid. A, Low power view showing basophilic material at different levels of the dermis. B, Higher magnification showing basophilic deposits of variable size and shape that correspond to the injected hyaluronic acid. C, In some areas, the basophilic material is surrounded by histiocytes and multinucleated giant cells. D, Close view of the injected hyaluronic acid. (Hematoxylineeosin stain; original magnifications: A, 320; B, 340; C, 3200; D, 3400)

rare than local side effects.90,91 However, nonallergic local side effects at the sites of injections are frequent, including pain, bruising, and transient edema, but they disappear in a few days and usually do not need any treatment.92 It has been suggested that the reason hyaluronic acid fillers cause more swelling and bruising than collagen fillers is the anticoagulant effect of hyaluronic acid, which has a structural similarity to heparin.93,94 The too superficial placement of hyaluronic acid fillers or an uneven distribution of the injected product can lead to visible, pale nodules in the skin. Uncommon additional nonallergic reactions that have been described secondary to hyaluronic acid injections into the skin include herpes reactivation, bacterial infections, aseptic abscess,95 generalized scleromyxedema,96 scar sarcoidosis,97 interferon-induced systemic sarcoidosis in patients with chronic hepatitis C—who also developed sarcoidal granulomas around the injected hyaluronic acid filler98—and necrosis and livedoid pattern after accidental arterial embolization.99 There are reports describing an outbreak of Mycobacterium chelonae infection after soft tissue augmentation with hyaluronic acid derivate

fillers,100,101 but is not clear whether the injected material was contaminated with the mycobacteria during the manufacturing process or whether they were inoculated during the injection procedure, because the administration was performed in a nonmedical setting.

HYALURONIC ACID PLUS DEXTRANOMER MICROPARTICLES Key points d

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Resorbable filler composed of a mixture of nonanimal stabilized hyaluronic acid and dextranomer microspheres A single case report of foreign body granuloma caused by this filler has been described Histopathologic study showed a suppurative granuloma surrounding the hyaluronic acid and the spherical dark bluish particles that represented the dextranomer microparticles

This is a new resorbable gel suspension filler composed of a mixture of nonanimal stabilized hyaluronic acid, cross-linked hyaluronic acid, and dextranomer microspheres (Matridex [BioPolymer,

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Siershahn, Germany] and Reviderm intra [Rofil Medical International, Breda, Netherlands]). It has been used for the aesthetic treatment of facial lines, wrinkles, folds, and lip augmentation. The main component of Matridex is the dextranomer microspheres, which are composed of cross-linked dextran molecules (80-120 m in diameter) with a positive surface charge.102 A single case report of foreign body granuloma caused by Matridex has been described.103 The patient, a 43-year-old woman, developed erythematous nodules on both cheeks and the periorbital skin 4 weeks after the injection of Matridex (Fig 5). The histopathologic study revealed a suppurative granuloma surrounding exogenous material, composed of bluish-greyish filamentous material of hyaluronic acid particles with bizarre configuration and spherical dark bluish particles, representing the dextranomer microparticles (Fig 6). Surgical incision of the nodules and conservative treatment with systemic cephalexin and topical methylprednisone aceponate allowed complete resolution of the lesions in 6 months.

POLY-L-LACTIC ACID Key points d

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Poly-L-lactic acid is a resorbable filler that induces tissue augmentation that lasts up to at least 24 months The development of nodules at the site of injection is frequent; they are palpable but generally not visible Histopathologically, granulomatous adverse reactions at the sites of injection reveal a foreign body granuloma, with numerous multinucleated giant cells around translucent particles of different sizes, most of them showing a fusiform, oval, or spiky shape; these particles are birefringent in polarized light examination

Injectable poly-L-lactic acid (Sculptra [SanofiAventis, Bridgewater, NJ] and New-Fill [Dermik Laboratories, Berwyn, PA]) is a dermal filler that has been used to correct the signs of lipoatrophy in HIV patients receiving antiprotease treatment and for facial cosmetic augmentation.104-113 Injectable poly-L-lactic acid is a biocompatible, biodegradable, synthetic filler that must be injected into the reticular dermis or subcutaneous fat. In animal models, this synthetic polymer seems to be able to stimulate the activity and proliferation of dermal fibroblasts with subsequent endogenous production of collagen.108,114 Histologic studies in humans have shown gradual dissolution of the injected poly-L-lactic and

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Fig 5. Erythematous nodules on the cheek 4 weeks after the injection of Matridex (BioPolymer, Siershahn, Germany).

dermal ingrowth of type I collagen over 8 to 30 months after injection.115,116 An increase in volume is correspondingly gradual, starting 3 months after the injection and achieving a maximum at approximately 5 to 6 months postinjection. Even though poly-L-lactic is gradually degraded into water and carbon dioxide by nonenzymatic hydrolysis over approximately 9 to 24 months,117,118 neoformed collagen remains and the cosmetic augmentation has been noted to last up to at least 24 months.110,116-120 Nodules at the site of injection, which are palpable but generally nonvisible, are frequently described in about 30% to 40% of patients, and without treatment they tend to persist for months or years.113 Visible papules can also be seen, but they generally resolve spontaneously in a few weeks. A significant reduction of the frequency of the nonvisible but palpable nodules has been achieved with higher reconstitution volume of the injected filler (5 mL of sterile water for injection rather than 3 mL), a longer time between reconstitution and injection (36-48 hours rather than 2-12 hours), injections into the subcutaneous tissue rather into the reticular dermis, and postinjection massage.108,111 Like with other fillers, local shortterm, injection-related adverse events are frequent, including erythema, bruising, swelling, pain, inflammation, and pruritus, but they resolve spontaneously in a few days. Late-onset infections and histopathologically confirmed foreign body granulomas at the sites of injection have also been described121-127 (Fig 7). Severe systemic adverse effects secondary to poly-L-lactic injections are very rare, with only one case being described as

