J Cutan Pathol 2008: 35: 536–548 Copyright # Blackwell Munksgaard 2007

doi: 10.1111/j.1600-0560.2007.00853.x
Blackwell Munksgaard. Printed in Singapore Journal of
Cutaneous Pathology
Continuing Medical Education Article

Adverse cutaneous reactions to soft

tissue fillers – a review of the
histological features
The enhanced use of exogenous substances for cosmetic and Ophelia Entsir Dadzie1,2,
reconstructive procedures is paralleled by an increase in reports of Meera Mahalingam3, Meire
cutaneous adverse reactions to several of these agents. Recognition of Parada4, Therese El Helou1,2,
the histological features of these reactions is of importance to both Tania Philips2 and
dermatologists and dermatopathologists but is not always easy for Jag Bhawan1,2
several reasons. First, cost-related issues are resulting in an increasing 1
Department of Dermatopathology and
number of these procedures being performed overseas. Thus, patients 2
Section and Department of Dermatology,
are often unsure about the exact product used. Compounding this is Boston University Medical Center, Boston,
the fact that practitioners who perform these procedures are not MA, USA
3
forthright in divulging this information, given that improper substances Dermatopathology Section, UMASS Medical
School, Worcester, MA, USA, and
may be admixed in the filler injected. Furthermore, cutaneous 4
Department of Dermatology, Federal
reactions may occur at sites distant from injected sites, secondary to University of Săo Paulo, Săo Paulo, Brazil
migration of the filler substance and a lapse of months to years may
occur prior to the development of a cutaneous reaction. Thus, a causal
relationship between the procedure and the reaction is often not made.
We present an overview of the histological features of adverse reactions
to currently available soft tissue fillers, both in the United States and
overseas, in an attempt to enhance awareness of the diversity of these Ophelia Entsir Dadzie, MD, Dermatopathology
reactions. Section, Boston University Medical Center, Boston,
MA 02118, USA
Dadzie OE, Mahalingam M, Parada M, El Helou T, Philips T, Tel: 1617 638 5514
Bhawan J. Adverse cutaneous reactions to soft tissue fillers – a review of Fax: 1617 638 5575
e-mail: opheliadadzie@hotmail.com
the histological features.
J Cutan Pathol 2008; 35: 536–548. # Blackwell Munksgaard 2007. Accepted for publication June 30, 2007

Soft tissue fillers used for cosmetic and reconstruc-
tive procedures fall into one of two broad categories
based on the ability of human enzymes to
metabolize these products – biodegradable agents
and those that are non-biodegradable.1 Adverse
cutaneous reactions to either are classified into those
that occur immediately (within days of the pro-
cedure) and those that are delayed (weeks to years
after the procedure).1 Late reactions include gran-
ulomatous reactions, which may present as papules,
nodules or plaques (Fig. 1). While adverse reactions
are often related to the filler product itself, pro-
Dr Ophelia Dadzie is a recipient of The Geoffrey Dowling Award,
from the British Association of Dermatologists.
cedural techniques and concentration of the product,
including the contaminating presence of impurities
are important determinants in influencing the
degree of response. While the precise pathogenesis
of reactions to the soft tissue filler itself is poorly
understood, infections are believed to trigger the
process.2 Given all of this, it is important that
dermatologists and dermatopathologists are aware
of the wide spectrum of histological features that
result as adverse reactions to the different filler
products available in the market today.
A review of the literature on available soft tissue
fillers shows an expanding number of agents,
marketed in different parts of the world under
different names1,3,4,5,6 (Tables 1 and 2). While

