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and rheumatoid arthritis have been attributed to lip, and the nose. A thorough examination of thesilicone.4 However, a definite association could notbe established.5 Systemic distribution of silicone cancause granulomatous hepatitis, pneumonitis, anddeath.6 Clinically, silicone granuloma may presentas diffuse swelling and redness, subcutaneous

patients history revealed injections of silicone forcosmetic nasal augmentation 18 months earlier. Theexact composition of the injection solution was notavailable, but was thought to contain collagen andsilicone. The severe disfigurement had caused de-pressive episodes, and the patient had been off paidwork as a nurse in elder care for several months.

On physical examination, several firm, well de-marcated subcutaneous nodules with overlying ery-thema were palpated on the upper part of the nose,the upper lip, and at the upper aspects of botheyelids. The biggest nodule, located at the left uppereyelid, was several centimeters in size. A diffuseswelling was noted that was most pronouncedaround both eyes (Fig 1, A). There was no palpablelymphadenopathy and the rest of the clinical exam-

This supplement is made possible through the

generous support of Stiefel Laboratories for the

American Academy of Dermatology.

From the Department of Dermatology, University of Cologne.

Funding sources: None.

Conflicts of interest: None identified.

Reprint requests: Meral J. Arin, MD, Department of Dermatology,

University of Cologne, 50924 Cologne, Germany. E-mail:

meral.arin@medizin.uni-koeln.de.

0190-9622/$30.00

2005 by the American Academy of Dermatology, Inc.Silicone granuloma ominoc

Meral J. Arin, MD, Jens Bate, MD, Thoma

Cologne,

Siliconoma represents a granulomatous foreign bodyaugmentation. Although considered as biologicallyvarious undesirable local and systemic reactions, somTreatment of siliconomas is difficult and granulomapresent a 43-year-old woman with a severely disfigtreated with minocycline. ( J Am Acad Dermatol 200

Various injectable materials have been used forcosmetic soft tissue augmentation includingsilicone, collagen, hyaluronic acid, and min-

eral oil.1 Silicone is a polymer of chemically relatedorganosilicon compounds of which polydimeth-ylsiloxane (silicone oil) is the most widely used.It has been shown that silicone polymers con-tain multiple contaminants including fumed silica,platinum, and low molecular weight polymers.2 Theadvantage of silicone is the biologic stability overlong periods of time compared to collagen andhyaluronic acid, which are eventually resolved.

Following intradermal or subcutaneous injection,silicon is deposited as droplets in the extracellularmatrix. A transient acute inflammatory reaction mayfollow, and at a later stage, the silicon droplets arefixed in the tissue upon development of surroundingfibrous capsules. Silicone granulomas may developwith a latency period of up to several decades3 anda variety of connective tissue disorders includingprogressive systemic sclerosis, lupus erythematosus,doi:10.1016/j.jaad.2004.07.014the face treated withcline

rieg, MD, and Nicolas Hunzelmann, MD

ermany

action to silicone, which is often used for soft tissuert for a long time, silicone has been implicated inimes with a latency period of up to several decades.involving the face are a therapeutic challenge. Weng facial silicone granuloma who was successfully52:S53-6.)

nodules, and in some cases, palpable adenopathy.The differential diagnosis includes granulomas insarcoidosis, tuberculosis and rheumatoid arthritis,lupus profundus, pseudolymphoma, and foreignbody granuloma of various origin. Treatment optionsare limited and include surgical excision, cortico-steroids, retinoids, and antibiotics.

We describe a case of a seriously disfiguringsilicone granuloma of the face following siliconeinjection for facial soft tissue augmentation that wassuccessfully treated with minocycline.

