Nodular fasciitis and solitary fibrous tumor of the oral region

Tumors of fibroblast heterogeneity

Lewis R. Eversole,a Russell Christensen,b Giuseppe Ficarra,c Lucina Pierleoni,c and J. Philip
Sapp,b San Francisco and Los Angeles, Calif, and Florence, Italy
UNIVERSITY OF THE PACIFIC SCHOOL OF DENTISTRY, UCLA SCHOOL OF DENTISTRY, AND UNIVERSITY OF
FLORENCE

Objective. Fibroblastic proliferations of the oral cavity are extremely varied, yet they share certain features—spindle cell
morphology, collagen synthesis, and fasciculation. Nodular fasciitis is a cellular fibroblastic lesion, uncommonly located in the
oral submucosa, that shows smooth muscle actin (SMA) immunoreactivity. Solitary fibrous tumor expresses a CD34 fibroblast
phenotype. The aim of this study is to report instances of nodular fasciitis and solitary fibrous tumor in the orofacial region and
investigate immunohistochemical markers to compare and contrast fibroblastic phenotypic heterogeneity in these tumors.
Study design. Seven benign cellular fibrogenic tumors intially diagnosed as nodular fasciitis over a 10-year period were exam-
ined. Immunohistochemical markers, including S-100 protein, SMA, CD68, CD34, and vimentin, were used to further charac-
terize these lesions.
Results. All tumors occurred in adults, and the buccal mucosa was found to be the favored site. The spindle cells in these
tumors showed phenotypic heterogeneity both within and between tumors. All were vimentin-reactive and harbored small
populations of CD68-positive macrophage/dendrocytes. Five tumors were SMA-positive and CD34-negative; the tumor in one
case was SMA-negative and CD34-positive, and that in another was SMA-positive and CD34-positive.
Conclusion. Although rare, nodular fasciitis and solitary fibrous tumor arise in oral submucosa, usually in the cheek. The
histopathologic features and immunomarkers indicative of myofibroblastic differentiation are seen in nodular fasciitis, whereas
solitary fibrous tumor is CD34-positive; however, one instance was found to be positive for both markers. All of these cases
harbored subpopulations of CD68-positive cells. Immunomarkers are a valuable adjunct in differentiating nodular fasciitis
from solitary fibrous tumor, yet some tumors may harbor heterogeneous fibroblast phenotypes.
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:471-6)

Fibroblastic proliferations are diagnostically challenging,
given the fact that a wide spectrum of histomorphologic
patterns may be encountered. Common to all of these
lesions is the spindled mesenchymal cell and its synthesis
product, collagen. Pathologic taxonomic schemes take
into account the degree of cellularity, mitotic index, de-
gree of cytologic atypia, and paths of differentiation.1-6
As assessed histopathologically, differentiation hetero-
geneity in fibroblastic lesions includes fibrohistiocytic,
myofibroblastic, periadnexal, and perineural lineages.1 In
the cell biology laboratory, various fibroblast cultures
have been shown to be heterogeneous with regard to
growth characteristics, growth factors, receptors, and
product synthesis of various glycosaminoglycans and
collagen fiber species.7-16 Therefore, the diverse cellular
patterns seen in fibroproliferative lesions could be attrib-
uted to the involvement of specific fibroblast phenotypes.
Pathologic subclassifications have been based on
aUniversity of the Pacific School of Dentistry.
bUCLA School of Dentistry.
cUniversity of Florence.
Received for publication May 12, 1998; returned for revision Sept
15, 1998; accepted for publication Oct 29, 1998.
Copyright © 1999 by Mosby, Inc.
1079-2104/99/$8.00 + 0 7/14/95702
morphologic observations in tumors, and hypotheses
relative to the putative origin of fibroblastic tumors from
cellular subpopulations are teleologic. Table I lists fibro-
blastic cell subpopulations identified in tumors and their
specific immunohistochemical expression characteristics
as obtained in tumor tissue sections.
Two myofibroblastic tumors are well defined: myofi-
bromatosis/myofibroma and the reactive lesion nodular
fasciitis (NF). The origin from or differentiation toward
contractile fibroblasts or myofibroblasts is based on
ultrastructural evidence of intracytoplasmic actin fila-
ments and the demonstration of intracytoplasmic smooth
muscle actin (SMA) or muscle-specific actin by
immunohistochemistry. In the head and neck area, NF is
rarely encountered in the oral cavity; it is somewhat
more common in other head and neck soft tissues
sites.17-21 Instances have been reported in the facial skin,
lips, temporomandibular joint region, pharynx, oral
mucosa, ear, orbit, and parotid gland.22-36 Myofibromas
may be single or multifocal tumors and are more
commonly encountered in children. These tumors are
histologically distinct from NF.1,6
Another fibroblastic proliferation, first described in
the pleural cavity, is solitary fibrous tumor (SFT).37-42
Tumors arising in the head and neck region have been

471
472 Eversole et al ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
April 1999

D
Fig 1. Histopathologic features. A, NF exhibits high degree of
cellularity (hematoxylin-eosin, original magnification ×100).
B, NF shows loose cellular arrangement (hematoxylin-eosin,
original magnification ×100). C, SFT (hematoxylin-eosin,
original magnification ×100). D, Submucosal lesion shows
features of both NF and SFT (hematoxylin-eosin, original
magnification ×100).