536

Fig. 1. A woman with bilateral hyperpigmented indurated plaques
on her gluteal region (A and B) secondary to paraffin injection.
Histology of a biopsy from lesional skin is shown in Fig. 6.
available information on histological features of
adverse cutaneous reactions is somewhat limited
for reasons enumerated earlier, we have attempted
to provide an overview of the currently available
information on reactions to both non-biodegradable
and biodegradable products used today (Tables 3
and 4). Our personal experience on this subject
matter has also been included in this review.
Biodegradable soft tissue fillers
This sub-group represents soft tissue fillers capable
of being metabolized by human enzymes and
therefore, are absorbed following cutaneous injec-
tion. Consequently, their clinical effects are typically
short-lived (2–18 months).1 Thus, granulomatous
reactions typically do not commonly occur as an
adverse effect to these products.
Autologous fat
Autologous fat, obtained by either liposuction or
dissection of fat from donor sites such as the thigh,
may be used for the correction of subcutaneous
Adverse cutaneous reactions to soft tissue fillers
lipoatrophy, facial rhytids and volume augmentation
of the lip and senescent face.7,8 It is injected into the
subcutis. Immediate cutaneous adverse reactions
include overcorrection, infections and vascular
occlusion following intra-arterial injection. Delayed
reactions include hypertrophy of the transplanted
site following weight gain, formation of lipomas and
liponecrotic pseudocysts.9 To date, no granuloma-
tous reactions have been reported as a direct
consequence of transplanted fat.
Excisional biopsies following hypertrophy of
recipient sites of transplanted fat show mature
adipose tissue encapsulated by leukocytes.10,11 The
transplanted fat is similar in structure to the original
donor site.
Dermis-fat graft
This technique involves autologous transplantation
of dermis and subcutis. To the best of our know-
ledge, there are no reports in the literature of the
histology of adverse reactions following this pro-
cedure. However, Niechajev12 performed lip aug-
mentation with dermis-fat graft in two women.
Routine lesional skin biopsies were taken at three
and a half months and at 11 months. After three
and a half months, histology showed two distinct
layers of tissue; adipose and vascularized connective
tissue associated with a slight lymphocytic inflam-
mation. After 11 months, histology showed that the
dermis-fat graft had completely integrated into the
adjacent lip tissue.12
Bovine collagen
Bovine collagen (commercially available as Zyderm
or Zyplast) is a popular soft tissue filler, composed of
95% type I collagen and 5% type III collagen.13 It is
similar in composition to that of normal human
dermis. Zyderm I and Zyplast are composed of
3.5% bovine collagen, however the former is cross-
linked with glutaraldehyde. Zyderm II is composed
of 6.5% bovine collagen.13 All three products are
approved by the USA Food and Drug Administra-
tion (FDA) for use as soft tissue fillers.13 Zyderm I
and II are injected into the superficial dermis and
are efficacious for the correction of superficial facial
furrows, notably glabellar, perioral and horizontal
forehead lines. Zyplast is injected deeper into the
dermis and at the subcutis interface and is used for
correcting deeper furrows and acne scars.13 Koken
Atelecollagen4 is a 2% monomolecular aqueous
solution of collagen produced by Koken Ltd, Japan.
It is not available in the USA. The indications,
contraindications and injection technique are the
same as those of Zyderm.
537
Dadzie et al.
Table 1. A list of biodegradable soft tissue fillers
Composition Commercial names Availability
Fat Autologous fat and dermis-fat grafting Autologous
Bovine collagen Zyderm I & II, Zyplast Inamed Aesthetics, Santa Barbara, CA-FDA approved
Koken Atelocollagen Koken, Ltd. Tokyo, Japan
Endoplast 50 Laboratories, Filorgra
Porcine collagen Fibroquel Aspid, Mexico
Permacol Tissue Science Labs, England
Evolence ColBar LifeScience, Herzliya, Israel
Human collagen CosmoDerm I, II & CosmoPlast Inamed Aesthetics, Santa Barbara, CA-FDA approved
Autologen Collagenesis, Inc., Beverly, MA
Isolagen Isolagen Technologies, Houston, Texas
Cymetra & Alloderm Lifecell Corporation, Branchburg, N.J-FDA approved
Fascian Fascia Biosystems, Beverly Hills, CA-FDA approved
Dermalogen Collagenesis, Inc., Beverly, MA
Hyaluronic acid (Bacterial origin)
Perlane, Fineline, SubQ, Macrolane Q-Med, Uppsala, Sweden
Restylane Medicis Aesthetics, Scotsdale, AZ FDA approved
Juvederm 18, 24 and 30 Leaderm, Paris and Inamed Aesthetics, Santa Barbara, CA
(Avian origin)
Hylaform, Hylaform Plus, Hylaform Fineline Inamed Aesthetics, Santa Barbara, CA-FDA approved
Captique Inamed Aesthetics and Genzyme, Boston-FDA approved
Rofilan Hylan Gel Rofil Medical International, Breda, Netherlands
AcHyal Tedec-Meiji, Farma, Spain
Matridur Biopolymer, Siershahn, Germany
Hyal-System Merz, Pharma, Franfurt, Germany
Puragen Mentor Corp, Santa Barbara, CA, USA
Poly-L-lactic acid New-fill Sanofi-Aventis
Sculptra Strasbourg and Dermik Aesthetics, Berwyn, PA-FDA approved
Calcium hydroxyl appatite Radiesse Bioform, Inc., San Matteo, CA-FDA approved
Dextran beads in hylauronic acid Matridex Biopolymer, Siershahn, Germany
Reviderm intra Rofil Medical International, Breda, Netherlands