CASE REPORTA 43-year-old woman presented to our depart-

ment with facial swelling which was most pro-nounced around the left eye and the upper lip.Small erythematous nodules were noted at the upperaspect of the left eye and at the root of the nose. Theswelling and the nodules progressed and becamemost pronounced at the left upper eye lid, the upperination was normal. Complete blood cell count as

S53

J AM ACAD DERMATOLS54 Arin et alwell as blood chemistry were within normal limits.Measurement of angiotensin-converting enzyme andsoluble interleukin-2 receptor in the serum wasperformed without any abnormal finding. A chestradiograph revealed an induration at both recessuscostodiaphragmalis. No granulomas or bihilarlymphadenopathy was noted.

An excisional skin biopsy was taken from the leftupper eye lid and revealed numerous swiss cheese-like cystic spaces of varying sizes throughout alllevels of the dermis compatible with siliconevacuoles (Fig 1, C ). They were surrounded bygranulomas composed of multinucleated giant cellsand Langerhans cells that infiltrated into the musclelayer. A diagnosis of silicone granuloma wasestablished and a treatment with minocycline (100

Fig 1. a, Firm erythematous nodules and facial swelling18 months after silicone injection for soft tissue augmen-tation, and (b) 4 months after treatment with minocycline.Note resolution of the biggest nodule at the left uppereyelid and regression of the erythematous induratededema of the face. c, Clear vacuoles of varying sizescompatible with former deposits of silicone. Arrow:multinucleated giant cell. (c, Hematoxylin-eosin stain;original magnification: c, 3 40).mg per day) was initiated since the patient hadpreviously developed glucose intolerance uponshort-term low dose (5-20 mg per day) oral prednis-olone. Since the lesions were distributed extensivelyover her face, surgical excision was not a goodoption. Within 4 weeks of treatment, the swellingand erythema improved substantially. During thefollowing weeks, the nodules became softer andsmaller; however, small nodules around the left eye-lid were still visible. Minocycline was continued anda follow-up visit 4 months after initiation of therapyshowed a significant clinical improvement (Fig 1, B).Minocycline was continued for 6 months, and 1 yearafter initiation ofminocycline, the patient s conditionwas still improving, showing an excellent regressionof induration and erythema. With improvement ofthe cosmetic appearance, the patient was able towork again and she re-engaged in social activity.

After initiation of treatment, the patient com-plained of nausea. Since food has not been re-ported to alter the absorption of minocycline, thedrug was administered after a meal, which ledto improvement of the gastrointestinal symptoms.Progression of roughly symmetric brown macules(melasma) on the malar aspects of the face wasnoted during therapy. The extent of the contributionof the patients co-medication (estradiol and le-vonorgestrel) remains unclear. Rigorous photopro-tection including sunscreen with an SPF of 60 andavoidance of excessive sun exposure preventedfurther accentuation of the hyperpigmentation.

DISCUSSIONSilicone granuloma is a severe granulomatous

tissue reaction following injection or implantationof silicone. Clinically, it can present as cellulitis withnodule formation, ulceration, skin induration, andlocal lymph duct and lymph node enlargement.Silicone can be identified and quantitated in the skinby electron spectroscopy for chemical analysis,which allows detection of even small amounts intissues.7 Migration of the injected material to distantlocations, so-called metastasis, has been reportedand was also noted in our patient. We think that thenodules around the eyes and the upper lip are theresult of migrated particles from the injection site atthe root of the nose. The time between injection andonset of cutaneous symptoms can vary from a fewmonths to several years.3,8 In our patient, thesymptoms started 7 months after silicone injection.

The pathogenesis of granuloma formation is stillunknown. Biologic substances such as collagen arephagocytized by macrophages within 1 to 3 monthsafter implantation and will be replaced by fibroblastsand collagen fibers.9 Phagocytosis has so far been

10

FEBRUARY 2005described for particles with a size of up to 15 m,but can also occur in the case of silicone that has

J AM ACAD DERMATOL Arin et al S55a mean diameter of 170 m.11 In vitro, siliconepolymers have been shown to elicit a significantchange in the cellular configuration and a progres-sive reduction in proliferation of dermal fibro-blasts.12 In a rat model, injection of silicone causedan inflammatory response with fibroblasts, macro-phages, and lymphocytes around the sites of im-plantation. The intensity of the cellular and capsularresponse was lowest for silicone oil; fumed silicaelicited the most highly reactive response.13