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Fig 6. Histopathologic features of granulomatous reaction to Matridex (BioPolymer, Siershahn, Germany). A, Scanning power showing a suppurative granuloma surrounding exogenous material. B, The exogenous material is composed of bluish-greyish filamentous material of hyaluronic acid and spherical dark bluish particles, which represent the dextranomer microparticles. C, Higher magnification of the filamentous hyaluronic acid. D, Higher magnification of a microsphere of dextranomer. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3400; D, 3400.)

an anaphylactic reaction necessitating treatment interruption.128 Histopathologic study of granulomatous adverse reactions at the sites of injection demonstrates a foreign body granuloma, with numerous multinucleated giant cells around translucent particles of different sizes, most of them showing a fusiform, oval, or spiky shape, similar to cholesterol clefts, but shorter and wider (Fig 8). Some of these particles may also be seen within the cytoplasm of the multinucleated giant cells.87 Poly-L-lactic acid particles are birefringent in polarized light examination (Fig 9). Some of the multinucleated giant cells may contain asteroid bodies within their cytoplasm and there is also a lymphocytic infiltrate intermingled with the foreign body granuloma. Histopathologically, the aspect of the particles of this filler is quite similar to that of suture remains frequently observed in routine skin biopsies, a useful histopathologic diagnostic clue. The granulomatous reaction to poly-L-lactic particles may persist at least 18 months after injection.82 Bacteria

Fig 7. Granulomatous reaction to injections of New-Fill (Dermik Laboratories, Berwyn, PA) for treatment of facial lipoatrophy in a HIV patient.

have been searched for to find etiology of this reaction, but no microorganisms were detected by polymerase chain reaction/DNA analysis in 6 cases of granulomatous reaction to poly-L-lactic particles.129

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Fig 8. Histopathologic features of granulomatous reaction to New-Fill (Dermik Laboratories, Berwyn, PA). A, Scanning power. B, Foreign body granuloma, with numerous multinucleated giant cells around translucent particles. C, Most of the particles show fusiform or oval shape. D, Higher magnification of the New-Fill particles surrounded by multinucleated giant cells. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

CALCIUM HYDROXYLAPATITE Key points d

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Resorbable filler composed of calcium hydroxylapatite microspheres that stimulate the endogenous production of collagen Histopathologically, microspheres of calcium hydroxylapatite stimulate almost no foreign body reaction and they appear bluish in color and round or oval in shape

Injectable calcium hydroxylapatite (Radiance FN and Radiesse [BioForm Medical, San Mateo, CA]) is, like poly-L-lactic acid, a resorbable filler containing microspheres that stimulate the endogenous production of collagen. The product has a texture resembling native soft tissue and migration is minimal.130 Initial augmentation is afforded by the implant itself, but in a few months the palpable implant diminishes further in size and has disappeared clinically at 9 to 12 months. When macrophages begin to degrade the implant, new collagen may form around the calcium hydroxylapatite microspheres.131 Injectable microspheres of calcium hydroxylapatite have been successfully used for correction of lipoatrophy of HIV patients receiving antiprotease

treatment and for smoothing moderate wrinkles.130-136 When this agent is injected in the lips, it tends to be associated with a high incidence of nodules137 (Fig 10). Migration to a distant location from the injection site has also been described.138 Histopathologically, microspheres of calcium hydroxylapatite stimulate almost no foreign body reaction, and because only few macrophages are seen around the particles,139,140 it is suggested that the microspheres of this implant are degraded by enzymatic breakdown rather than phagocytosis. The microspheres appear packed together, with bluish color, round or oval shape, 25 to 40 m in size, and surrounded by some fibrin fibers but little cellular infiltrate. In some patients, however, calcium hydroxylapatite microspheres may induce a foreign body granulomatous reaction (Fig 11), seen as blue-gray microspheres in the extracellular matrix or within multinucleated giant cells.1,85

PARAFFIN Key points d

Paraffin is no longer used as filler because of its frequent adverse reactions, but

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Fig 9. The same section of the previous figure seen under polarized light examination showing birefringent particles of New-Fill (Dermik Laboratories, Berwyn, PA). (Hematoxylineeosin stain and polarized light microscopy; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

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because it is a nonresorbable material, today it is still possible to see granulomatous reactions secondary to injections from many years ago Sclerosing lipogranuloma results from injection of paraffin in the penis causing fibrosis and deformity of the penis body Histopathologically, paraffinoma shows a mostly lobular panniculitis, in which the subcutaneous fat exhibits a Swiss cheese appearance, with cystic spaces of variable size and shape, surrounded by foamy histiocytes and multinucleated giant cells

Paraffin was used in the past as a filler for augmentation of tissues, mostly in the breasts, penis, buttocks, and calves, and it is included here only because of historical interest. Although no longer in use because of frequent adverse reactions and the advent of better fillers, this nonresorbable material may still today induce granulomatous reactions, which are known to appear many years after the injection. Moreover, accidental injections of paraffin and other mineral oils, such as sheep lanolin, petroleum jelly, and vitamin E, can still be seen today, and patients with psychiatric or personality disorders