Cutaneous complications13 following injection of
Zyderm I, II and Zyplast include infections,
formation of cysts, vascular occlusion following
direct injection into a vessel, non-specific inflamma-
tion (presenting as localized recurrent erythematous
swelling of the face), type 1 hypersensitivity reactions
and granulomatous nodules.
On histology14 the bovine collagen implant
presents as irregular and variably sized islands,
situated in the deep dermis (Fig. 2A,B). They may

Table 2. A list of non-biodegradable soft tissue fillers

Composition Commercial names Availability
Saturated hydrocarbons Paraffin Non-medical sources
Silicon MDX-4-4011 Dow Corning No longer available
PMS 350 (liquid silicone of low viscosity) Vikomed, Germany
Silikon 1000 Alcon Laboratories, Fort worth, Texas
SilSkin 1000 Richard-James Development Corp, Peabody, MA
PMMA-silicone suspension Bioplastique Uroplasty BV, Netherlands
PMMA microspheres and bovine collagen Arteplast No longer available
Artecoll Rofil Medical International, Breda
Artefill Artes Medical, San Diego, CA
Aphrodite gold European Medical Contract Manufacture
Nijmegen, The Netherlands
PMMA microspheres suspended in Metacrill Nutricel Laboratories, Rio de Janeiro, Brazil
carboxygluconate gel
Acrylic hydrogel particles suspended in DermaLive and DermaDeep Dermatech, Paris
hyaluronic acid
2.5%PAAG, 4% PAAG cross-linked with Aquamid Ferrosan AS, Copenhagen, Denmark
polyalkylimide Interfall Interfall Ltd., Kiev, Ukraine
Bio-Alcamid, Polymekan, Milan, Italy
Formacryl & Argiforn Bioform, Moscow, Russia
Outline ProCytech, Bordeaux, France
Amazing gel FuHua Ltd, ShenZhen, China
Polyvinyl microspheres suspended in Evolution ProCytech Labs, Bordeaux, France
polacrylamide
PTFE Teflon No longer available
e-PTFE Advanta Atrium Medical
GORE S.A.M W.L. Gore Associates, Inc. Az
SoftForm & UltraSoft Tissue Technology, Inc, CA
Polyoxyethylene & polyoxypropylene Profill Laboratories Filorga, France

PAAG, Polyacrylamide gel; PMMA, Polymethylmethacrylate; PTFE, polytetrafluoroethylene; e-PTFE, e-polytetrafluoroethylene.

538
 Adverse cutaneous reactions to soft tissue fillers
Table 3. A summary of the histological features associated with biodegradable soft tissue fillers
Soft tissue filler Location Nature of implant Type of infiltrate Polarizing microscope
Autologous fat Subcutis Similar to normal Leukocytes Non-birefringent
adipose tissue
Bovine collagen Dermis Acellular, eosinophilic Non-granulomatous reactions Weakly birefringent
and distinct from (lymphocytes, eosinophils & neutrophils),
native collagen Foreign body granuloma
Human collagen Dermis Amorphorous and distinct Foreign body granuloma Non-birefringent
from native collagen
Hyaluronic acid Dermis, subcutis Amorphous, basophilic, Foreign body Non-birefringent
and muscle positive staining with granuloma and eosinophils
Alcian blue
Poly-L-Lactic acid Dermis, subcutis Long, fusiform Foreign body Positively birefringent
and translucent granuloma and lymphocytes
Calcium hydroxylapatite Dermis Blue-gray clacific microspheres Foreign body granuloma Non-birefringent

