Article Type : Review Article
Authors : Bajaji A
Keywords : Fibrous dysplasia; Osteogenesis
Fibrous dysplasia is a
benign bone lesion demonstrating intramedullary fibro-osseous proliferation
occurring on account of modified osteogenesis. Fibrous dysplasia was initially
scripted by Lichtenstein and Jaffe in 1942 and chronicled as “Jaffe-Lichtenstein
syndrome” [1]. Fibrous dysplasia was also designated as osteitis fibrosa or
generalized fibrocystic disease of bone. Fibrous dysplasia can incriminate a
singular bone, denominated as monostotic fibrous dysplasia or multiple bones,
termed as polyostotic fibrous dysplasia. The developmental bony disorder is
associated with failure to configure mature lamellar bone. Tumefaction is
comprised of immature woven bone and fibroblast-like, spindle - shaped cells.
Absence and arrested maturation of woven bone is associated with distinct
clinical or syndromic manifestations. Age
of incriminated subjects, occurrence of non-aggressive lesions with predilection
for diaphysis of long bones and a “ground glass” matrix on radiography are
features indicative of fibrous dysplasia. Cogent sampling of bone is
necessitated in order to exclude malignant metamorphosis where clinical
representation and imaging studies are inconclusive. Malignant metamorphosis
into a sarcoma is exceptional and may be engendered with previous exposure to
irradiation.
Disease Characteristics
Fibrous dysplasia
displays an incidence of roughly 1: 5,000 to 1:10,000 individuals and comprises
of around 5% of benign bone lesions. The condition is commonly discerned in
children or young adults and usually manifests before 30 years. Polyostotic
fibrous dysplasia usually represents in childhood. Fibrous dysplasia can be
incidentally discovered in adults subjected to imaging for unrelated
conditions. A specific gender predilection is absent and male are incriminated
in equivalent proportion as females [2,3].
Monostotic fibrous
dysplasia is preponderant and lesions can arise within the ribs, long bones as
femur and craniofacial bones as maxilla or mandible although no site of tumour
emergence is exempt. Lesions are uncommon within the hands, sternum and
vertebral column [2,3].
Fibrous dysplasia occurs
due to developmental arrest within the cortical bone with consequent emergence
of irregular trabeculae of woven bone and immature, fibroblast-like spindle-shaped
cellular aggregates. Fibrous dysplasia is associated with missense or gain in
function mutation within the guanine nucleotide-binding protein /?-subunit
(GNAS1) gene situated upon chromosome 20q13.2.3. Subsequent overexpression of
Gs? protein and enhanced downstream activity of adenyl cyclase is observed.
Activation of c-jun, c-fos and Wnt/? catenin accompanies activation of Gs?. The
activating mutation engenders an aberrant proliferation of fibrous tissue.
Variable manifestation of GNAS mutations contribute to diversity of clinical
representation [2,3].
Monostotic fibrous
dysplasia is a frequent variant and comprises of nearly 75% to 80% instances
[2,3]. Fibro-osseous tissue replaces normal bone thus incurring complications
such as pathological fracture and compression of adjacent soft tissues or
neurovascular bundles. Malignant metamorphosis is exceptional and is discovered
in around <1% subjects. Malignant conversion may arise secondary to
radiation therapy adopted for treating lesions confined to distant sites [2,3].
Clinical Elucidation
Fibrous dysplasia is
associated with gradual expansion of bone on account of proliferation of
irregular trabeculae of woven bone devoid of peripheral accumulation of
osteoblasts admixed with a fibrous tissue component composed of bland,
spindle-shaped cells. Lesions are intramedullary and lack destruction of
superimposed cortical bone. Monostotic fibrous dysplasia is frequently
asymptomatic. Fibro-osseous replacement of incriminated bone can engender
pathological fracture, particularly within weight-bearing bones or upper
extremities in athletic, physically active individuals [4,5].
