3. The patient was seen regularly for follow-up, and surgical
correction of the facial asymmetry was planned once growth
had ceased. The patient was seen regularly also for orthodon-
tic treatment since the age of 8 years. The upper left second
premolar was congenitally missing, and the teeth on the left
side were larger than on the right side. Development and
eruption of the dentition was premature on the left side
compared with the right side. There was crowding in both
upper and lower dentition and scissors bite on the left side.
Asymmetry in the upper and lower midlines was noted.
The patient complained of impaired vision at the age of 14
years. She was found to have myopia, astigmatism, and, in the
left eye, amblyopia. Movements of the eyes were normal.
Occasional nasal obstruction occurred, and there was devia-
tion of the nasal septum to the left. Pigmented macules had
been present on the skin of the left cheek and neck since early
childhood. On a recent consultation with a dermatologist,
these lesions were diagnosed as epidermal nevi (Fig. 1, C).
There were no signs of neurofibromatosis on the skin.
Several imaging studies were done during the course of
treatment and follow-up. Computerized tomography showed
enlarged maxillary and mastoid air sinuses, enlarged zygo-
matic bone, and narrowing of the nasal cavity on the left side
(Fig. 1, D). Increased activity was observed on the bone scans
in the left maxilla and in the area of zygomatic bone. Mag-
netic resonance imaging showed increased size of maxillary
sinus, zygomatic bone, and masseter muscle as well as in-
creased thickness of the subcutaneous fat tissue on the left
side. Left cerebellar hemisphere was larger than the right side
and contained abnormally structured cortex with white matter
strands running from center to periphery (Fig. 1, E). Pan-
oramic x-ray at the age of 19 years showed mandibular bone
to be hyperplastic in the region of the lower left molars and
angle of mandibula. The mandibular canal was enlarged.
Posteroanterior view showed the processus coronoideus to be
slightly longer and the area of zygomatic bone to be denser on
the left side.
On a visit in January 2005, 2 nodules of about 2 cm in
diameter were observed on the left buccal mucosa (Fig. 1, F).
The lesions were clinically suspicious for neurofibromatosis.
One of the nodules was excised, and histopathologic exami-
nation revealed a hypertrophic proliferation of neural tissue in
a pseudo–onion bulb pattern (Fig. 2, A and B). In these “onion
bulbs” small number of S-100 protein–positive cells were
Fig. 1. A and B, The patient at the ages of 8 years (A) and 18 years (B), with marked left hemifacial hyperplasia: enlarged lower
lip, cheek, cheek bone, and lower rim of the orbita. C, Epidermal nevi on the left side of cheek and neck. D, Computerized
tomography of head at the age of 17 years, showing marked asymmetry of the facial structures: enlarged left maxillary sinus,
mastoid air sinus and zygomatic bone, and narrowing of the left nasal cavity. E, Magnetic resonance imaging of face and brain
(age 18 years), showing increased size of maxillary sinus, zygomatic bone, and masseter muscle as well as increased thickness
of the subcutaneous fat tissue on the left side. The left cerebellar hemisphere is larger than the right and contains abnormally
structured cortex: white matter strands running from center to periphery. F, Two submucosal masses on the left buccal mucosa
near corner of mouth.
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Volume 104, Number 1 Siponen et al. e39
4. noted centrally. The surrounding concentrically arranged
spindle cells were positive only for EMA (Fig. 2, C and D).
The patient was operated on in December 2005 to correct
the facial asymmetry. Before the surgery, a 3-dimensional
stereolythic skull model was made to better visualize the
relative hard and soft tissue contributions to the facial asym-
metry and to help accurately plan the hard tissue reduction
surgery. The soft tissues of the left side of the face contained
a spongy yellowish lipomatous material with some discrete
nodules. Extensive removal of the tissue was deemed impos-
sible, because the spongy yellowish lesional tissue encased
the branches of the facial nerve. Instead, the hyperplastic
frontal and temporal bones, zygoma, and maxilla were con-
toured through coronal, subciliary, and intraoral incisions.
Soft tissue specimens were obtained from the left infraorbital
and suprazygomatic areas. The microscopic findings from the
tissue of the infraorbital area were identical to previous bi-
opsy from left buccal mucosa, showing features of intraneural
Fig. 2. A and B, Hypertrophic neural proliferation in a pseudo–onion bulb pattern (A: H-E ⫻50; B: H-E ⫻200). C, Tumor cells
are reactive for epithelial membrane antigen (⫻100). D, S-100 protein is nonreactive for tumor cells, but some residual Schwann
cells at the center of perineurial whorls are stained (⫻100).