Table I. Putative fibroblast subpopulations and their respective benign neoplasms

Phenotype Neoplasm Immunohistochemical marker
Fibroblast Fibroma, fibromatosis Vimentin
Myofibroblast Myofibroma SMA
Myofibromatosis SMA
NF SMA
Fibrohistiocyte Fibrous histiocytoma CD68
Skin periadnexal fibroblast Dermatofibrosarcoma protuberans CD34
SFT CD34
Perineural fibroblast Neurofibroma S-100 protein
Epineurium Neurothekoma EMA
Schwann cell Neurilemmoma S-100 protein
CD, Cluster of differentiation; EMA, epithelial membrane antigen.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Eversole et al 473
Volume 87, Number 4

A
Fig 2. Clinical photograph shows NF in buccal mucosa.

reported, but like NF they are rare in this location.43-48

These lesions are usually patternless but may show a
hemangiopericytoid appearance. When immunohisto-
chemical markers are used, SFTs are vimentin-positive
and CD34-positive. In general, SFT does not stain for
SMA. In normal skin, periadnexal fibroblasts are
immunoreactive for CD34, as are some nerve sheath
tumors and the dermal fibroproliferative tumor
dermatofibrosarcoma protuberans.49 Other neoplasms
composed of specific fibroblast immunophenotypes
B
include nerve sheath tumors and fibrohistiocytic tumors,
the former being positive for S100 protein and the latter
for macrophage markers such as CD68 and MAC387.1
In this article, we report a small series of cases of NF
and SFT occurring in the orofacial region, with an assess-
ment of immunohistochemical differentiation markers.

MATERIAL AND METHODS

From the pathology archives and clinical case records
at the University of California, Los Angeles and the
University of Florence, 7 instances of fibroblastic
tumors meeting the criteria for NF and SFT were
reviewed. Excluded from this study were nerve sheath
tumors, fibromatoses, and myofibroma. The criterion
for NF is a loose spindle cell proliferation with delicate
fascicles of collagen fibers and foci of mucinous ground
substance yielding a “feathered” appearance. The cells
have large fusiform nuclei without pleomorphism, and
mitotic figures are rare. The lesion is nodular and
demarcated, yet it tends to infiltrate adjacent skeletal
muscle fibers and fat. The degree of infiltration at the
margins is not extensive.17-21
SFT may be confused with NF inasmuch as it is a
fibroblastic proliferation that is represented by spindle
cells and shows no distinct growth pattern, though
sometimes a hemangiopericytoma pattern is seen.
Unlike NF, SFT is characterized by the absence of a
C
Fig 3. Immunomarkers for NF. A, SMA positivity is shown by
tumor cells (DAB, original magnification ×200). B, CD34
stains perivascular cells only (DAB, original magnification
×200). C, CD68 macrophages are scattered throughout (DAB,
original magnification ×200).
nodular pattern, and mature collagen is commonly
encountered. The margins may infiltrate adjacent struc-
tures. Malignant forms have also been described, and
they also exhibit CD34 immunoreactivity.37-40
All cases were retrieved from archived, formalin-fixed,
paraffin-embedded material. Sections 5 µm in thickness
were obtained and processed for immunohistochemical
474 Eversole et al ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
April 1999

A A

B B

C C
Fig 4. Immunomarkers for SFT. A, SMA stains vessels only
(DAB, original magnification ×200). B, Tumor cells are Fig 5. Immunomarkers for hybrid fibrous tumor. A, Strong
strongly positive for CD34 (DAB, original magnification positivity is seen for SMA (DAB, original magnification
×200). C, CD68 cells are found throughout and in clusters ×200). B, CD34 positive cells are abundant (DAB, original
(DAB, original magnification ×200). magnification ×200). C, Scattered CD68 cells are present
(DAB, original magnification ×200).