Fibrous dysplasia is
associated with diverse conditions such as
·
McCune-Albright
syndrome which is an exceptional disorder demonstrating frequently unilateral
polyostotic fibrous dysplasia along with cutaneous pigmentation and endocrine
dysfunction, generally manifesting as female precocious puberty [4,5].
·
Mazabraud
syndrome is an extremely exceptional variant demonstrating polyostotic fibrous
dysplasia associated with singular or multiple intramuscular or soft tissue
myxomas [4,5].
Monostotic fibrous
dysplasia is frequently asymptomatic. Bone pain is occasional and may enhance
with occurrence of pathological fracture arising due to minimalistic trauma and
appearing as initial clinical manifestation. Pregnant female subjects display
an enhanced possible occurrence of pain and pathological fracture. Features
such as bone tenderness, bony protuberances, osseous asymmetry, associated
endocrine disturbances and dermatological manifestations require evaluation
[4,5]. Assessment of skeletal deformity, bone asymmetry, leg length
discrepancy, classic “shepherd’s crook” deformity of proximal femur or facial
involvement with orbital asymmetry is necessitated. Additional possible facial
manifestations are proptosis, frontal bossing or mandibular enlargement [4,5].
Severe bone deformity is accompanied by bowing, musculoskeletal dysfunction or rapid progression of osteoarthritis. Lesions of spine predispose to scoliosis and subsequent functional impediment. Craniofacial tumefaction delineates associated deficits of cranial nerves such as loss of vision or hearing and mandate appropriate evaluation. Hereditary forms of fibrous dysplasia such as cherubism are accompanied by a pertinent family history. Malignant transformation into a sarcoma may be significantly delayed and can be assessed when associated with aggressive evolution of lesions [4,5].Histological Elucidation
On gross examination, a
well circumscribed, cortical lesion is circumscribed by a sclerotic perimeter.
Expansion of lesion results in an attenuated bone cortex [6,7]. On microscopy,
irregular, branching and anastomosing trabeculae of woven bone appear devoid of
a peripheral osteoblastic layer. Particularly, "C" and "S"
shaped trabeculae of woven bone can be exemplified [6,7].
Fibrous dysplasia is
composed of immature collagen and immature bone trabeculae intermingled within
a fibrocellular matrix. Osteoblastic maturation arrest contributes to an
absence of osteoblastic rimming of trabeculae of woven bone. Therefore,
metamorphosis from normal bone to aberrant bone is sudden and abrupt [6,7].
Fibrous tissue stroma commingled with the bone trabeculae is composed of bland,
spindle-shaped cells. Cytological atypia and mitotic activity is exceptional.
Intervening stroma may depict foci of myxoid and adipose tissue metaplasia. Secondary
aneurysmal bone cyst-like alteration can be enunciated [6,7]. Additionally,
lesions of fibrous dysplasia may undergo cartilaginous metaplasia or aneurysmal
bone cyst-like modification [6,7].
Immune Histochemical Elucidation
Majority (90%) of bone
forming neoplasms express SATB2. Fibrous dysplasia is immune non-reactive to
keratin [2,3].
Differential Diagnosis
Fibrous dysplasia
incriminates diverse osseous sites and a variable representation upon imaging.
Therefore, the neoplasm requires segregation from various benign and malignant
neoplasms such as central and parosteal osteosarcoma which are destructive, low
grade, gradually progressive bone neoplasms. Characteristic amplification of
MDM2 gene is exemplified [8,9]. Central osteosarcoma is a tumefaction depicting
cellular permeation with replacement of medullary spaces, erosion of native
bone trabeculae, cortical destruction and infiltration of adjacent soft tissue.
Neoplastic cells are pleomorphic, hyperchromatic and depict multiple morphologies
as epithelioid, plasmacytoid, spindle-shaped, miniature spherical, clear cell
and multinucleated tumour giant cells. Foci of neoplastic osteoid are deposited
upon pre-existing bony trabeculae. Non neoplastic giant cells may be scattered
within the tumour parenchyma [8,9]. Parosteal osteosarcoma is a gradually
progressive surface neoplasm originating from extraneous periosteal layer and
contributing to roughly 65% of surface osteosarcomas. The low grade,
hypo-cellular neoplasm is composed of well-formed bony trabeculae, osteoid,
cartilaginous component and a fibrotic, malignant, spindle-shaped cellular
stroma. Mitotic figures or osteoclast-like, multinucleated giant cells are
absent.
