Fibrous Dysplasia: Clinicopathologic Presentation of 36 Cases
Mine ÖZŞEN1, Ülviye YALÇINKAYA1, Muhammed Sadık BILGEN2, Zeynep YAZICI3
1Department of Surgical Pathology, Uludag University Faculty of Medicine , BURSA, TURKEY
2Department of Orthopedics, Uludag University Faculty of Medicine , BURSA, TURKEY
3Department ofRadiology, Uludag University Faculty of Medicine , BURSA, TURKEY
Keywords: Fibrous dysplasia, Bone, McCune-Albright syndrome
Fibrous dysplasia is a slowly progressing bone lesion resulting from displacement of the normal medullary bone with abnormal
fibroosseous tissue. The aim of this study was to assess the similarities and differences of our cases in relation to published reports.
Material and Method: In this study, the archives of the Uludag University Medical Faculty Department of Pathology were screened for fibrous
dysplasia cases between 2004 and 2016.
Results: Within the mentioned period, there were 36 cases diagnosed as fibrous dysplasia. There were 21 male, and 15 female cases with an
average age of 27.8±14.8 years (range 7-79 years). The most frequently affected sites were femur, costae, and craniofacial bones. There was one
case localized to metacarpal bone, a very rare affection site. There were 4 polyostotic cases including 2 cases of McCune-Albright syndrome.
Pelvic bone was affected in the polyostotic type, similar to published reports. Unlike former reports, however, long tubular bones were affected
in male patients in our series. In our series, 32 cases had classical fibrous dysplasia, 3 cases had fibrocartilaginous, and one case had fibroosseous
variants. Four cases localized to costae were accompanied by aneurysmal bone cyst. The presenting symptom was pathological fractures in a
total of 4 cases, 3 localized to the femur, and 1 to the costa. Recurrence occurred in 5 cases treated with curettage. Two of the monostotic fibrous
dysplasia cases developed malignant transformation into osteosarcoma.
Conclusion: We conclude that our series of fibrous dysplasia cases have slight differences and mainly similar characteristics with the series
reported earlier, when all features are taken into consideration.
Fibrous dysplasia (FD) was first defined as an anomalous
dysplastic development of the bone in 1938. The etiology
of this slow developing lesion with displacement of normal
medullary bone with abnormal fibroosseous tissue,
however, is not clear yet (1-3). A possible mechanism may
be the polyzygotic activated mutation of GNAS1 gene
localized at 20q13 chromosome within somatic cells during
embryogenesis (4, 5). FD may present as either monostotic
(i.e. effecting a single bone), or polyostotic (i.e. effecting
multiple bones) in the clinical setting. The polyostotic
form may be accompanied by various endocrine disorders
as in McCune-Albright syndrome (1). Prognosis of FD
is usually good and biological behavior of the tumor is
unrelated to localization. Local recurrence may occur
following inadequate surgical therapy. FD localized to
long bones is easy to diagnose in light of adequate clinical
and radiological information and typical microscopical
findings. Histopathological findings of FD localized to craniofacial bones, however, are more challenging and
The aim of this study was to report clinicopathological
properties of our series, and to assess the similarities
and differences between our findings and former reports
concerning this developmental disorder presenting with
various forms and predilection sites.
In this study, the archives of the Uludag University Medical
Faculty Department of Pathology were screened for FD
cases between 2004 and 2016. The hematoxylin-eosin
stained slides were re-evaluated and the histopathologic
findings were noted. The cases were summarized according
to age, gender, site, and clinicopathological properties in a
retrospective setting. Special attention was paid to tumors
of craniofacial bones, costae, long bones, and flat bones and
their clinicopathological findings.
