Overview
Fibrous dysplasia is a congenital, noninherited, benign intramedullary bone lesion in which the normal bone marrow is replaced by abnormal fibro-osseous tissue. [1] It can result in pain, deformity, fractures, or abnormalities in bone mechanics. [2] This condition was first described in 1942 by Lichtenstein and Jaffe [3] ; hence, fibrous dysplasia is also sometimes referred to as Lichtenstein-Jaffe disease. The disorder can be monostotic (involving a single bone) or polyostotic (involving multiple bones). [4] When fibrous dysplasia occurs in the setting of other extraskeletal abnormalities, skin pigmentation, and endocrine dysfunction, the resulting syndrome is named McCune-Albright syndrome. [5]
Fibrous dysplasia has been reported in association with several endocrinopathies, such as hyperthyroidism, hyperparathyroidism, acromegaly, diabetes mellitus, and Cushing syndrome. [6] Rarely, it can also be associated with solitary or multiple soft-tissue myxomas (Mazabraud syndrome). [7]
The image below depicts distinctive pigmentation that can be seen in patients with fibrous dysplasia and endocrine abnormalities. Note that the border of the lesion is jagged and irregular.
Fibrous Dysplasia Pathology. This clinical photograph shows the distinctive pigmentation in patients with endocrine abnormalities associated with fibrous dysplasia.
See Fibrous Dysplasia Imaging for complete information about imaging on this topic.
Epidemiology
Fibrous dysplasia represents 2.5-5% of benign bone lesions; however, the true incidence is unknown, as many patients are asymptomatic. [8, 9] Fibrous dysplasia is a slowly growing lesion that usually appears during periods of bone growth, and is thus seen in the early teen and adolescent years. However, it can present at any age, and the vast majority of cases are detected by age 30 years. [10]
Monostotic fibrous dysplasia accounts for 75-80% of the cases, [11] whereas the polyostotic form accounts for 20-25% of cases, and patients tend to present at a slightly earlier age (mean age, 8 years). [12] Males and females are equally affected, although the polyostotic variant associated with McCune-Albright syndrome is seen more frequently in females. [13]
Clinical Features
Fibrous dysplasia is often asymptomatic and is usually found when imaging is performed for other clinical reasons. When symptoms are present, swelling or obvious deformity are the most common clinical manifestations. When deformities are severe, pathological fractures can occur as a result of altered bone strength of weight-bearing bones. Limb-length discrepancies can be observed as well. [14] Pain can be present and, based on the affected anatomic area, its severity can be variable. Majoor et al found that lesions in lower extremities and ribs were more painful. [2]
Monostotic lesions are mostly asymptomatic, but they may progress during skeletal growth, and they tend to stabilize after puberty. Rarely, lesions may keep growing in adulthood. Pregnancy can cause increased growth of the lesion, as well as secondary changes of aneurysmal bone cyst formation. [15]
Polyostotic forms involve a few bones of a single body area or can affect more than 50% of the skeleton. These are characterized by early onset and rapid progression. Patients who have fibrous dysplasia associated with McCune-Albright syndrome usually present with skin lesions along the midline of the body and include jaggedly bordered macules. [1] In this setting, fibrous dysplasia typically manifests during the first few years of life, usually with a classic “Shepherd’s crook” coxa vara deformity. In females, precocious puberty is the most common manifestation of the syndrome. Other endocrinopathies (hypercortisolism, thyroid disorders, growth hormone excess, etc) can also be associated with the syndrome. Rare but severe extraskeletal complications may occur, ranging from gastrointestinal reflux to cardiac involvement with arrhythmias and even sudden death.
This section will briefly review the common affected locations of fibrous dysplasia, fibrous dysplasia deformity and fracture, and malignant transformation for this lesion.
Affected locations
The most common sites of skeletal involvement in monostotic fibrous dysplasia are the ribs, proximal femur, and craniofacial bones, typically the posterior maxilla. [4, 12, 16] The lesion may involve only a small segment of bone, or it may occupy its entire length.