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e40 Siponen et al. July 2007
5. perineurioma, whereas the specimen from suprazygomatic
area contained normal tissue structure with no evidence of
intraneural perineurioma.
DISCUSSION
Etiology
Intraneural perineurioma was previously considered
to be a reactive process, referred to as localized hyper-
trophic neuropathy or hypertrophic mononeuropathy.2,5
Both intraneural and extraneural perineuriomas are now
recognized as benign nerve sheath tumors composed of
perineurial cells, with evidence of the neoplastic nature
of the tumor presented recently in several reports de-
scribing clonal cytogenetic aberrations of chromosome
22.12,16,17
Most recently, rearrangements and/or dele-
tions in chromosome 10q have been found in the scle-
rosing variant of perineurioma.18
Abnormalities of
chromosome 22 are found also in a variety of other
neural tumors and meningiomas.17
It has been found
that the long arm of chromosome 22 contains a tumor
suppressor gene, possibly the NF-2 gene, involved in
the pathogenesis of nerve sheath tumors.16
Clinical features
Intraneural perineuriomas are most often found in
young individuals, equally in both genders. They typi-
cally affect peripheral nerves of the extremities, caus-
ing muscle weakness and sometimes sensory deficits.1,2
Extraneural perineuriomas are seen in adults of all
ages, with a female predilection.2
They occur in a wide
anatomic distribution, but usually in the superficial soft
tissues of the extremities, and cause most often a symp-
tomless mass.3
Both intraneural and extraneural peri-
neuriomas may rarely arise intraosseously.7,10,12
Histopathologic and ultrastructural features
Normally, the epineurium surrounds peripheral
nerves, which are composed of a bundle of nerve fas-
cicles. These individual nerve fascicles are in turn
surrounded by 1 or more layers of perineurial cells,
forming the perineurium. Inside the nerve fascicles
the endoneurial stroma ensheaths axon–Schwann cell
complexes.19
In intraneural perineuriomas the affected nerve is
enlarged symmetrically forming a fusiform expansion
of the nerve.5
Most lesions are less than 10 cm in
length.2
Extraneural perineurioma is typically unassociated
with nerve and measures 0.3-20 cm (mean 4.1 cm).3
Perineuriomas are typically well circumscribed, often
having a fibrous pseudocapsule. However, they may
have poorly defined infiltrative margins, such as the
gingival soft tissue perineurioma described by Graadt
van Roggen et al.8
Cytologically, the cells in both intraneural and ex-
traneural perineuriomas share similar features: the neo-
plastic cells are spindle-shaped, have elongated cell
processes and elongated often wavy, tapered nuclei and
inconspicuous nucleoli.2,17
Occasionally atypical cells
are seen but mitotic activity is rare.2
Histologically, intraneural perineuriomas are com-
posed of perineurial cells proliferating in concentric
layers around nerve fibers; in transverse sections they
form a pseudo-onion bulb pattern.2
In the center of
these proliferating “onion bulbs” a degenerating axon
and some Schwann cells are seen.
Extraneural perineuriomas are in contrast morpho-
logically heterogeneous, showing spindle or epithelioid
cytological features.3,15
The cells are arranged in
whorls, in storiform or in fascicular patterns.3
Stroma
may be collagenous, myxomatous or markedly hyalin-
ized.3
Several variants of extraneural perineurioma
have been described, sclerosing perineurioma being
probably the most common.5
Other variants include
reticular/retiform8,14
and plexiform.14
It has been sug-
gested that identification of unusual variants of peri-
neurioma requires ultrastructural confirmation.5
Ultrastructural features of perineurial cells include
long thin cytoplasmic processes with large numbers of
pinocytotic vesicles, abundant collagenous stroma, in-
continuous basement membrane and rudimentary inter-
cellular junctions.2,3
Diagnosis and differential diagnosis
Although ultrastructural identification of perineurial
cell differentiation has long been and still is regarded
by some investigators as the “gold standard” of diag-
nosis of perineurioma,17
many now consider light mi-
croscopic features combined with immunohistochemi-
cal findings of EMA positivity and S-100 negativity of
the neoplastic cells sufficient for the diagnosis.15,18
The staining pattern of EMA is membranous, and in
intraneural perineurioma some residual axons and
Schwann cells in the center of the “onion bulbs” show
positivity with GFAP and S-100, respectively.2
How-
ever, in the series of 81 soft tissue (extraneural) peri-
neuriomas by Hornick and Fletcher,3
4 (5%) showed
focal perineurial cytoplasmic and nuclear staining for
S-100. In some cases, the intensity of EMA staining
may be weak or focal.8,15
Perineurial cells are also
positive for vimentin and show membranous laminin
and collagen IV positivity, although this is not a spe-
cific finding.1,3
Glut-1, again not specific for perineurial
cells, has been suggested recently as a useful marker for
detecting or confirming perineurial differentiation.18
Also focal Claudin-1 (tight junction–associated pro-
tein), cytokeratin, SMA, and CD34 positivity may be
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Volume 104, Number 1 Siponen et al. e41
6. found.3,8,15
The proliferative activity of perineuriomas
using MIB-1 ranges from 3.7% to 17%.2,16
The differential diagnosis of intraneural perineu-
rioma includes other spindle cell lesions that may pro-
duce an onion bulb–like histologic pattern. Palisaded
encapsulated neuromas, neurofibromas and traumatic
neuromas may have a histologic growth pattern that
superficially resembles that of intraneural perineu-
rioma.11,16
In hereditary hypertrophic neuropathies of
Charcot-Marie-Tooth disease and of Dejerine-Sottas
disease, there are periaxonal lamellar proliferations of
Schwann cells of the affected nerves producing an
onion bulb–like pattern.11,16
However, immunohisto-
logic evaluation with S-100 and EMA enables the dis-
tinction to be made easily, with the majority of the
lesional cells reacting with S-100 in these lesions in
contrast to mostly EMA-positive cells in intraneural
perineurioma.