Fig 10. Nodules in the lower lip after injections of calcium hydroxylapatite microspheres.

may be capable of injecting themselves with a wide variety of substances.141-163 A specific form of paraffinoma is the so-called sclerosing lipogranuloma, which results from injection of paraffin in the penis causing fibrosis and deformity of the penis body143,145,148,150,151,154,156,158,161,162 (Fig 12). The involved areas of paraffinoma appear as erythematous indurated plaques and in rare instances the lesion may ulcerate the overlying epidermis, mimicking a squamous cell carcinoma.145 Some of these patients suffer from psychiatric problems and have

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Fig 11. Histopathologic features of granuloma secondary to injections of calcium hydroxylapatite microspheres. A, Scanning power showing a diffuse involvement of the corium of the oral mucosa. B, The epithelium of the oral mucosa is not involved. C, Granulomas surrounding the calcium hydroxylapatite microspheres. D, Higher magnification showing that microspheres appear bluish in color, are round or oval in shape, and are surrounded by histiocytes and multinucleated giant cells. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400. Photographs courtesy of Mark Jacobson, MD, New York, NY.)

self-administered the injections with resulting factitial panniculitis—an often challenging diagnosis. Adverse effects are typically confined to the sites of injections and adjacent skin, but there are also reports of involvement of lymph nodes and lungs, presumably from lymphatic or hematogenous spread. A case of disseminated lipogranulomas and sudden death from self-administered mineral oil injections has been also reported.147 Histopathologically, lesions of paraffinoma involve the reticular dermis and subcutaneous tissue that shows a mostly lobular panniculitis, in which the subcutaneous fat exhibits a Swiss cheese appearance, with cystic spaces of variable size and shape, surrounded by foamy histiocytes and multinucleated giant cells149,162 (Fig 13). The stroma is composed of bundles of sclerotic collagen between the foamy histiocytes and the cystic spaces. The connective tissue septa show an inflammatory infiltrate of mostly lymphocytes and plasma cells. If frozen sections are available, the mineral oils stain with Oil-red-O, Sudan, Nile blue, and Osmic acid. Infrared absorption

Fig 12. Sclerosing lipogranuloma secondary to paraffin injections for augmentation of the penis.

spectrophotometry and thin layer chromatography can also be used to identify the presence of paraffin in tissue specimens.85

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Fig 13. Histopathologic features of paraffinoma. A, Scanning power showing a mostly lobular panniculitis. B, Subcutaneous fat exhibits a Swiss cheese appearance, with cystic spaces of variable size and shape. C, Cystic spaces are surrounded by foamy histiocytes and multinucleated giant cells. D, Higher magnification revealing foamy histiocytes around the cystic space. Note the sclerotic collagen bundles of the stroma. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

SILICONE Key points d

d

d

d

Silicone is the most widely studied filler material for soft tissue augmentation There are credible reports of silicone gel migrating to sites distant from the injection site There is no scientific basis for any association between silicone breast implants and any well-defined connective tissue disease Histopathologic findings in local reactions to implants of silicone are variable and depend largely on the form of the injected silicone; solid elastomer silicone induces an exuberant foreign body granulomatous reaction, whereas silicone oil and gel induce a sparser inflammatory response; silicone particles appear as groups of round empty vacuoles of different sizes between collagen bundles or within macrophages; silicone particles are not birefringent under polarized light

Silicone is a polymeric hydrophobic compound of dimethylsiloxanes that may be injected as oil (Silikon

1000 and Silskin [both from Richard-James, Peabody, MA]) or gel (MDX 4-4011 [Dow Corning, Midland, MI]), or implanted as solid silicone rubber implants (Silastic [Dow Corning]).164 Dimethylsiloxanes are compounds of methane, oxygen, and elemental silica. In its liquid and gel forms, injections of silicone have been used in more than 100,000 patients for cosmetic correction of small wrinkles or scars of the face (Fig 14) and volume augmentation of soft tissues. More recently, it has also been used as a filler to circumvent facial lipoatrophy in HIV patients receiving antiprotease treatment,165 making this gel the most widely studied of all filler materials for soft tissue augmentation.166,167 Medical-grade silicone refers to a pure and sterile preparation with consistent viscosity of 360 centistokes. Silicone gel is a hydrophobic oil-like compound that has a high affinity for cell membranes,168 entering into the cytoplasm of circulating inflammatory cells, mostly macrophages,169-173 and by this route migrating along the reticuloendothelial system to regional lymph nodes,174,175 the liver,176 and the spleen.177 To avoid the side effects that result from using large amounts of liquid silicone, ‘‘bag-gel’’ implants were introduced, mostly for augmentation of the

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Fig 14. Granulamatous reaction secondary to injections of silicone gel for the treatment of acne atrophic scars. A, Nodules on the chin. B, Lateral view of the nodules on the chin. C, One of the nodules is opened to the skin surface. D, Close-up view of the eroded skin surface.