Polyostotic fibrous dysplasia is most often found in the femur, tibia, pelvis, and foot. Other sites less commonly affected include the ribs, skull, and bones of the upper extremity. [17] Uncommonly affected bones include the lumbar spine, clavicle, and the cervical spine.
Deformity and fracture
Fracture is the most common complication in fibrous dysplasia. [18] It is seen in more than half of patients with the polyostotic form of the disease. Deformities in weight-bearing bones can occur. Almost 75% of patients with polyostotic fibrous dysplasia are symptomatic with pain, deformity, or pathologic fractures. [3]
Malignant transformation
Malignant transformation of fibrous dysplasia occurs very infrequently; reported prevalence ranges from 0.4% to 4%. [18] The rate of malignant transformation is higher for polyostotic lesions than for monostotic lesions. Previous irradiation has been reported as a risk factor for malignant transformation; however, fibrous dysplasia also can develop in subjects who have been never exposed to radiation therapy. [19] Oh et al reported malignant transformation of a monostotic fibrous dysplasia of the left maxilla into an epithelioid-type angiosarcoma. [20]
The most common malignant tumors arising from fibrous dysplasia are osteosarcoma, fibrosarcoma, and chondrosarcoma, and the majority of patients are older than 30 years when the sarcoma is diagnosed. The craniofacial region is the most common site of involvement, followed by the femur, tibia, and pelvis. [19, 21] Additionally, an increased risk for breast and prostate cancers has been observed in subjects with fibrous dysplasia. [22]
Differential Diagnosis
Other conditions to consider in the workup of fibrous dysplasia (FD) include the following:
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Osteofibrous dysplasia: The tibia and fibula are almost exclusively affected. [23] The fibrous tissue and mature bone trabeculae are rimmed by osteoblasts, as opposed to the lack of osteoblastic rimming seen in FD.
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Ossifying fibromas: These lesions develop exclusively in the craniofacial region, unlike fibrous dysplasia, which affects any skeletal bone. [24] The use of copy number alterations (CNAs) profiling appears to improve differentiating between ossifying fibromas and fibrous dysplasias, and it may aid in predicting disease progression. [25]
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Metaphyseal fibrous defect: Fibrous tissue is whorled and storiform as in FD, but usually hemosiderin and lipid-laden macrophages can be found. Chronic lymphoplasmacytic infiltration and giant cells are commonly present; however, curvilinear bone formation is not seen.
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Desmoplastic fibroma: There is a similar fibrous component to that of FD. Entrapped lamellar bone can be seen; however, the bone should not be curvilinear or woven.
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Paget disease: Mature FD lesions can resemble the trabeculae pattern seen in Paget disease. However, the peculiar mosaic pattern and cement lines observed in Paget disease should not be seen in FD. Moreover, Paget disease typically affects older people.
Plain Radiography
On plain films, fibrous dysplasia appears as an intramedullary, expansile, and well-defined lesion in the diaphysis or metaphysis. The lesions can vary from completely radiolucent to completely sclerotic; however, most lesions have a characteristic hazy ground-glass appearance (see the following images). [3] The degree of haziness shown radiographically by a given lesion correlates directly with its underlying histopathology. More radiolucent lesions are composed of predominantly fibrous elements, whereas more radiopaque lesions contain a greater proportion of woven bone.
Fibrous Dysplasia Pathology. This plain film shows a lytic lesion of the femoral neck with surrounding sclerosis and a hazy or "ground glass" appearance (red arrow).
Fibrous Dysplasia Pathology. This plain film is that of a larger lesion of the femoral neck than shown in the previous image. It demonstrates the physical distortion that can accompany fibrous dysplasia (red arrow).
Endosteal scalloping of the overlying cortex may also be seen. [7] In addition, the lesion may be surrounded by a layer of thick, sclerotic reactive bone termed a "rind." Repeated fractures through lesions in the proximal femur can result in a varus angulation called a "shepherd's crook deformity."
See Fibrous Dysplasia Imaging for complete information about imaging on this topic.