marker studies through use of a streptavidin-peroxidase

detection method with diaminobenzidine (DAB) chro-
mogen and Gill’s hematoxylin counterstain. All slides
were pretreated with an antigen retrieval system (DAKO)
in which citrate salt in a boiling water bath was used for
20 minutes. In addition, those sections processed for
vimentin were predigested with 0.1% trypsin in phos-
phate-buffered saline for 30 minutes. The monoclonal
antibody markers used in this investigation included S-
100 protein, SMA, CD34 (Biogenix, prediluted),
vimentin (Monosan, diluted 1:20), and CD68 (DAKO,
diluted 1:50).The positive control sections for CD34,
SMA, S-100, and CD68 were dermatofibrosarcoma
protuberans, myofibroma, neurilemmoma, and benign
fibrous histiocytoma, respectively. Parallel sections were
mock-treated by incubation with phosphate-buffered
saline with 1:500 nonimmune mouse serum.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Volume 87, Number 4
RESULTS
On the basis of histologic features, 1 case was desig-
nated SFT and 6 cases were designated NF, although 1
of these 6 cases was more fibrous, with features of both
NF and SFT (Fig 1). The buccal mucosa was affected
in 4 instances and appeared as an ulcerated or nonul-
cerated nodule (Fig 2). All patients were adults; four
were female and three were male. The mean followup
was 3 years, and there was no history of recurrence in
any of the cases after excision.
All cases diagnosed as NF showed the same immuno-
histochemical marker profile. All exhibited variability
in vimentin positivity from weak to strong. SMA was
seen in fibroblastic cytoplasmic processes, and the
staining was generally more intense in the cellular
forms of NF. CD34 stained small vessels within the
lesional tissue and scattered CD68 cells, both polygonal
and spindle, were found in a patchy distribution
throughout (Fig 3). S-100 was negative in all but one
instance of NF; in this single case, the tumor was
located directly below the surface mucosal epithelium,
and S-100 dendritic cells were identifiable in the epithe-
lium and diffusely scattered throughout the tumor.
The spindle cells in the single case of SFT failed to
stain for SMA, although perivascular cells were found
to be positive. The spindle cells were found to be
strongly positive for vimentin and CD34. Scattered
nests of polygonal cells and occasional spindle cells
were positive for CD68 (Fig 4). No S-100 immunore-
activity was observed.
A final case showing features of both NF and SFT
exhibited positivity in the spindle cell population for
vimentin, SMA, and CD34; scattered CD68-positive
cells could also be identified in this hybrid tumor (Fig
5). S-100 was found to be negative.
DISCUSSION
Spindle cell fibrogenic neoplasms can be benign or
malignant, and their diagnosis is based on histopatho-
logic patterns augmented with immunohistochemical
marker studies.1,2 All are presumed to arise from fibro-
blasts; however, there are diverse patterns of growth and
variations from one tumor to another regarding nuclear
morphology, collagen fiber thickness, cellularity, cyto-
plasmic morphology, and immunophenotype. A malig-
nant diagnosis is usually assigned to those tumors with
either high cellularity or nuclear pleomorphism with
mitotic figures. Although some fibrogenic tumors show
specific site predilections within the body, almost all
have been reported to occur within the head and neck
region.1-7 Two benign fibrogenic tumors of the head and
neck that are occasionally located in the submucosa of
the upper aerodigestive tract are NF and SFT.22-36,43-48
Both of these fibroproliferative tumors are composed of
Eversole et al 475
spindle cells and collagen fibers. NF is compacted into
multiple nodular foci with a loose, “feathered,” or tissue-
culture pattern and margins that may infiltrate contiguous
tissues; SFT, on the other hand, is patternless and its
collagen fibers are thicker and more mature than the deli-
cate fibers observed in NF. Typically, NF is vimentin-
immunoreactive and SMA-immunoreactive, whereas
SFT is actin-negative and CD34-positive.1,21,37,40
SMA is found not only in NF but also in other myofi-
broblastic or myogenous spindle cell tumors, including
myofibroma, myofibromatosis, and leiomyoma.1
CD34 labels spindle cells in dermatofibrosarcoma
protuberans and some nerve sheath tumors as well as in
SFT.48 The cases reported here did not show
histopathologic features of neurogenic fibroprolifera-
tive tumors, and none of these cases were immunore-
active for S-100, with the exception of a single tumor
that was populated by S-100 dendrocytes assumed to
represent Langerhans cells. All of our cases of NF and
SFT harbored populations of CD68-reactive polygonal
and spindle cells, yet histologically these lesions did
not show features of fibrous histiocytomas.
A single case with histologic features of both NF and
SFT exhibited positivity for both CD34 and SMA. The
benign fibrous tumors in this group appear to be pheno-
typically diverse, with a tendency for myofibroblasts in
some (NF) and CD34-positive fibroblasts in others
(SFT); however, they also contain fibrohistiocytes, as
defined by immunoreactivity with anti-CD68. Benign
fibrogenic tumors of the head and neck are probably
histopathologically diverse as a consequence of pheno-
typic heterogeneity in fibroblast cell populations.
Although one phenotype may predominate, some
tumors may be composed of more than one phenotype.
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Reprint requests:
L. R. Eversole, DDS
University of the Pacific
School of Dentistry
Department of Oral and Maxillofacial Pathology
2155 Webster Street
San Francisco, CA 94115