Within the mentioned period, there were 36 cases
diagnosed as FD (Table I
). There were 21 male (58.4%), and
15 female (41.6%) cases with an average age of 27.8+14.8
years (range 7-79 years). FD was diagnosed at a total of 39
different sites in these 36 cases including 15 femur (38.4%),
9 costae (23%), and 9 craniofacial bone (23%). Of all cases,
4 were polyostotic (11.1%). All pelvic bone tumors were of
polyostotic form. Ten of the 16 cases with long tubular bone
tumors were male.
The presenting complaint was pain in 17 (47.2%), and
localized swelling in 9 (25%) of the cases. Clinically
pathological bone fractures were encountered in 4 (11.1%)
cases. Three of these cases were localized to femur, and the
remaining 1 case was localized to costa. Two cases were
under surveillance for McCune-Albright syndrome. The
first case was a 13-year-old female patient presenting café
au lait spots, osteoporosis, and hyperandrogenism. Her 3
siblings had similar symptoms. The case was diagnosed
as FD following curettage of the lytic lesion localized
in her right femur, expressing benign features. Detailed radiological examination revealed multiple lesions in
the maxilla and craniofacial bones. The second case
was a 7-year-old female patient. She also had café au lait
spots and anomalous secondary sexual development. She
presented with walking disorder following a trauma, and
had a pathological fracture in left femur and multiple bone
lesions. She was diagnosed as FD following curettage and
bone grafting. She had lesions in skull bones, both lower
limbs, both hands and feet, metacarpal and carpal bones,
tarsal bones, and pelvis.
Radiological images of 12 cases were obtained from the
archive. All had expansile yet non-destructing mass lesions
appearing as ground glass density, benign in nature (Figure
Click Here to Zoom
|Figure 1: A-C) Frontal radiograph of
the thighs shows bilateral coxa vara
angulation of the proximal femurs
(shepherds crook deformity). Bones
are abnormal with mixed sclerosis
and lucency and remodeling, which is
particularly evident at the left femur
and tibia and some phalanges and
metacarpals. D) Lateral radiograph of
the skull demonstrates thickening and
A B sclerosis of the frontal calvarium.
Histopathologically 32 cases were classical FDs. Microscopically
they show fold of irregular, anastomosing immature
bone trabeculae scattered within a fibrous tissue without
cytological atypia. There were no osteoblastic cell surrounding
this areas expressing metaplastic woven bone features.
In 3 cases due to benign cartilage nodules and enchondral
ossification accompanying classical FD appearance the diagnosis was fibrocartilaginous dysplasia. All of these
cases were localized in femur and two were of polyostotic
form. An 8-year-old male patient had a metacarpal lesion
localized at the third metacarpal bone in his left hand showing
psammoma-like cementoid bodies and was diagnosed
as fibroosseous dysplasia. In four cases there were aneurysmal
bone cysts all localized in costae (Figure 2A-D).
Click Here to Zoom
|Figure 2: A) Typical low-power appearance of fibrous dysplasia. The lesion contains branching and anastomosing, circular and irregular
immature bone trabeculae (Chinese letters) scattered within a fibrous tissue (H&E; x40). B) Secondary aneurysmal bone cyst areas with
fibrous dysplasia (H&E; x40). C) Fibrocartilaginous dysplasia, broad islands of cartilage (H&E; x40). D) Fibroosseous dysplasia, the
tumor produces spherical masses of osteoid (H&E; x40).
The first line of treatment consisted of curettage and bone
grafting in 18 (50%), radical resection in 8 (22.2%), and
surveillance following biopsy in 7 (19.4%) of the cases. No
problems were encountered during surveillance of these
7 cases. Three cases were referred to our department for
consultation from other centers.
In five of the cases, recurrence was found (13.8%). Treatment
of recurrence was curettage in all cases (Table II).