In the case of extraneural (soft tissue) perineurioma,
a considerably wider range of spindle and epithelioid
cell lesions have to be considered in the differential
diagnosis. Generally, the immunohistochemical detec-
tion of EMA and Claudin-1 positivity and S-100 neg-
ativity is sufficient to make the diagnosis of extraneural
perineurioma. Benign lesions that may mimic extran-
eural perineurioma histologically include, for example,
fibromatosis, nodular fasciitis, neurofibroma, nerve
sheath myxoma, and the rare soft tissue meningioma.15
Some neurofibromas are rich in perineurial-like cells,
and may be therefore difficult to distinguish from peri-
neuriomas.13
Rare examples of hybrid tumors showing
a combination of perineurioma and schwannoma or
neurofibroma have recently been reported.20
Of malig-
nant tumors, for example, low-grade fibromyxoid sar-
coma may closely resemble extraneural perineurioma
but lacks EMA or Claudin-1 positivity.15
Malignant
peripheral nerve sheath tumors (MPNST) may show
perineurial differentiation and therefore cause difficul-
ties in the differential diagnosis.21
Treatment
Therapy for intraneural perineurioma remains con-
troversial. The progression of the tumor may justify
surgical excision and nerve grafting even before symp-
toms; however, this approach often results in the loss of
nerve function.11
Many authors prefer no treatment
after biopsy or neurolysis, because of the benign nature
of the process and in order to retain neurologic function
as long as possible.2,11,16
For extraneural perineurio-
mas, a conservative excision is advocated.2,9
Prognosis
Perineuriomas are benign peripheral nerve sheath
tumors composed exclusively of perineurial cells with
no tendency for recurrence.2
In a series of 81 extran-
eural (soft tissue) perineuriomas, only 2 recurred, one
with atypical histologic features.3
Atypical cellular fea-
tures such as pleomorphic or multinucleated cells, hy-
percellular areas, or infiltrative margins are not uncom-
mon in perineuriomas, and many investigators believe
these cellular features to be a degenerative change and
therefore to have no clinical or prognostic signifi-
cance.3,7,21
Metastases from perineuriomas have not
been reported.
Conclusion
Previous reported cases of perineuriomas of the oral
and maxillofacial area are summarized in Table I. Most
Table I. Reported cases of perineuriomas of the oral and maxillofacial regions
Authors Age/gender Location Variant
Kusama et al., 19817
31/F Mandible Extraneural (reticular)*
Giannini et al., 199717
59/F Maxillary sinus Extraneural
Graadt van Roggen et al., 20018
42/F Gingiva Extraneural (reticular)
Senghore et al., 200122
70/F Facial skin Extraneural
Barrett et al., 200210
53/M Mandible Extraneural
Meer et al., 20039
46/F Nasolabial area Extraneural
Damm et al., 200311
26/F Tongue Intraneural
Huguet et al., 200412
64/M Mandible Intraneural
Ide et al., 200413
59/F Gingiva Extraneural
Mentzel and Kutzner, 200514
60/F Lower lip Extraneural (plexiform)
Hornick and Flecther, 20053
15/F Tongue Extraneural
44/M Upper lip Extraneural
10/F Nostril Extraneural
70/M Retrotonsillar Extraneural
37/F Temple Extraneural
Present case 19/F Buccal mucosa and infraorbital area Intraneural/intraneural
*Kusama et al. thought the case should be classified as a variant of neurilemmoma.