migrate into the subcutis.15 The implanted bovine
collagen differs from native collagen in being
acellular, thicker and more eosinophilic.16,17 How-
ever, like normal collagen, it is weakly birefringent
when polarized.15,17,18 Differences exist in the
structure of the different types of bovine collagen
used; Zyplast has a more fibrillar appearance
compared with Zyderm.
There are two histological patterns associated
with bovine collagen injection: a non-specific cuta-
neous inflammation and a granulomatous reaction.
The former shows2,17,19 a superficial and mid-dermal
perivascular and periappendageal mononuclear
infiltrate, with infiltration of the implanted collagen
by neutrophils, lymphocytes, histiocytes and eosino-
phils. This correlates with a clinical picture of re-
current erythematous swelling at the site of injection
of the soft tissue filler.
Granulomatous reactions14,20 to bovine collagen
may manifest as a foreign body type giant cell
reaction (Fig. 2A,B). Rare reports exist of a palisad-
ing granuloma-annulare like lesion triggered by
implantation of bovine collagen21 in a patient with
a prior history of granuloma annulare.
Endoplast 50
Endoplast 504 is composed of solubilized bovine
elastin peptides and collagen and is currently not
FDA approved for use as soft tissue filler in the USA.
However, it is available in Europe. It is injected
intradermally for correction of facial rhytids. No
reports detailing histological features of adverse
reactions to this agent currently exist in the English
literature.
Porcine collagen
A range of porcine collagen4 are available for the
correction of facial rhytids. This includes Fibroquel,
Permacol and Evolence. Their use for this indication
is not approved by the FDA in the USA. To the best
of our knowledge, there are no reports describing
the histological features of cutaneous adverse
reactions to this class of products.
Human collagen
This class of soft tissue fillers includes autologous
collagen and fibroblasts, as well as allogenic
bioengineered collagen and human dermal matrix.
CosmoDerm I, II and CosmoPlast13 are both
bioengineered human Type I and III collagen
derived from cultured fibroblasts. Both products
are approved by the FDA for use in the USA.
CosmoDerm I contains 35 mg/ml of human-based
collagen, while CosmoDerm II has twice the con-
centration of human collagen compared with Cosmo-
Derm I. CosmoPlast is similar to CosmoDerm I
but is cross-linked by glutaraldehyde. CosmoDerm I
and II, injected into the superficial dermis, are used
for correction of superficial furrows. CosmoPlast
used for augmentation of the lips and correction of
deeper furrows, is injected into the deeper reticular
dermis. Autologen13 consists of autologous tissue
matrix (composed predominantly of collagen fibrils)
and when injected into the dermis, is used for lip
augmentation and correction of scars and furrows. It
has also been used for the treatment of vocal fold
paralysis. It is produced from autologous skin,
obtained during elective procedures such as abdom-
inoplasties or facelifts. The autologous skin is sent for
processing and the collagen fibrils, elastin, fibro-
nectin and glycosaminoglycans are isolated and used
as Autologen. Autologen is no longer available in
the USA and this is probably related to the filed
bankruptcy of the company, Collagenesis Corpora-
tion, which produced this agent. Isolagen22 involves
injection of cultured autologous fibroblasts into the
superficial dermis for the correction of facial rhytids
and more recently, acne scarring. This product is not

539
Dadzie et al.

Polarizing microscope
available in the U.S.A, but has been available in

(angulated impurities)

Positive birefringence
Positive birefringence
Europe. AlloDerm,13,23 an acellular allograft of
Non-birefringence

Non-birefringent

Non-birefringent

Non-birefringent

Non-birefringent
Non-birefringent
Birefringent and
human dermal matrix derived from cadaveric skin,
is approved for use in the USA by the FDA. It is
used in the treatment of full-thickness burns, surgical
defects and acne scars. Cymetra13,24, available in the
USA since 2000, is an injectable form of AlloDerm.
Fascian4 is another allogeneic agent, which is

Foreign body granuloma and lymphocytes

Foreign body granuloma and lymphocytes

Foreign body granuloma and Neutrophils
approved by the FDA for soft tissue augmentation.
Foreign body granuloma, lymphocytes

Foreign body granuloma, lymphocytes

It is harvested from cadaveric fascia lata, processed
and freeze-dried. The product is rehydrated with
saline containing lidocaine, and injected above the
superficial subcutaneous fat. Dermalogen13,23 is
Foreign body granuloma

Foreign body granuloma

Foreign body granuloma

homologous human dermal proteins (predominantly
Epithelioid granuloma

type 1 and III collagen), derived from skin obtained

Type of infiltrate

and eosinophils

and eosinophils

from tissue banks. Dermalogen, (like Autologen)

was manufactured by Collagenesis Corporation, and
for this reason is no longer available in the U S A.
There are limited reports in the literature
detailing the histological features of adverse reac-
tions to the agents discussed above. Moody and
particles (extracellular) in a fibrotic matrix
Polymorphic vacuoles, foamy appearance

cystic spaces (extracellular) in a sclerotic

(extracellular and in multi-nucleate giant

projections and suspended in a sclerotic

Translucent microspheres located within

Sengelmann25 reported the case of a woman who

cells) and impurities seen as angulated

Irregular, translucent polygonal shaped

Amorphorous, basophilic and positive
spaces, (extracellular) in a hyalinized

Jagged Ôpopcorn-shaped’ translucent

Microspheres-seen as monomorphic

developed an erythematous nodule at the site of

particles, (extracellular), arabesque
Located within polymorphic cystic

a test dose injection of Dermalogen. An excisional

biopsy of lesional skin showed injected collagen,
polymorphic cystic spaces

amorphous and distinct from native collagen, with

staining for Alcian blue

an associated foreign body giant cell reaction.