In two cases (5.5%), malignant transformation into
osteosarcoma was seen 9 months and 5 years following
initial diagnosis and treatment, and both were monostotic
FD (Figure 3A-D). These cases did not receive radiation
therapy. One of the cases was a 29-year-old male with a lesion localized in the distal portion of right femur. This
patient underwent resection at the distal femur level, and
was scheduled for chemotherapy. Unfortunately the patient
passed away 5 months following malignant transformation
due to disseminated lung metastases. The other case was
a 42-year-old female with a lesion localized in the distal
portion of right humerus. She suffered from a swelling at
her right elbow for two years. Radiological examination
revealed an expansile, well circumscribed, radiolucent
lesion. Tru-cut biopsy of the lesion revealed FD. The
lesion started to grow 9 months following initial diagnosis
leading to destruction in the cortical portion of the bone.
She underwent resection at the distal humerus level. The
specimen was diagnosed as low grade osteosarcoma.
In order to exclude the differential diagnosis of FD like
osteosarcoma since the beginning, immunohistochemical staining of the initial slides with CDK4 and MDM2 had
negative results. Ki67 proliferative index was high in the
resection specimen unlike the initial biopsy (Figure 4A, B).
Re-evaluation of the initial radiological images revealed no
features suggesting malignancy. The medullary tip and the
surrounding surgical margins were intact. She is still alive
and under surveillance.
Click Here to Zoom
|Figure 3: A) Malignant transformation of fibrous dysplasia, fibrous dysplasia areas (FD) and osteosarcomatous areas (OS) (H&E;
x10). B) Areas of fibrous dysplasia; curvilinear trabeculae of metaplastic woven bone in hypocellular, fibroblastic stroma (H&E; x40).
C) Areas of sarcoma contains malignant spindle cells arranged in intersecting fascicles and there are foci of necrosis (H&E; x40).
D) Osteosarcomatous areas composed of mineralized neoplastic bone and tumor cells. The tumor cells show moderate cytological atypia
Click Here to Zoom
|Figure 4: A) Low Ki67 proliferative index
in the initial biopsy material in the case
presented with malignant transformation
(IHC; x200). B) High Ki67 proliferative
index in osteosarcomatous areas in the
A B resection material (IHC; x200).
The real incidence of FD is hard to determine due to
asymptomatic cases. Yet, it is well accepted that this clinical
entity compromises 5-7% of all primary bone tumors (6, 7).
The two genders are affected equally, and the peak incidence
is in adolescents and young adults (1-3). Our series included
mostly young male cases.
Although FD may affect simply every bone in the skeleton,
femur, costae, and the craniofacial region are more
frequently involved (8). Vertebrae, pelvic bones, radius,
fibula, and short tubular bones of hand and foot are rarely
affected (2, 6, 8). Metacarpal involvement is extremely rare
and is reported as sporadic cases only (9). In a multi-central
clinicopathological study supported by the European
Pediatric Orthopedic Society, the femur was the most
frequent site of the lesion, followed by the tibia. Fourteen
cases out of 23 monostotic FD, 9 cases out of 10 polyostotic
FD, and all 20 cases with McCune-Albright syndrome
had lesions localized in the femur (10). In our series, the
femur was involved in 15 out of 36 cases, followed by the
craniofacial bones and costae. There was one case with metacarpal involvement, and in a case with McCune-
Albright syndrome the short tubular bones in both hands
and feet are involved. In a report from the Mayo Clinic,
jaw, the long bones and flat bones are mainly involved in
female patients, whereas the costae and cranial bones are
mainly involved in the male (2). In our series, male cases
had mainly long tubular bone involvement.
FD may be divided into two somewhat overlapping forms
as monostotic, and polyostotic. The former has an incidence
of 70-80%, while the latter may be seen as frequent as 20-
30% (1-3). In our series, four cases (25%) were polyostotic.
Craniofacial bones and especially the maxilla, costae,
and long bones are frequently affected in the monostotic
form. Pelvic bones and scapula are frequently affected in the polyostotic form (1-3). In our series, pelvic bone
involvement was found in polyostotic FD cases.