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e42 Siponen et al. July 2007
7. of these have been extraneural (soft tissue) variants of
perineurioma. To the best of our knowledge, only 3
cases of intraneural perineuriomas (including the
present one) have been published so far in this location.
Damm et al.11
described an intraneural perineurioma in
a small unnamed nerve of the tongue in a 26-year-old
woman, and Huguet et al.12
reported an intraneural
perineurioma related to inferior alveolar nerve in the
mandible in a 64-year-old man. Intraneural perineurio-
mas almost exclusively affect major nerves, causing
symptoms such as motor and sensory deficits. The
present case is thought to have arisen from branches of
the facial nerve, in the buccal mucosa and in the in-
fraorbital area. The tumors have not caused any motor
or sensory symptoms so far and excision of tumors has
not been attempted after incisional biopsies.
The patient presented in this report has hemifacial
hyperplasia and multiple orofacial intraneural perineu-
riomas. Hemifacial hyperplasia is a sporadic congenital
condition which classically presents as a unilateral
overgrowth of the orofacial soft tissues, bones, and
teeth.23
The condition is also called hemifacial hyper-
trophy, but actually the number of cells is increased
rather than the size of cells. Hemifacial hyperplasia is a
segmental form of congenital hemihyperplasia. Other
forms of congenital hemihyperplasia include simple
(limited to a single digit) and complex (so called hemi-
body hyperplasia). Although usually unilateral, limited
bilateral crossover may occur in hemihyperplasia.24
Other possible findings in patients with hemihyperplasia
include Wilms’ tumor, nevus, pigmentation and telangi-
ectasia of the skin, unilateral enlargement of the cerebral
hemisphere, seizures, mental retardation, and conductive
hearing loss.23,24
A tumor surveillance protocol with ab-
dominal ultrasound examinations is recommended for
children with congenital hemihyperplasia.25
Hemihyperplasia may also be a feature in other syn-
dromes. It is sometimes seen in association with Pro-
teus syndrome, Beckwith-Wiedemann syndrome, or
Schimmelpenning (epidermal nevus) syndrome. It is
possible that there may be overlap of clinical manifes-
tations between hemihyperplasia and these syndromes.
In Proteus syndrome, the patients are said to have
asymmetry of the limbs, overgrowth of hands and/or
feet, lipomas, connective tissue nevi, and vascular and
lymphatic malformations.26
In Beckwith-Wiedemann
syndrome, the patients usually have increased birth
weight, postnatal gigantism, macroglossia, omphalo-
cele, and distinctive ear lobe grooves.26
In Schim-
melpenning syndrome (epidermal nevus syndrome), the
patients have epidermal nevi, of which sebaceous nevi
is said to be the hallmark of the syndrome. Also com-
mon features of Schimmelpenning syndrome are sei-
zures, developmental delay, hemangiomas, kyphosis/
scoliosis, and extention of nevus to the lid.26
Although
the epidermal nevus extended to the lower lid of the left
eye in our patient, the other features common in Schim-
melpenning syndrome were not present.
The management of this patient’s condition was
greatly influenced by the results of the surgical biopsy.
The patient was assumed to have hemifacial hyperpla-
sia, but the possibility of neurofibromatosis was enter-
tained. The knowledge that the patient’s biopsy showed
the intraoral protuberance of the buccal mucosa to be a
perineurioma, which might have arisen from the facial
nerve, allowed the surgical team to counsel the patient
to limit their surgical treatment to bony recontouring,
rather than risking morbid facial nerve–related compli-
cations associated with soft tissue resection procedures.
Perineuriomas are almost exclusively solitary lesions
affecting a single nerve. There is only 1 report of an
intraneural perineurioma affecting 2 nerve roots; no
association with phakomatosis was noted.16
Recently,
Chen et al.27
described a patient with Beckwith-Wiede-
mann syndrome and an intraneural perineurioma of the
wrist. This seems to be the only previously reported
association of perineurioma to a syndrome. We report a
rare, previously undescribed, case of multiple orofacial
intraneural perineuriomas in a young woman with
hemifacial hyperplasia. Whether this represents a coin-
cidental finding or a previously unknown syndrome
remains unclear. However, it seems possible that the
multiple intraneural perineuriomas are related to the pa-
tient’s underlying condition of hemifacial hyperplasia.6
The authors thank Dr. Birkan Ozkan for collecting
some of the reference material and Dr. Jukka Rosberg
for help in analyzing the radiologic images in this
case report.
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Reprint requests:
Maria Siponen
Department of Diagnostics and Oral Medicine
Institute of Dentistry
P.O. Box 5281
90014 University of Oulu
Oulu
Finland
maria.siponen@oulu.fi
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e44 Siponen et al. July 2007
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