breasts.178 However, leakage of silicone may also occur through these bags, either by diffusion or after trauma (Fig 15), and silicone gel is capable of migrating to distant sites, where it may give rise to an inflammatory reaction and hamper clinical diagnosis178-182 (Fig 16). It appears, however, as if most cases of migration is favored by gravity in patients with very lax skin and subcutaneous tissue, where the silicone implant has sagged downward distally from the injected site. Several disparate side effects secondary to silicone implants have been described in the literature, but none of them are clearly related to the silicone itself. Localized morphea has been described in the skin adjacent to the site of a leaking silicone gel breast implant,183 and in the past decade there has been considerable controversy in the literature about the relationship between systemic scleroderma and other connective tissue diseases and the use of breast implants containing silicone gel.174,175,184-187 There appears to be little scientific basis for any association between silicone breast implants and any welldefined connective tissue disease.188 A recent report raised the possibility of a relationship between silicone breast implants and mesenchymal tumors of the breast, describing six cases of fibromatoses and one case of pleomorphic

Fig 15. Inflammatory reaction secondary to rupture of a ‘‘bag-gel’’ implant of silicone for breast augmentation.

undifferentiated sarcoma. Nevertheless, the authors concluded that surgical trauma, perhaps occurring in patients with a predisposition to develop desmoid tumors, could account for fibromatosis in this setting and that the relationship between implants and the sarcoma was probably casual.189 The rare finding of an anaplastic large cell lymphoma of the breast and silicone breast implants is probably coincidental.190 Local reactions at the sites of injections include pain, erythema, ecchymosis, hyperpigmentation and hypopigmentation of the overlying skin, induration and inflammatory nodules, also named

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Fig 16. A, Transsexual patient who received injections of liquid silicone for buttock augmentation. B, Five years later, silicone migrated to distant sites of the lower leg, where it produced an inflammatory reaction. C, Nodules and inflammatory reaction to silicone in the lower leg.

‘‘siliconomas,’’ which are sometimes resolved with dystrophic scars.121,178,191-198 The diagnosis is not always clinically suspected, because these reactions may develop many years after the tissue augmentation. Granulomas have also been described in the skin at the point of entry of acupuncture and venepuncture needles coated with silicone and particles of silicone have been detected in macrophages with radiographic microanalysis.199 Although rare, severe local reactions with ulceration of the skin overlying areas of subcutaneous injections of liquid silicone have also been reported.191,200-202 Other complications of solid silicone implants in deeper tissues are rare, but the literature shows descriptions of bone erosion, infection, seroma, and implant extrusion.203 Pulmonary embolism, acute pneumonitis, and granulomatous hepatitis are very rare systemic complications after the fraudulent use of large amounts of liquid silicone in transsexual patients.204,205 Histopathologic findings in local reactions to implants of silicone are variable depending mainly on the form of the injected silicone (liquid, gel, or solid elastomer type) and the amount of product implanted in the tissues.30,178,206 Solid elastomer silicone, both as the outer shell of a breast implant

and as fragments in a gel (see next paragraph), induces an exuberant foreign body granulomatous reaction in the dermis and subcutaneous tissue, with abundant numbers of macrophages and multinucleated giant cells (Fig 17). Often, some of the multinucleated giant cells contain asteroid bodies in their cytoplasm (Fig 18), and the adjacent dermis shows perilesional fibrosis. Silicone oil induces a sparser inflammatory response in the tissues than does solid silicone (Figs 19 and 20), and the implant appears in the form of interstitial vacuoles and cystic spaces of different sizes between collagen bundles, surrounded by a few macrophages, some of them with a foamy cytoplasm as a consequence of engulfed silicone.207 This histopathologic pattern has been named ‘‘Swiss cheese’’elike, and sometimes residual glassy-appearing material is found inside the vacuoles and cystic spaces. Although most of the silicone liquid is removed during paraffin embedding process, small amounts may persist, both inside the cytoplasm of macrophages and interstitially as groups of empty vacuoles of different sizes between collagen bundles. The vacuoles may simulate adipocytes, but they are smaller.178 Also, the histopathologic pattern should be not mistaken for a well-differentiated liposarcoma.208,209 In rare

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Fig 17. Histopathologic findings in a local reaction to a silicone breast implant. A, Diffuse inflammatory infiltrates involving the reticular dermis and subcutaneous tissue. B, Cystic spaces and vacuoles of different sizes in the reticular dermis. C, Cystic spaces and the smaller vacuoles are surrounded by multinucleated giant cells. D, Higher magnification of the vacuoles of different sizes that correspond to the implanted silicone. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

instances, eosinophils may be abundant in the infiltrate. Silicone particles are not birefringent under polarized light and the angulated translucent birefringent particles that occasionally are seen in silicone granulomas probably result from impurities by adulteration of the nonemedical-grade silicone compounds injected by nonprofessionals178 or from deposition of talc introduced at the time of the implant surgery.210 Sometimes, these impurities are nonbirefringent206,211 (Fig 21). Silicone can be detected by spectroscopy, by scanning electron microscopy, and by energy dispersive radiographic analysis.176,212-214 Silicone granulomas have been successfully treated with topical applications of imiquimod,215 intralesional injections of corticosteroids,216 and oral minocycline.217

POLYVINYLPYRROLIDONE-SILICONE SUSPENSION Key points d

This is a permanent filler comprised of particles of polymerized silicone elastomer dispersed in a carrier of polyvinylpyrrolidone

d

Histopathologically, granulomas secondary to this filler consist of irregularly shaped cystic spaces containing translucent, jagged ‘‘popcorn,’’ nonbirefringent particles of varying size dispersed in a sclerotic stroma surrounded by abundant multinucleated foreign body giant cells