The most frequent presenting complaint is pain, followed
by swelling, and pathological bone fractures. The
complaints depend on the age, site, accompanying lesion,
and endocrine disorder (5). In a study by Chapurlat et al,
the authors reported that pain was more frequent among
adult patients than children; 67% of the patients suffered
from pain at the involvement site (11). The monostotic
form is usually asymptomatic, whereas the polyostotic form
leads to deformation in craniofacial bones and femur (i.e.
the shepherds crook), and fractures. Pathological fractures
and bending is frequent in load bearing bones. Polyostotic
FD accompanied by various endocrine disorders, irregular
skin pigmentation, and early sexual maturity is called
McCune-Albright syndrome. Another syndrome is called
Mazabraud syndrome in which FD is accompanied by
intramuscular myxoma (1-3, 12). In our series, the most
frequent complaint was pain as well. This complaint was
followed by swelling and pathological bone fractures. Of
the four cases with pathological fractures, 3 had lesions in
the femur, the other was localized in the costa.
Radiologically FD presents as an expansile, intramedullar
lesion with ground glass appearance within a well circumscribed
cortical contour (13). Secondary changes such as cyst
formation or fractures may be present. Sometimes punctate
or focal calcification may indicate cartilage differentiation, and this form is called fibrocartilaginous dysplasia (1). We
were able to find radiological images of only 12 cases from
the archive, and all had expansile and non-destructing mass
lesions showing ground glass density.
Microscopically the tumor presents narrow, circular and
usually shaped as a fish hook, irregular, immature bone
trabeculae scattered within a fibrous tissue showing various
degrees of cellularity. This net-like bone is found in various
amounts and shape and resembles the Chinese letters. These
trabeculae are not surrounded by osteoblasts, and thus they
do not evolve into mature bone. The number, distribution
and maturity of bone trabeculae differ from area to area and
case to case. Mature lamellar bone trabeculae may be present
in FD cases particularly localized in the jaw. In cases with
pathological bone fracture or recurrence following initial
interventions, osteoblasts may be present surrounding the
reactive bone trabeculae, as well. In some instances, bone
formation may be prominent. In the fibrocartilaginous
type, benign chondral nodules and enchondral ossification
may be present. Focal cementoid bodies may be found
in lesions localized in skull bones. Such lesions are
called fibroosseous dysplasia and may be mistaken for
meningiomas. Aneurysmal bone cyst formation-like cystic
degeneration, hemorrhage, and foamy histiocytes may be
present in some cases. Sometimes intralesional hemorrhage
may lead to osteoclastic reactions. And finally, there may
be diffuse myxoid degeneration in the fibrous stroma. All
these secondary changes are usually seen in lesions present for a long time (1-3, 13, 14) . In our series, 4 cases had
secondary aneurysmal bone cyst, all localized in costae.
One case localized in the costa showed diffuse myxoid
degeneration, and a case localized in the metacarpal bone
presented with cementoid bodies. There were 3 cases of
fibrocartilaginous FD involving the femur, 2 polyostotic
and one in monostotic form.
Malignant transformation is reported in 0.4-6.7% of FD
cases in the literature. Such transformation may lead to osteosarcoma,
chondrosarcoma, and fibrosarcoma formation
and is more frequent in the polyostotic form. Radiation
therapy has an accepted effect on malignant transformation
(15-17). In our series two cases presented with malignant
transformation into osteosarcoma, one after 9 months and
the other 5 years following the diagnosis. They were both
monostotic, and had no former history of radiation therapy.