Filamentous threads
Nature of implant

Filamentous
Table 4. A summary of the histological features associated with non-biodegradable soft tissue fillers

collagen

Hyaluronic acid
stroma

stroma
bodies

Hyaluronic acid (HA), found in the extracellular

matrix of connective tissue, synovial fluid and other
human tissues, is composed of polyanionic disac-
Deep reticular dermis, subcutis 1/2

charide units of glucoronic acid and N-acetylglucos-

Deep reticular dermis, subcutis and

amine connected by alternating b1-3 and b1-4

Reticular dermis and subcutis

bonds. HA derived from bacteria or avian sources

is available for the correction of facial rhytids,
nasolabial folds and volume augmentation.26 It is
Dermis and subcutis

Dermis and subcutis

Dermis and subcutis

Dermis and subcutis

best injected into the dermis. While there are four

FDA approved HA skin fillers currently available
in the USA (Hylaform, HylaformPlus, Captique
Subcutis
Subcutis

and Restylane)3, a variety of other HA soft tissue

muscle

muscle
Site

fillers are available worldwide (Table 1). The dif-

ferent products vary in their derivation (bacterial vs.
avian), HA concentration and cross-linking to other
suspended in carboxygluconate (Metacrill)
Polyvinylpyrrolidone-silicone suspension

products.
Acrylic hydrogel particles in hyaluronic
Polymethyl-methacrylate microspheres
and bovine collagen (Artecoll, Artefill)

Clinically, adverse reactions seen with these

E-polytetrafluoroethylene (Gortex)

agents include ecchymoses, erythema, intermittent

Polymethacrylate microspheres

Polytetrafluoroethylene (Teflon)
acid (DermaLive/DermaDeep)

swelling, pruritus and nodules. Rongioletti et al.27

Polyacrylamide (Aquamid)

have reported a case of generalized scleromyxoe-

dema (presenting as papules and generalized
cutaneous thickening) 9 months after injection of
Soft tissue filler

hyaluronic acid. The possible role of the soft tissue

(Bioplastique)

filler in triggering a hypersensitivity reaction was

Silicone
Paraffin

proposed as one of the possible mechanisms of this

reaction.