This filler is comprised of particles of polymerized silicone elastomer, 100 to 600 m in size, dispersed in a carrier vehicle, polyvinylpyrrolidone (Bioplastique; Uroplasty BV, Geleen, The Netherlands). The suspension should be injected in the subcutaneous tissue and has been mostly used for the correction of facial rhytids and lip augmentation. The large size of the silicone particles prevent them from being phagocytosed by macrophages, and therefore they remain at the injected site, where they produce a local foreign body reaction and fibrosis, which contributes to the filling effect.218 Local side effects that have been described secondary to injections of Bioplastique include induration, swelling (Fig 22), and granuloma formation.219-221 Most investigators1,222,223 believe that granulomas occur more frequently after injection of

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Fig 18. Granulomatous reaction to a silicone breast implant. A, Exuberant foreign body granulomatous reaction. B, The granulomatous reaction is surrounding cystic spaces of variable size. C, This granulomatous reaction shows an abundant number of multinucleated giant cells. D, Some of the multinucleated giant cells contain asteroid bodies in their cytoplasm. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

particles with an irregular surface, such as Bioplastique or Dermalive (Dermatech, Paris, France), than after implantation of microspheres with a smooth surface, such as Artecoll (Artes Medical, San Diego, CA), NewFill, or Radiesse. The histopathologic study of granulomas secondary to Bioplastique injections reveals82,221 irregularly shaped cystic spaces containing translucent, jagged ‘‘popcorn,’’ nonbirefringent particles of varying size dispersed in a sclerotic stroma (Fig 23). The cystic spaces are surrounded by multinucleated foreign body giant cells, some of them containing asteroid bodies within their cytoplasm and many showing cytoplasmic ‘‘arabesque’’ projections into the lumina of the cystic cavities. Usually, some small lymphocytes and eosinophils are also present in the surrounding infiltrate.218,221

POLYMETHYL-METHACRYLATE MICROSPHERES AND BOVINE COLLAGEN Key points d

Biphasic filler composed of permanent implant of polymethylmethacrylate microspheres suspended in a degradable bovine collagen solution as a carrier

d

d

Intradermal tests are mandatory before the first use of this filler Histopathologically, adverse reactions to this filler show a nodular or diffuse granulomatous infiltrate surrounding rounded vacuoles of similar shape and size that mimic normal adipocytes and that correspond to the implanted polymethylmethacrylate microspheres

This is a biphasic filler composed of 30- to 42-m polymethylmethacrylate (PMMA) microspheres suspended at a 3.5% bovine collagen solution in a proportion of 4:1 (Artecoll, Arteplast, and Artefill [all from Artes Medial]).224,225 It also contains 0.3% lidocaine hydrochlorate for pain reduction at injection. This filler has been used in Europe since 1994 as a cosmetic microimplant for the correction of facial wrinkles and furrows, perioral lines, lip and philtrum augmentation, scar revision, and other subdermal defects. It was introduced in 1991 by Lemperle in Germany.226 The solid phase (permanent implant) is represented by PMMA microspheres, whereas the liquid phase is represented by degradable bovine collagen solution.225 The biocompatibility of PMMA has been shown

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Fig 19. Granulomatous reaction to silicone liquid. A, Silicone liquid induces sparser inflammatory response. B, The injected silicone appears in the form of interstitial vacuoles of different sizes between collagen bundles surrounded by a few macrophages. C, Some of the histiocytes show a foamy appearance of their cytoplasm as a consequence of the engulfed silicone. D, Higher magnification of the vacuoles of silicone, both within the cytoplasm of the macrophages and extracellularly. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

previously by its use in bone cement and dental prosthesis.226 Collagen of bovine origin induces allergy reactions in approximately 3% to 4% of the patients,15,227 and it is therefore mandatory to perform an intradermal test before the first use of this filler.228 One case of anaphylactic shock has been observed after the eighth treatment.224 Collagen, however, is merely a carrier substance that eases the injection of the microspheres and prevents them from agglomerating during tissue ingrowth, and 80% of it is gone after 1 to 3 months. The PMMA microspheres, on the other hand, persist for years and induce a granulomatous foreign body reaction, with a deposition of fibrous tissue, which is part of the wanted effect of the filler. A uniform size and shape and smooth surface of the PMMA microspheres—combined with the correct injection technique—seem to be important for obtaining a controlled granulomatous reaction with adequate volume for cosmetic purposes.224,225 The filler must be implanted into the reticular dermis. If the injection is too deep into the subcutaneous fat, the filler will have no effect, and if it is injected too

superficially into the superficial dermis, the filler will result in a whitish nodule and is likely to produce a more evident granulomatous reaction, with undesirable cosmetic effects.90,223,229 It has been claimed that size and the smooth surface of the particles hinder their phagocytosis by macrophages, but some authors disagree.228 Although not very common, this filler may cause some undesirable side effects, with a total rate estimated at 3%, including telangiectasias, hypertrophic scarring, allergic reactions, and granuloma formation.225,230 Granulomas generally appear from 6 to 24 months after the treatment,231 with a 0.6% occurrence rate232,233 (Fig 24), but they may also emerge several years after the injection.129 One patient with chronic hepatitis C infection receiving treatment with peginterferon alfa-2a and ribavirin developed disfiguring facial swelling, requiring plastic surgery in foci where Artecoll had been injected 10 years earlier.234 The histopathologic findings of granulomas related to this filler were first described by Rudolph et al,221 and other cases have since