The differential diagnosis of FD includes various entities
such as osteofibrous dysplasia, non-ossifying fibroma
when excessive foamy histiocytes are present, desmoplastic
fibroma when a fibrous component is prominent, healing
fracture, Pagets disease, low grade osteosarcoma resembling
fibrous dysplasia, enchondroma when the chondroid
component is prominent, and growth plate. The enchondral
ossification surrounding the cartilaginous islands in fibrocartilaginous
dysplasia is disorganized unlike the growth
plate. There are typical FD areas among these cartilaginous
islands. Presence of fracture may lead to misdiagnosis, but
typical FD areas along with areas of enchondral ossification
and organization of osteoblasts around lamellar bone trabeculae
are of help in the diagnosis. Osteofibrous dysplasia
is localized in the cortex unlike FD. The fibrous stroma
presents a storiform pattern with osteoblasts surrounding
bone trabeculae and single epithelial cells positive for cytokeratin.
There is a zonal structure where the periphery of
the lesion is more mature with mineralized bone trabeculae.
The most important differential diagnosis is with low
grade osteosarcoma. Hypercellularity, nuclear atypia and
pleomorphism, increased mitotic activity, and high Ki67
proliferative index suggest malignancy. The absolute indicators
of malignancy include permeative growth between
the cortical/spongy bone trabeculae, infiltration, and presence
of soft tissue involvement (1-3, 6). Immunostaining
with MDM2 and CDK4 is also of help in distinguishing
low grade sarcoma from benign fibroosseous lesions. The
sensitivity of these markers are reported to be 89-100%,
and the selectivity may be between 97.5-100% (18, 19). We
performed MDM2 and CDK4 immunostaining in 6 of our
cases with hypercellularity and slight pleomorphism with
negative results. In these cases the Ki67 proliferative indices
were low, as well.
Prognosis is well in FD, and is generally unrelated to
biological behavior and anatomic site. Yet, it may lead to
deformities and uneven extremities, affect cranial nerves,
and polyostotic form may even cause paralysis. Malignant
transformation into sarcoma indicates poor prognosis, and
lung metastases are frequent (1, 15-21).
FD is usually diagnosed based upon radiological images, and
biopsy is unnecessary in typical cases. The best treatment
in asymptomatic and undeformed cases is surveillance.
In polyostotic cases and when surgical treatment is not
proper, medical treatment is advised to end the pain,
stabilizing the lesion, and support bone structure to avoid
fractures. Bisphosphonates are preferred in such treatments
at various dosages (21). Surgical therapy is preferred in
treating deformities, to avoid pathological fractures, and
treating symptomatic lesions. Treatment options include
radical resection, conservative local resection, or curettage.
Sometimes internal fixation may be needed while treating
deformities (20, 22, 23). Pathological fractures may be
treated with curettage and bone cement installation. Many
suggest that bone cement is a temporary solution and that
bone grafting should be preferred especially in children.
Consequently the graft may be removed by the tumor
and the tumor may recur. This resorption is infrequent in
the adult cases. The growth of lesions in FD are expected
to slow down following puberty. Yet in craniofacial bones
growth may speed up secondary to aneurysmal bone cyst
and biopsy in this period. The growth hormone excreted
in McCune-Albright syndrome may also lead to growth of
the lesions. Thus, surgical procedures are better performed
after puberty if not vital (20-23). Li et al. reported that
surgical therapy should be combined with medical therapy
in pediatric patients with monostotic type FD involving
immature skeletal structures (22). Incomplete resections
lead to recurrence in especially aggressive tumors (20).
Recently, the GNAS gene mutation has been reported to be
positive in 93% of all FD cases. The possible mechanism
of FD depends on the polyzygotic activation mutation of
GNAS1 gene in somatic cells. There is also a relationship
between inadequate curettage and recurrence. This may be
due to the fact that all mutant cells cannot be removed with
curettage. Radical excision should be preferred in order to
avoid recurrence (20-23). In our series, 16 cases underwent
curettage and bone grafting, and 6 had radical resection. All
5 recurrences were seen following curettage.
FD is a rare bone tumor, caused by interruption of regular
bone growth, and is usually benign in nature. Proper
diagnosis and personalized treatment planning may prevent
recurrence and malignant transformation.
CONFLICT of INTEREST
The authors declare no conflict of interest.
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