Ossifying fibroma is
composed of irregular bony trabeculae, akin to fibrous dysplasia. However,
rimming of trabeculae with osteoblasts is prominent [8,9].
liposclerosing
myxofibromatous tumour (LSMFT) is a condition which simulates fibrous dysplasia
on clinical and morphological grounds. Characteristically, activation of
protein G is observed. The neoplasm is typically located within proximal femur.
Tumefaction depicts an amalgamation of diverse histological patterns such as
curvilinear trabeculae of woven bone intermingled within a pauci-cellular
myxofibromatous tissue. Additionally, foci of ossification and adipose tissue
or cartilaginous metamorphosis are delineated [8,9].
Additionally, radiological
expression of monostotic fibrous dysplasia requires a segregation from
conditions such as simple bone cyst, giant cell tumour, fibroxanthoma,
osteoblastoma, haemangioma, osteofibrous dysplasia or Paget’s disease [8,9].
Investigative Assay Plain
radiography contributes significantly to cogent discernment and assessing
disease extent of fibrous dysplasia. Upon plain radiography, singular or
multiple, well circumscribed intramedullary lesions are encompassed by zones of
sclerosis. Tumefaction is usually confined to metaphysis or diaphysis and
demonstrates a “ground glass” appearance. Expansion of lesion is associated
with attenuation of superimposed bone cortex [10,11]. Computerized tomography
(CT) and magnetic resonance imaging (MRI) can be optimally employed to
demarcate adjunctive bone lesions, assessment of soft tissue injuries secondary
to fractures, neurovascular complications arising from craniofacial lesions and
malignant metamorphoses. CT and MRI may also be adopted for assessing endocrine
dysfunction engendered by adrenal hyperplasia, thyroid nodules and pituitary
neoplasms [10,11]. Classically, plain radiographs and computerized tomography
(CT) of bone lesions delineates an intrinsic “ground glass” matrix. However,
aforesaid appearance may vary on account of lytic or sclerotic tumour
components, probable bone expansion and attenuation of bone cortex. Bowing
deformities such as femoral shepherd's crook deformity, discrepant limb length
and short stature secondary to premature fusion of growth plates can be
distinguished with precise imaging [10,11]. Bone scan can exemplify enhanced
uptake of Technetium-99m radiotracer within polyostotic lesions which aids the
assessment of disease extent [10,11].
Pertinent evaluation of
tumour tissue may be mandated in lesions where imaging features indicate
malignant metamorphosis [11]. Alkaline phosphatase levels are elevated in
progressive neoplasms [10,11].
Therapeutic Options
Fibrous dysplasia can be managed conservatively. Appropriate management of
clinical symptoms is usually sufficient. Instances associated with pathological
fracture or bony deformity can be subjected to surgical intervention. Asymptomatic
monostotic fibrous dysplasia can be periodically monitored and does not require
therapy [10,11]. Bisphosphonates are appropriately employed in order to
alleviate bone pain and disease-associated osteoporosis in adults. Bisphosphonates
prohibit osteoclastic bone resorption and conserve cortical bone mass, thereby
reducing possible occurrence of fractures [10,11].
Surgical management is
employed for treating symptomatic fibrous dysplasia and is achieved by
prophylactic internal fixation of pathological fractures, especially within
weakened weight-bearing bones [10,11]. Additionally, surgical manoeuvers such
as correction of extremity and spine deformities or limb length discrepancies
may be adopted. Craniofacial surgery can relive symptoms of nerve compression
[10,11]. Cogent surgical procedures are curettage, bone grafting or insertion
of fixatives such as metallic rods, plates and screws [10,11].