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Fig 20. Histopathologic features of panniculitis secondary to migration of the liquid silicone in the patient seen in Figure 13. The patient had a history of injections of liquid silicone on the buttocks and 5 years later developed nodular lesions on the lower legs. This biopsy specimen came from the nodule seen in Figure 13, C. A, Scanning power showing a mostly septal panniculitis. B, Higher magnification reveals a thickening of the connective tissue septa with sparse inflammatory infiltrate. C, The septa showed a multivacuolated appearance because of the deposits of liquid silicone. D, Higher magnification showed the multivacuolated appearance of the liquid silicone. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

been added.84,121,220,228,235-238 Some of the cases that were reported as Artecoll granulomas should correctly have been classified as silicone granulomas235,239 or Dermalive granulomas240 (see below). Artecoll-related granulomas may involve the dermis, subcutaneous fat, and, occasionally, adjacent sweat glands241 and the skeletal muscle.221 They are characterized by a nodular or diffuse granulomatous infiltrate, and at higher magnification, rounded vacuoles of similar shape and size mimicking normal adipocytes are easily identified.242 These round bodies correspond to the implanted PMMA microspheres, which are markedly homogeneous in size and shape (Fig 25). They are round, sharply circumscribed, translucent, nonbirefringent, and characteristically extracellular. Epithelioid histiocytes, multinucleated giant cells, lymphocytes, and occasional eosinophils often surround the microspheres, which are individually disposed or arranged in clusters surrounded by sclerotic stroma. In our experience, asteroid bodies are not present in Artecoll

granulomas. This is in consonance with the complex washing procedure and ultrasound technology224 that has been described as part of the purification process. Other authors, however, have described asteroid bodies in their granuloma cases.121,238 Management of this exaggerated granulomatous reactions to Artecoll can be achieved with diluted triamcinolone (1:3 in anesthetic solution) injected inside the nodules. One case report described a positive response of Artecoll-induced granuloma to allopurinol236 and another to intralesional injections of 5-fluorouracil.237

HYDROXYETHYLMETHACRYLATE/ ETHYLMETHACRYLATE FRAGMENTS AND HYALURONIC ACID Key points d

Permanent biphasic filler composed ethylmethacrylate and hydroxyethylmethacrylate particles suspended in a hyaluronic acid gel

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Fig 21. Granulomatous reaction secondary to impurities of silicone. A, Scanning power. B, Numerous angulated translucent particles are present in the dermis. C, Most of the granulomatous reaction and multinucleated giant cells are around the angulated translucent particles. Note that the vacuoles of silicone originated little inflammatory response. D, In this case, the angulated translucent particles of the impurities were not birefringent under polarized light. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3200. Polarized light.)

d

Histopathologically, granulomatous reactions to this filler consist of nodular infiltrates of macrophages and multinucleated giant cells with numerous pseudocystic structures of different sizes and shapes containing polygonal, pink, translucent, nonbirefringent foreign bodies

This is another biphasic cosmetic filler made of 40% acrylic hydrogel composed of ethylmethacrylate (EMA) and hydroxyethylmethacrylate (HEMA) particles with a variable diameter, and 60% hyaluronic acid produced by microbiologic engineering techniques (Dermalive and Dermadeep [Dermatech]). Both components are of nonanimal origin, so allergy reactions are less probable than with Artecoll. The acrylic hydrogel contained in Dermalive is the same as the one used for intraocular lens implants in cataract surgery.243 Hyaluronic acid is used as a carrier; it is broken down by hyaluronidase and disappears in 3 months, whereas fragments of EMA and HEMA persist for years. Acrylic hydrogel particles in Dermalive are

Fig 22. Asymmetric swelling of the upper lip caused by a granulomatous reaction to Bioplastique (Uroplasty BV, Geleen, The Netherlands).

solid, polygonal, translucent, intentionally irregular in shape, but of smooth surface, and sized between 45 and 65 m. Dermadeep is very similar to Dermalive, but with larger particles of EMA and HEMA (80-110 m), and it is used for the correction of larger defects than Dermalive. Indications for the use of Dermalive are similar to those for Artecoll. It must be implanted in the same place: the reticular dermis or at the dermosubcutaneous junction. In a similar way, superficial deposition of

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Fig 23. Histopathologic features of a granulomatous reaction to Bioplastique (Uroplasty BV, Geleen, The Netherlands). A, Scanning power. B, Irregularly shaped cystic spaces containing translucent, jagged ‘‘popcorn,’’ nonbirefringent particles of varying size dispersed in a sclerotic stroma. C, Cystic spaces are surrounded by multinucleated foreign body giant cells. D, Higher magnification of the translucent particles of Bioplastique surrounded by multinucleated giant cells. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

Dermalive can induce overcorrection and granulomatous evident reactions. Like Artecoll, the prolonged cosmetic effect of Dermalive is related to the acrylic hydrogel added to the limited granulomatous reaction, with a deposition of fibrous tissue. The immediate side effects of Dermalive injections are similar to those after other cosmetic fillers and include redness, pain, edema, or hematoma, all disappearing spontaneously within a few days. Long-term side effects have been estimated in 1.2 per 1000 by one publication222 and in 28% by another.244 They appear months after injection and present as indurations (Fig 26), edema, and nodules. A case of keratoacanthoma-like reaction has been recently described at the site of injection of this filler.245 Granulomatous reactions to Dermalive and their histopathologic features have been well described.1,82,121,129,222,223,246-250 They consist of nodular granulomatous infiltrates involving the reticular dermis and superficial hypodermis. The epidermis and superficial dermis are usually spared. At higher magnification, numerous pseudocystic