Scintigraphy, CT Scanning, and MRI
Scintigraphy may be used to demonstrate the extent of disease at the patient's initial presentation. Active fibrous dysplasia lesions in younger patients have greatly increased isotope uptake; the uptake becomes less intense as the lesions mature.
Computed tomography (CT) scanning best demonstrates the extent of the lesion. This imaging modality is helpful in distinguishing fibrous dysplasia from other lesions in the differential diagnosis.
Magnetic resonance imaging (MRI) is a sensitive means of establishing the lesion's shape and content. [26] Because fibrous dysplasia is composed mainly of fibrous tissue and bone, T1-weighted images have a low-intensity signal. [18] T2-weighted images have a higher intensity signal that is not as bright as the signal of malignant tissue, fat, or fluid.
See Fibrous Dysplasia Imaging for complete information about imaging on this topic.
Gross and Microscopic Features
Rarely, the fibrous dysplasia specimen is surgically excised. On gross examination, fibrous dysplasia generally shows a fusiform expansion, and the bone cortex is thinned. The lesion is firm, well defined, intramedullary, and consists of tan-gray, dense fibrous, gritty tissue (see the image below). If excessive mineralization or ossification is present, focal yellow areas may be observed. Minimal to extensive cystic formation filled by clear to yellow fluid or blood can be present.
Fibrous Dysplasia Pathology. This gross specimen displays fibrous dysplasia of the mandible, cross-section. The cut surface of the tumor is firm, tan, and densely fibrous.
Typically, the specimen is received as a core needle biopsy. Histologically, fibrous dysplasia is composed of fibrous tissue with irregular, randomly oriented bony trabeculae. The fibrous stroma is composed of low cellularity, with bland fibroblasts with a spindle cell appearance in a dense collagenous matrix showing a whorled or storiform pattern. [27] Atypia, pleomorphism, or mitoses are usually not present.
Bone trabeculae are composed of immature woven bone and are usually devoid of rimming osteoblasts. Generally, the trabeculae outline varies from solid, round islands to short, irregular, curvilinear, or serpiginous shapes, giving the characteristic "Chinese character" or "alphabet soup" appearance. [27] The ratio of fibrous tissue to bone ranges from fibrous fields to those filled with dysplastic trabeculae. [3] In mature lesions, bone trabeculae can show matrix mineralization that resembles cementoid bodies. Osteoclasts are frequently observed, especially on the concave side of the trabeculae.
See the following images.
Fibrous Dysplasia Pathology. This photomicrograph of fibrous dysplasia demonstrates irregularly shaped islands of woven bone with a bland mononuclear background stroma.
Fibrous Dysplasia Pathology. A medium-power view of a microscopic field of fibrous dysplasia is shown. The segments of bone demonstrate an intensely pink osseous matrix that is part of the woven bone formation process.
Fibrous Dysplasia Pathology. A low-power photomicrograph of a more mature lesion than that observed in the previous image is demonstrating maturation and coalescence of the woven bone. There is a more noticeable hyalinization of the stroma that can be seen in older lesions. Inflammation can also be noted.
Fibrous Dysplasia Pathology. This is a low-power histologic section that shows a stroma-predominant fibrous dysplasia.
Multiple, delicate capillaries are found throughout the lesion and, when injured, incite a giant-cell reactive process. Intralesional hemorrhage can lead to a giant cell reaction, thereby requiring a differential diagnosis of giant cell tumors. A cartilaginous component, composed of mature hyaline cartilage (fibrocartilaginous dysplasia), may be encountered, most often in the proximal femur.
Hemorrhage and cystic change may occasionally be found. Secondary aneurysmal bone cyst formation can also occur, which appears as expansile lesions. Dense ossification is usually observed in craniofacial locations. An important diagnostic feature is a polarization pattern of irregular, haphazard deposits of woven bone seen on the bone trabeculae under polarized light examination (see the following image).
Fibrous Dysplasia Pathology. An examination of fields of fibrous dysplasia with polarized light demonstrates the woven nature of the collagen deposition characteristic of this tumor.