Interestingly, secreted protein, acidic and rich incysteine (SPARC), a matricellular glycoprotein thatmodulates the interaction of cells with the extracel-lular matrix, has been implicated as an importantmodulator of encapsulation of implanted biomate-rial.14 In mice lacking SPARC, a significant decreasein capsular thickness around implanted poly-dimethylsiloxane disks was noted compared towild-type mice, indicative of a diminished foreignbody reaction. In contrary, mice lacking throm-bospondin 2 (TSP2), another protein that modulatescell-matrix interaction, show an enhanced foreignbody reaction with formation of highly vascularizedcapsules around implanted polydimethylsiloxanedisks supporting the role for TSP2 as a physiologicinhibitor of angiogenesis.15 These findings implicatean important role of the extracellular matrix in theregulation of foreign body reactions.

Treatment of silicone granuloma is difficult andvarious regimes have been used. Surgical excisionhas been suggested when possible; however, totalremovement may not be possible or may requireextensive debridement when silicone migrates todistant areas. Moreover, the cosmetic result may notbe satisfactory and is hardly predictable beforesurgery. The large extent of involvement in ourpatient with nodules on both eyelids, nose, andupper lip precluded surgical removal. Since thenodules were located deep in the dermis, topicaltreatment was not considered. Injection of steroids ortreatment with oral steroids may have a temporarybeneficial effect; however, a relapse is often seenwhen the dose is tapered.16 Complete resolution ofsilicon granulomas on the face has been reportedfollowing treatment with low dose retinoids (iso-tretinoin 20 mg per day) over 6 months.16 Variouscytokines have been implicated in granulomatousconditions and tumor necrosis factor (TNF)ea isthought to play a primary role.17 Pentoxifylline,which decreases TNF-a production from macro-phages, has been used in a few cases of sar-coid granulomas and silicone granulomas, withvariable results.18,19 Recently, successful treatment

VOLUME 52, NUMBER 2with allopurinol of foreign body granulomas causedby a mixture of polymethylmethacrylate and colla-gen has been reported.9 Treatment over 24 weeksresulted in almost complete regression of the cuta-neous symptoms. Allopurinol is thought to act asa catalyst in the formation of superoxides or asa scavenger of free radicals, which may play a role inthe pathogenesis of granulomatous diseases. Theexact mode of action remains to be elucidated.

The rationale for administration of minocycline ingranulomatous tissue reactions is its anti-inflamma-tory, immunomodulating, and anti-granulomatouseffect.20-21 In previous reports describing mino-cycline in the treatment of silicone granuloma,minocycline was administered in a higher dose(100 mg twice daily) either as monotherapy or incombination with oral prednisone.22 Improvementof the condition was noted within several weeks;however, the follow-up period of up to 4 months isstill short. In a patient in whom breast-injectedsilicone was delivered to multiple body sites, in-cluding the face, minocycline treatment (100 mgonce daily) resulted in improvement of the condi-tion; however, specific information and follow-upare not available.23

We report the succesful treatment of severedisfiguring facial silicone granuloma with a low doseminocycline regime (100 mg once daily). Clinicalimprovement was noticed 4 weeks after initiation oftreatment, and significant regression of the nodulesand the inflammatory response was seen after4 months. Minocycline was administered for 10months and a follow-up of the patient aftermore than1 year after initiation of therapy showed excellentclinical improvement. Compared to previous re-ports, minocycline (100 mg once daily) as a mono-therapy was as effective as oral prednisone ora combination of oral prednisone and minocycline(100 mg twice daily). Side effects, such as pigmen-tation, were minimal and were well tolerated. Ourdata highlight the prolonged course of the disease,which sometimes necessitates a long duration oftreatment. In our opinion, minocyclinemonotherapyrepresents a useful treatment option, especially forsilicone granuloma of the face.

We thank Professor G. Mahrle for valuable commentson the manuscript.

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