Fig 24. Granulomatous reaction to Artecoll (Artes Medical, San Diego, CA) involving the lower eyelids and the cheeks.

structures of different sizes and shapes containing polygonal, pink, translucent foreign bodies are easily seen (Fig 27). These extracellular particles look like clear broken glass gravel and they are not birefringent under polarized light microscopy. The granulomatous infiltrate consists of numerous epithelioid histiocytes, many multinucleate giant cells, and some lymphocytes. Abundant asteroid bodies

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Fig 25. Histopathologic features of Artecoll-related granuloma (Artes Medical, San Diego, CA). A, Scanning power showing a nodular or diffuse granulomatous infiltrate. B, With higher magnification, rounded vacuoles of similar shape and size mimicking normal adipocytes are easily identified. C, These round bodies correspond to the implanted polymethylmethacrylate microspheres, which are markedly homogeneous in size and shape. D, Higher magnification of the round, sharply circumscribed, translucent, nonbirefringent, extracellular microspheres of Artecoll surrounded by a sclerotic stroma. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

may be present in the cytoplasm of giant cells. Transepidermal elimination of the product may occur.82 Intralesional injections of corticosteroids or 5-fluorouracil221 have been described to be effective in treating granulomas secondary to Dermalive.

POLYACRYLAMIDE HYDROGEL Key points d

d

d

Permanent filler composed of a hydrophilic gel of polyacrylamide Nodules may develop after the injections that have been found to be localized bacterial infection Granulomas secondary to this filler are composed of macrophages, foreign body giant cells, lymphocytes, and red cells surrounding a basophilic multivacuolated nonbirefringent material, which corresponds to the polyacryalamide hydrogel

Injected hydrophilic gel of polyacrylamide (Aquamid [Contura International, Copenhagen,

Denmark], Interfall [FuHua Aesthetics, Shenzen, China], OutLine [ProCytech SA, Bordeaux, Fance], Royamid [Fluka Chemie AG, Buchs, Switzerland], Formacryl [Bioform, Moscow, Russia], Argiform [Bioform], Amazingel [NanFeng Medical, Shijiazhuang, People’s Republic of China], Bio-Formacryl [Progen, Ancona, Italy], and Kosmogel [Styling Medical Devices, Engelberg, Switzerland]) has been used in large quantities mostly in China, Ukraine, and the former Soviet Union for breast, buttock, and calf augmentation. More recently, it has been used in European countries for the treatment of antiretroviral-related facial lipoatrophy in HIV patients and for the correction of acquired or congenital malformations with depressed skin.251-255 Polyacrylamide hydrogel is a polymer hydrogel consisting of 2.5% polyacrylamide polymer backbone and 97.5% water and should be injected deeply into the subcutaneous fat, the muscle or into the supraperiosteal plane.256 When medium to large quantities of this hydrogel are injected under pressure, a cellular foreign body reaction can be observed histologically, but clinically visible nodules are rarely seen in connection with these large

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Fig 26. Granulomatous reaction in the lips after injections of Dermalive (Dermatech, Paris, France). A, Erythema and diffuse swelling of the upper and lower lips. B, Close view of the erythematous lips. C, Lateral view showing that the induration extended beyond the limit of the upper lip to adjacent skin. D, The lesions eroded the mucous surface of the upper lip.

deposits.257,258 Nodules may develop after injection of small amounts in the face, and these have been found to be related to localized bacterial infection.259 Other side effects of polyacrylamide hydrogel, described mostly in breast augmentation, include pigmentation of the skin surface caused by the periodic exacerbation of the protracted inflammatory process, hematoma, infections (Fig 28), indurations, lumps, mastodynia, unsatisfactory contour results, abnormal skin sensations, gel migration, and axillary lymphadenitis.251-265 More severe, although rare, complications include bone erosion and facial ulceration.266 Two cases of breast cancer occurring after injection of polyacrylamide hydrogel injections in augmented breasts have been also described, and although they did not appear to be etiologically related to the implant, a delayed detection and diagnosis because of its presence were recorded.267 Contraindications to polyacrylamide hydrogel injections include previous injection of any filler at the same site, dental work, face lift or peeling at the same site in the days before the injection, Crohn disease, ulcerative colitis, pemphigus vulgaris, and insulin-dependent diabetes mellitus.259 The histopathologic study of breast tissue bordering the gel has revealed three different patterns: large

collections of gel are surrounded by a thick, softlooking cellular membrane of macrophages and foreign body giant cells; medium-size deposits were surrounded by just a thin layer of macrophages; and small deposits were not associated with any reaction in the surrounding tissue. Granulomas have been seen in some patients and they are composed of macrophages, foreign body giant cells, lymphocytes, and red cells surrounding the polyacryalamide hydrogel (Fig 29). This material shows some histopathologic similarity to hyaluronic acid, although granulomas secondary to hyaluronic acid usually consist of a less dense inflammatory infiltrate than those secondary to polyacrylamide hydrogel. Polyacrylamide hydrogel is positive with Alcian blue stain and it is not birefringent under polarizing microscopy. A thin layer of fibrous connective tissue is occasionally present around the foreign body membrane, but the thick fibrous capsule, as seen with silicone implants, is usually completely absent.82,257,259 Instead, it has been shown in an experimental study in the pig, that vessel in-growth takes place anchoring the gel to its surroundings, and that a 0.2-mL deposit will be completely traversed within 14 months.268 The histopathologic findings of the local reaction at the cheek mucosa after injection