540

Fig. 2. Acellular, eosinophilic bovine collagen implant with an
associated mixed inflammatory cell infiltrate (A and B). Haematox-
ylin and eosin stain, 320 and 340, respectively.
The cutaneous histology14,28,29 of adverse reac-
tions is well described for Restylane. Briefly, these
include (Fig. 3) a foreign body giant cell reaction,
with macrophages, eosinophils and neutrophils
Fig. 3. Extracellular deposition of hyaluronic acid (Restylane)
associated with mulitinucleate giant cells. Haematoxylin and eosin
stain, 340.
Adverse cutaneous reactions to soft tissue fillers
surrounding isolated extracellular amorphous baso-
philic HA. Scant HA may also be seen within
multinucleated giant cells. This reaction pattern is
observed in the deep reticular dermis, subcutis and
even underlying muscle. Fibrosis may be a feature.
The HA stains positively for Alcian Blue at a pH of
2.7 and is negative when examined under polarized
light.
Poly-L-lactic acid
A polymer of lactic acid monomers derived from corn
dextrose fermentation, Poly-L-lactic acid (PLLA)30,31,32
has a long history of use in the medical field notably,
within orthopedic fixative devices (screws, pins and
plates), in urethral and tracheal stents, as a vehicle
for vaccines and sustained-release injectable medi-
cation and as components of Vicryl sutures.
Injectable PLLA is marketed as either Sculptra or
New-Fill. Sculptra is available in the USA and is
FDA approved for volume augmentation in Human
immunodeficiency virus (HIV) related lipoatrophy.3
The same formulation is marketed in Europe as
New-Fill for the same indication and for correction
of facial rhytids. PLLA is typically injected into the
dermal-subcutis interface or at the periosteum.
Histologically, granulomatous reactions may be
seen following use of this agent. The exogenous
product is present both in the extracellular matrix
and within giant cells and is translucent, fusiform or
spiky in shape and birefringent under polarizing
light (Fig. 4A,B). The giant cells may have asteroid
bodies.
Calcium hydroxylapatite (Radiesse formerly known as
Radiance FN)
This implant consists of calcium hydroxylapatite
microspheres, between 25 and 45 mm in diameter,
suspended within an aqueous carboxymethylcellu-
lose gel carrier.33 In the USA, Radiesse has recently
been approved by the FDA as a filler for correcting
nasolabial furrows and for HIV related lipoatro-
phy.34 It already had FDA approval for use in the
treatment of vocal cord insufficiency, oral and
maxillofacial defects and radiographic tissue mark-
ing.33,34 In Europe, this product is also approved
for use as a soft tissue filler. Radiesse is injected into
the deep dermis, where the biodegradable calcium
hydroxylapatite microspheres are able to support
fibroblast growth and the subsequent deposition of
collagen.
Clinically, cutaneous adverse reactions occurring
with this product include ecchymoses, edema and
granulomatous nodules.
541
Dadzie et al.
Fig. 4. Foreign body-type giant cells with long spiky and translucent
particles consistent with New-Fill (A) Haematoxylin and eosin stain,
340. (B) Polarizable spiky translucent particles consistent with New-
Fill (320). Courtesy of Ute Zimmermann.14
Macroscopically, the calcific specks are visible.
Microscopic33 examination of lesional skin shows
blue-gray calcific microspheres in the extracellular
matrix or within giant cells (Fig. 5). The surrounding
dermis may show fibrosis.
Fig. 5. Calcium hydroxylapatite microspheres consistent with Rad-
iesse (Haematoxylin and eosin stain, 320).
542
Dextran beads in hyaluronic acid
Matridex and Reviderm intra consists of dextran
beads suspended in hyaluronic acid.3 These agents
are available in Europe. There are no reports of the
histological features associated with adverse reac-
tions to these agents.
Non-biodegradable products
This subgroup represents a range of products which
cannot be metabolized by human enzymes and
therefore, persist indefinitely in tissues. Given this,
while their clinical effect is long-term, a higher
frequency of associated cutaneous adverse reactions
occurs.
Paraffin/mineral oil
Paraffins, a group of high molecular weight straight-
chain saturated hydrocarbons, have historically been
used in the treatment of male pattern hair loss.35
They may be abused by individuals to augment their
breasts, penis, calves and buttocks36,37 Clinically,
their use is associated with the development of
localized plaques, nodules, ulceration and/ or
necrosis often presenting after several years (Fig. 1).
A similar finding occurs following the injection of
oily materials of similar chemical structure, such as
sheep lanolin, Vaseline and vitamin E.38,39
The histological14,35–43 reaction pattern of paraf-
finomas or sclerosing lipogranulomas are character-
istic. There is replacement of the normal reticular
dermis and subcutaneous tissue by empty pseudo-
cystic spaces of variable size, in association with
a foreign body giant cell reaction and fibrosis
(Fig. 6A–D). The pseudocystic spaces contain en-
cysted oil, as shown by positive staining of frozen
tissue sections with Oil Red-O21, Sudan 44, 12,16,
Nile Blue 12 and Osmic Acid 4, 12,16. In addition,
infrared absorption spectrophotometry and thin-
layer chromatography can be used to identify the
presence of the paraffin in tissue specimens. Rare
complications include the development of squamous
cell carcinoma35 at the site of a paraffinoma and
extracutaneous42 involvement of lymph nodes and
lungs, presumably from lymphatic or haematoge-
nous spread.
Silicone
Silicones are compounds composed of long poly-
mers of dimethysiloxanes. Dimethylsiloxanes are
composed of methane, oxygen and elemental silica.
Medical grade silicone gel, introduced by Dow
Corning in 1960, was used initially in soft tissue
augmentation.44–46 However, increased reports of
