Abstract:
Introduction:Fibrous
dysplasia is an uncommon bone disease that has a rare but clear
potential for malignant transformation. The treatment of fibrous
dysplasia is limited to maintenance of maximum bone density via
diet, exercise and therapeutic medications (i.e. bisphosphonates),
as well as surgical reinforcement of bowing deformities and
fractures as they occur. Currently, there is no therapy for
preventing advance of the disease or malignant transformation.
In light of recent development in novel targeted therapy to
HER2, epidermal growth factor receptor (EGFR) and CD 117 (C-KIT)
have shown therapeutic promise in many neoplasms, both benign
and malignant; we investigated the expression of these markers
in six cases of fibrous dysplasia in hopes of finding new
treatment methods for this uncommon and sometimes devastating
disease.
Methods: A retrospective computer assisted query of a large
community hospital identified six cases of fibrous dysplasia in
3 years. Immunohistochemical analysis was performed on 4-5 µm
sections of formalin fixed paraffin embedded tissue blocks from
the above cases by Ventana autostainer using HER2, EGFR, and CD
117 antibodies (Ventana, Tucson, AR) with appropriate controls
following the manufacture’s recommendation. Four of these
cases had been decalcified. Positive reactivity is scored
following generally accepted standards among pathologists. Other
tumor tissue with known HER2, EGFR and CD117 expression before
decalcification were also stained after decalcification in
parallel with fibrous dysplasia cases to ensure that the decal
process do not cause false negative immunohistochemical
results.
Result :Six cases of fibrous dysplasia are uniformly
negative for all three biomarkers. The controls worked
appropriately.
J.Orthopaedics 2009;6(2)e4
Keywords:
Fibrous
Dysplasia treatment; CD117, EGFR; HER2Neu
Introduction:
Fibrous
dysplasia is an uncommon bone disease that has a rare but clear
potential for malignant transformation. The treatment of
fibrous dysplasia is limited to maintenance of maximum bone
density via diet, exercise and therapeutic medications (i.e.
bisphosphonates), as well as surgical reinforcement of bowing
deformities and fractures as they occur. Currently, there
is no therapy for preventing advance of the disease or malignant
transformation. In light of recent development in novel
targeted therapy to HER2, epidermal growth factor receptor (EGFR)
and CD 117 (C-KIT) have shown therapeutic promise in many
neoplasms, both benign and malignant; we investigated the
expression of these markers in six cases of fibrous dysplasia in
hopes of finding new treatment methods for this uncommon and
sometimes devastating disease.
Methods:
A
retrospective computer assisted query of a large community
hospital identified six cases of fibrous dysplasia in 3 years.
Immunohistochemical analysis was performed on 4-5 µm sections
of formalin fixed paraffin embedded tissue blocks from the above
cases by Ventana autostainer using HER2, EGFR, and CD 117
antibodies (Ventana, Tucson, AR)
with appropriate controls following the manufacture’s
recommendation. Four
of these cases had been decalcified.
Positive reactivity is scored following generally
accepted standards among pathologists.
Other tumor tissue with known HER2, EGFR and CD117
expression before decalcification were also stained after
decalcification in parallel with fibrous dysplasia cases to
ensure that the decal process do not cause false negative
immunohistochemical results.
Results :
Six cases
of fibrous dysplasia are uniformly negative for all three
biomarkers. The controls worked appropriately.
Discussion :
Fibrous dysplasia (FD)
is a benign fibro-osseous lesion which may present in monostotic
or polyostotic form, with or without additional morbidities
(1),(2). The monostotic form (MFD) represents approximately
70-80% of fibrous dysplasia cases and most frequently occurs in
the craniofacial bones, rib, femur, tibia, and humerus. MFD
usually presents with pain or pathologic fracture in patients
aged 10-70 years, but most commonly occurs in those aged 10-30
years. The degree of bone deformity in MFD is relatively less
severe compared with that of the polyostotic type. To date there
is no documented evidence supporting the conversion of the
monostotic form to the polyostotic form 1,(3). Approximately
20-30% of fibrous dysplasia cases are polyostotic (PFD). The
common sites of involvement are the femur, tibia, skull and
facial bones, pelvis, ribs, upper extremities, lumbar spine,
clavicle, and cervical spine. The sites of dysplasia may be
unilateral or, less commonly, bilateral. Two-thirds of patients
with PFD are symptomatic before adolescence. The initial symptom
is commonly pain in the involved limb(s) associated with a limp
in the case of lower extremity involvement, spontaneous
fracture, or both. Leg-length discrepancy of varying degrees
occurs in about 70% of patients with limb involvement due to the
weakened structural integrity of the bone leading to significant
bowing (1, 2, 4, 5). Fibrous dysplasia often is associated with
a shepherd’s crook deformity, curvature of the femoral neck and
proximal shaft resulting in a coxa vara deformity, which can be
severe and is a pathognomonic for fibrous dysplasia. Pregnancy
can reactivate dormant bony lesions and occurs more commonly in
PFD than MFD.
A
small, but important subset of polyostotic fibrous dysplasia
occurs along with endocrine abnormalities and coast of Maine café-au-lait
spots, a triad called McCune-Albright syndrome,
named for two physicians who separately described the syndrome
in 1937, Donovan McCune and Fuller Albright 4.
The most common endocrine abnormality is precocious puberty,
once treated by removal of the active gonad, now treated with
anti-hormonal medications. Rarely, patients may have only
two of the three characteristics and may have one or more of the
numerous endocrine symptoms, which include disturbances of the
thyroid gland, parathyroid calcium regulation, adrenal hormonal
regulation, as well as an over-active pituitary. Approximately
3% of FD cases will qualify for McCune-Albright syndrome.
The disease is more common among females and holds no racial
predilection. Separate from McCune-Albright and involving
an even smaller fraction (~1%) of FD patients are those with
associated intramuscular myxomas, typically around the sites of
the bony lesions, an entity called Mazabraud’s syndrome 5.
This disorder is also more common in women. FD is
generally thought of as a benign pediatric disease with
dormancy of the lesions typically reached by early adulthood,
however, patients with FD should be aware that malignant
transformation may rarely occur (1% average, 4% in McCune
Albright). Rapidly increasing pain without apparent trauma or a
significant rapid change in radiological appearance should alert
the clinician to further investigate.
Currently,
treatment of fibrous dysplasia is limited to maintenance of
maximum bone density via diet, exercise and therapeutic
medications (i.e. bisphosphonates), as well as surgical
reinforcement of bowing deformities and fractures as they occur.
There is no therapy for preventing advance of the disease
or malignant transformation, nor any role for chemotherapy, nor
any study investigating the potential role of novel targeted
therapy to HER2, EGFR and CD 117.
Conclusion:
We studied
the immunostain pattern of the above biomarkers in 6 cases of
fibrous dysplasia and found
uniformly negative immunoreactivity.
We also have confirmed that the negative results of the
above markers was not caused by the decalcification process.
This signifies that therapies targeted against these
biomarkers should have no utility in the treatment of FD. We
strongly encourage further investigations to discover optimal
therapy for FD. This disease may cause not only bone deformity
with associated pain and morbidity, but also has clear potential
malignant transformation.
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