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Fig 27. Histopathologic features of Dermalive-related granuloma (Dermatech, Paris, France). A, Nodular granulomatous infiltrates involving the reticular dermis and superficial hypodermis. B, At higher magnification, numerous pseudocystic spaces are seen. C, These spaces contain polygonal, pink, translucent foreign bodies with different sizes and shapes. D, The extracellular particles of Dermalive are pink in color and they are not birefringent under polarized light microscopy. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

of polyacrylamide hydrogel has in one case been reported to mimic a mucoepidermoid carcinoma.269

POLYALKYLIMIDE GEL Key points d

d

d

Permanent hydrophilic filler composed a polyalkylimide polymer Complications secondary to this filler include edema, bruising, nodules, and infections, but no granulomas have been described Histopathologically, this filler appears as basophilic amorphous material with granular appearance surrounded by sparse numbers of epithelioid histiocytes, foreign body multinucleated giant cells, neutrophils, and red cells

This is a permanent translucent gel made of a hydrophilic biopolymer with 96% sterile water and 45% polyalkylimide polymer (Bio-Alcamid; Polymekon, Brindisi, Italy), and different from polyacrylamide. It has been used to increase volume in the

Fig 28. A pustular reaction secondary to Aquamid (Contura International, Copenhagen, Denmark) injections for treatment of facial lipoatrophy in a patient with HIV. Cultures of the lesions isolated Staphylococcus aureus.

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Fig 29. Histopathologic features of granulomatous reaction to Aquamid (Contura International, Copenhagen, Denmark). A, Scanning power showing granulomas at different levels of the dermis. B, Higher magnification showing macrophages and foreign body giant cells surrounding basophilic multivacuolated material. C, The basophilic material at the center of the foreign body granulomas is the polyacryalamide hydrogel. D, Higher magnification showing the bluish and multivacuolated appearance of the polyacrylamide hydrogel. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

cheeks in HIV patients with facial lipoatrophy related to antiretroviral therapy and for gluteal augmentation, correction of irregularities after liposculpture, scar depressions, and posttraumatic subcutaneous atrophy and filling of pectus excavatum or other malformations of the skeleton.270-278 Complications secondary to the injections of Bio-Alcamid include edema (Fig 30), bruising, and nodules and, in particular, infections.279-286 To our knowledge, no granulomas secondary to Bio-Alcamid have been described. There are few histopathologic studies describing the findings in the local reactions to Bio-Alcamid, and the microscopic study of the material obtained from an indurated nodule has shown basophilic amorphous material corresponding to the implanted material, surrounded by epithelioid histiocytes, foreign body multinucleated giant cells, neutrophils and red cells281 (Fig 31). In accordance with this histology, late-appearing abscesses have been seen in HIV patients treated with this filler for lipoatrophy following antiretroviral therapy.279-286

Fig 30. Edema of the upper lip after injection of BioAlcamid (Polymekon, Brindisi, Italy).

POLYVINYLHYDROXIDE MICROSPHERES SUSPENDED IN POLYACRYLAMIDE GEL Key points d

d

Permanent filler composed of polyvinylhydroxide microspheres suspended in polyacrylamide gel There are not descriptions of adverse reactions to this filler

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Fig 31. Histopathologic features of a late-appearing abscess after injections of Bio-Alcamid (Polymekon, Brindisi, Italy). A, Scanning power. B, Several areas of basophilic amorphous material corresponding to the implanted material, surrounded by neutrophils and red cells. C, The implanted material has a basophilic granular appearance. D, Higher magnification of the polyalkylimide gel. Gram stain revealed the presence of abundant Gram-positive bacteria intermingled with these basophilic granular material. (Hematoxylineeosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

This filler is composed of a suspension of 6% polyvinylhydroxide microspheres suspended in 2.5% polyacrylamide gel (Evolution; ProCytech SA) and has been used mostly for lip augmentation. To our knowledge, there are not reports on this rarely used filler other that the observation made by Lemperle et al1 who, in their comparative paper on fillers, injected Evolution (and later excised it from the first author’s forearm) and found the filler to give little local reaction and diminish slowly over 9 months.

CONCLUSION A wide variety of cosmetic fillers are now available worldwide, and new ones will likely appear in the immediate future. The ideal filler is still missing, because all of them known today may cause adverse reactions. These side effects are less severe after injection with quickly biodegradable cosmetic fillers, where most will disappear spontaneously within a few months. Unfortunately, however, after injection with slowly or nonbiodegradable fillers, adverse reactions may appear that need active treatment. If these are related to bacterial infection as seen with

the polyacrylamide gel and if bacterial resistance (biofilm) has developed,287 or if they present as foreign body granulomas, as seen after the other fillers of this category, surgical removal of the implanted material often remains the only effective therapeutic possibility. Because medicolegal problems may arise with the use of these fillers and because they may be implanted in nonmedical settings—not infrequently with incomplete or even fraudulent information about the nature of the implanted filler given to the patients—histopathology remains the criterion standard for identification of the responsible filler. The variation in microscopic morphology of the implanted particles and hydrogels allows dermatologists and dermatopathologists to precisely classify most cases, and this appears to be particularly important in cases where different fillers have been applied over time, so that the filler responsible for the adverse reaction can be identified and treated accordingly.

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