 Adverse cutaneous reactions to soft tissue fillers
Fig. 6. A) Polymorphic pseudocystic spaces in dermis, (B and C) subjacent lobular panniculitis and (D) with associated foreign body giant cell
reaction consistent with a paraffinoma (Haematoxylin and eosin, 34 and 340, respectively).
adverse reactions, probably because of the presence
of contaminants, led to a ban against its use in the
USA. More recently, the FDA has approved limited
investigational study of several types of high-grade
liquid injectable silicone (SilSkin and Silikon) for the
correction of nasolabial folds, marionette lines, mid-
malar depression and HIV lipoatrophy.45
Clinically, adverse reactions presenting as firm
subcutaneous nodules, have been reported in asso-
ciation with injected silicone of varying purity.
Histologically,14,29,40,47–51 a diffuse epithelioid
granulomatous infiltrate, with asteroid bodies involv-
ing the dermis and or subcutis may be seen. Round
pseudocystic spaces of variable size and shape,
representing injected liquid silicone particles, are
also present within and surrounding multinucleated
giant cells and histiocytes (Fig. 7A,B). This reaction
pattern is described as ÔSwiss-cheese’ like in appear-
ance and may mimic liposarcoma.51 In addition,
occasional angulated translucent, birefringent foreign
bodies may also be seen in the cytoplasm of foreign
body giant cells, representing impurities in the
silicone. Interestingly, the granulomatous reactions
may be seen at a distant site from the injected lesional
site, because of migration of the soft tissue filler.51
Polyvinylpyrrolidone-silicone suspension (Bioplastique)
This soft tissue filler, popular in Europe, is composed
of solid silicone particles dispersed in a carrier
vehicle, polyvinylpyrrolidone. It is injected into the
dermal/subcutis interface and is used for the
correction of facial rhytids.
Clinically, adverse reactions present as firm
indurations or nodules at the site of injection.
Histology,14,47 of lesional skin, shows pandermal,
extracellular, irregularly shaped cystic spaces, con-
taining jagged Ôpop-corn’ shaped particles, dispersed
in a sclerotic stroma occasionally extending into the
subcutis. The cystic spaces are outlined by multinu-
cleated giant cells (with asteroid bodies). The giant
cells have characteristic cytoplasmic Ôarabesque’
projections into the lumen. Examination under
polarizing microscope is negative.
Polymethylmethacrylate microspheres and bovine collagen
Soft tissue fillers composed of liquid bovine collagen
and polymethylmethacrylate (PMMA) microspheres
have been in use since 1989.14,52–53 Following their
injection, while there is absorption of the bovine
collagen, the PMMA microspheres persist in tissues
and produce a long-lasting bulking effect. For this
reason, these agents are used for the correction
of facial rhytids, subdermal defects and for chin
augmentation. They should be injected at the
dermal/subcutis border. Arteplast is the first gener-
ation of this class of products and it was used
extensively in Europe between 1989 and 1994.
Cutaneous adverse reactions to this product were
believed to be secondary to the presence of
impurities and over a period, purer products
(Artecoll and Artefil) were developed. The second-
generation product, Artecoll52,53, extensively used
worldwide (excluding the USA) between 1995 and
543
Dadzie et al.
Fig. 7. Macrophages with multiple cytoplasmic vacuoles, with
a foamy appearance, consistent with silicone (A and B-Haematox-
ylin and eosin, 310 and 340, respectively).
2004, is composed of 25% PMMA microspheres
and 75% of 3.5% bovine collagen. This same
product has been repackaged and distributed out-
side Europe as Aphrodite Gold. The third genera-
tion agent, Artefil, the only one approved for use by
the FDA in the USA as a soft tissue filler, is
a suspension of 20% PMMA microspheres, com-
posed of 80% bovine collagen and 0.3% lidocaine.
Clinically, cutaneous adverse reactions include an
infiltrative nodule presenting months to years after
injection of these fillers. Histological features
include4,47,48,50,54–56 a nodular or diffuse foreign
body granuloma associated with well-circumscribed,
monomorphic cystic spaces, distributed singly and in
small clusters in a sclerotic stroma in the dermis and
subcutis (Fig. 8A,B). Non-birefringent, translucent
foreign bodies can be identified within the cystic
spaces, corresponding to the PMMA microspheres.
Polymethylmethacrylate microspheres suspended in
carboxygluconate
Metacrill is composed of particles of PMMA
suspended in carboxygluconate. It is not FDA
544
Fig. 8. Foreign body giant cells with round and regular vacuoles
consistent with Artecoll (A and B-Haematoxylin and eosin stain,
320 and 340, respectively).
approved for use in the USA but is used as a soft
tissue filler in South America for the correction of
facial rhytids, acne scars and facial hemiatrophy.
Clinically, adverse reactions may present as infiltra-
tive nodules months to years after the procedure.
Histology,29 of lesional skin shows a focal or
diffuse infiltrate of foreign body giant cells and
epithelioid histiocytes in the reticular dermis and
subcutis. Round cystic spaces of variable size some
containing translucent, round, non-birefringent
microspheres may be seen (Fig. 9A,B).
Acrylic hydrogel particles suspended in hyaluronic acid
(DermaLive/DermaDeep)
This soft tissue filler, used in Europe, is composed of
60% hyaluronic acid (produced by bacterial fer-
mentation) and 40% acrylic hydrogel. The latter is
composed of 45–65 mm copolymer fragments of
hydroxyethylmethacrylate and ethylmethacrylate,
which are non-biodegradable.14 This product is
injected in the deep reticular dermis at the dermal/
subcutis boarder and is of use in the correction of
skin furrows and for volume augmentation.

Fig. 9. Foreign body type giant cells with multiple round and
irregular sized vacuoles with adjacent granulomas consistent with
Metacrill (A and B-Haematoxylin and eosin stain, 320 and 340,
respectively).
Clinically, the risk of adverse reactions following
the injection of this agent is rare and appears on an
average 6 months after the procedure. This presents
as facial nodules.
Histological14,57–59 findings include the presence
of granulomas and small cystic spaces in the
reticular dermis and subcutis embedded in a fibrotic
stroma. Translucent, non-birefringent, polygonal
shaped extracellular particles, surrounded by a for-
eign body giant cell reaction with asteroid bodies
may also be seen (Fig 10. A,B).
Polyacrylamide gel
There are different subtypes of Polyacrylamide
gel (PAAG)3,60,61 available on the market world-
wide; Aquamid, Interfall, Outline, Formacryl,
Bio-formacryl, Argiform, Amazing Gel and Bio-
Alcamid. These agents are injected into the subcutis
and are reportedly useful for volume augmentation
and correction of facial rhytids.
Clinically, adverse reactions present as erythema
and swelling at the sites of injection. Migration of
Adverse cutaneous reactions to soft tissue fillers
Fig. 10. Translucent polygonal shaped extracellular particles within
pseudocystic spaces associated with a foreign body type giant cell
reaction consistent with DermaLive (A and B-Haematoxylin and
eosin stain, 310 and 340, respectively).
this agent can occur as evidenced by the findings
of Kawamura et al.62 They reported the presence
of buccal granulomatous nodules, a few months
following the injection of Aquamid for the correc-
tion of nasolabial folds.
Histologically, granulomatous reactions occurring
as a complication 14,29,62 are well described for
Aquamid. Typically, a foreign body type granulo-
matous reaction surrounding amorphorous baso-
philic material is evident in the deep reticular
dermis, subcutis and underlying muscle. This
basophilic material corresponds to PAAG and it is
positive by Alcian blue stain. The basophilic debris
may also be found in the cytoplasm of the giant cells.
Lymphocytes are also present. It is negatively
birefringent under polarizing microscope (Fig. 11).
Polyvinylhydroxide microspheres suspended in
polyacrylamide (evolution)
Composed of a suspension of 6% Polyvinylhydr-
oxide (PVOH) microspheres (5–80 mm) suspended
in 2.5% PAAG, this filler is available in Europe and
545
Dadzie et al.
Fig. 11. Basophilic material among necrotic tissue consistent with
Aquamid (Haematoxylin and eosin stain, 320).
is used for lip augmentation. It is injected into the
dermis or subcutis. While there is no data on the
cutaneous histological findings of adverse reactions
to this agent, a perspective on the recognition of this
implant in histological samples is available by a study
of its effects in normal volunteers. The PVOH
microspheres are located within uniform cystic
spaces and the PAAG is normally reabsorbed by
6 months post injection.2
Polytetrafluoroethylene (Teflon)
Composed of polytetrafluoroethylene paste, this
filler has been used for facial augmentation,
including augmentation rhinoplasty.
There are limited reports in the literature on
adverse reactions to this soft tissue filler. Maas et al.63
reported the case of a woman who developed nasal
cellulitis following augmentation rhinoplasty. Histol-
ogy of the lesional site showed refractile filamentous
foreign materials consistent with Teflon paste with
a surrounding inflammatory infiltrate of lympho-
cytes and multinucleated giant cells.
e-Polytetrafluoroethylene
A variety of agents composed of expanded fibrillated
polymer made of e-polytetrafluoroethylene (e-
PTFE),4 are available as threads or tubes of different
diameters, firmness and porosity. They are marketed
under a variety of brand names, including GORE
S.A.M, SoftForm, UltraSoft, UltraSoft RC and
Advanta. While e-PTFE has a long history of use
in cardiac and vascular surgery, more recently it has
been used for the correction of nasolabial folds and
volume augmentation of the lips. These agents are
implanted just below the dermis at the junction with
546
the subcutis and persist because human enzymes are
unable to degrade the carbon-fluorine bond.
Clinically, adverse reactions include fistula forma-
tion, extrusion of the implant, infections, indura-
tion/granuloma formation and even migration of
the implant. Histologically, granulomatous reactions
may occur,64 and on histology threads of e-PTFE
are filamentous and birefringent under polarizing
microscope.
Polyoxyethylene and polyoxypropylene
Profill4 is a block co-polymer of polyoxyethylene and
polyoxypropylene with mineral salts, amino acids
and vitamins. This filler is a liquid, which upon in-
jection, becomes a gel implant. Often used together
with Endoplast 50 it is not approved for use in the
USA for soft tissue augmentation, but has been
available in Europe for this purpose. There is limited
information available in the literature on this
product, although some reports document lipoa-
trophy as a complication of this product.65
Conclusion
A wide range of soft tissue fillers are available
worldwide. Biodegradable soft tissue fillers, produce
immediate and short-term cutaneous adverse reac-
tions, such as infections, type 1 hypersensitivity
reactions and rarely granulomatous reactions. For
non-biodegradable soft tissue fillers, which persist
longer at sites of injections, more long-term cuta-
neous adverse reactions, such as granulomatous
reactions may be seen. Regardless of where patients
have had these procedures, they are likely to present
to physicians in the USA for treatment of compli-
cations. For this reason, all physicians should have
an awareness of the histological features associated
with the wide range of soft tissue fillers in use
worldwide.
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