Molecular/Genetics
Fibrous dysplasia is caused by a somatic mutation in the GNAS1 gene located on chromosome 20q13.2-13.3, which encodes the alpha subunit of the stimulatory G protein, Gsα. [28] As a consequence of this mutation, there is a substitution of amino acid arginine in position 201 (R201) of the genomic DNA in the osteoblastic cells with amino acid cysteine (R201C) or histidine (R201H).
The abnormal G1 protein stimulates cyclic adenosine monophosphate (AMP), and the osteoblastic cells expressing this mutation have a higher rate of DNA synthesis than normal cells. [28] This abnormal growth leads to the formation of a disorganized fibrotic bone matrix with primitive bone formation and a lack of maturation to lamellar bone. Mineralization is also abnormal. failure of the bone to align in response to mechanical stress occurs. This defect is seen in the monostotic as well as the polyostotic forms of fibrous dysplasia. The extent of disease is related to the stage at which the postzygotic mutation in Gsα has occurred, whether during embryonic development or postnatally.
A meta-analysis found an overall positive rate of GNAS mutation in 71.9% of fibrous dysplasia cases. [29] The major types of mutations were the missense mutations of R201H and R201C, although at least one new site of mutation was revealed at codon 224 (V224A). Mutation was more commonly seen in tubular bone lesions than in flat bone lesions. [29]
Tabareau-Delalande et al evaluated the sensitivity and specificity of GNAS mutations in fibrous dysplasia, to assess the value of investigating this mutation in the diagnosis of fibro-osseous lesions. [30] In their study of 91 cases of fibrous dysplasia, 23 cases (45%) showed mutations of codon 201 (exon 8, p.R201H or p.R201C). No mutation was found on codon 227 (exon 9). GNAS mutations in conventional fibrous dysplasia were detected in the same proportion (47%) as in the other histologic subtypes (47%, P = 0.96) regardless of sex, age, and location, [30] but these mutations were not detected in any other fibro-osseous lesions. The GNAS mutation was found to be specific to fibrous dysplasia. The particular mosaicism of mutant and nonmutant cells within the lesion or the existence of other mutations not already described could explain the lack of GNAS mutation in cases of fibrous dysplasia. [30] Furthermore, the detection of GNAS mutations may be reduced in specimens that have been decalcified. [31]
Relatively recent research shows that protein kinase A (PKA) activation also leads to cAMP-response element binding (CREB) phosphorylation, which promotes target gene expression at promoters containing CREs. [32] CREB targets the receptor activator of nuclear factor kappa-Β ligand (RANKL) gene, potentially leading to the elevated osteoclastic activity and osteolysis present in fibrous dysplasia. [33]
Clinical Management
Incidentally discovered, asymptomatic, radiographically characteristic fibrous dysplasia lesions do not require further assessment and require only clinical observation. [34] Follow-up radiographs every 6 months to look for progression has been recommended. In newly identified cases, a bone scan is needed to exclude a diagnosis of polyostotic disease. When polyostotic disease is found, referral to an endocrinologist for early detection of possible systemic abnormalities is warranted. Bisphosphonates, primarily intravenous pamidronate, have been utilized to decrease bone pain in symptomatic patients with polyostotic disease. [34]
Open biopsy may be indicated to confirm the diagnosis of fibrous dysplasia when there is a nonclassic presentation. Surgical procedures are required for correction of deformities, prevention of pathologic fractures, or eradication of symptomatic lesions. [35] Treatment of malignant transformation is based on the subtype of sarcoma, but the prognosis tends to be worse for patients with malignant transformation than it is for those with a similar primary sarcoma not associated with fibrous dysplasia.
Prognosis
The recurrence rate of fibrous dysplasia after curettage and bone grafting is high. However, the majority of the monostotic lesions stabilize with skeletal maturity. [36] As a rule, the monostotic form does not convert to the polyostotic form.
Although the manifestations of the polyostotic form may be severe, they do not proliferate and generally become quiescent at puberty. However, the existing deformities may progress.
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Fibrous Dysplasia Pathology. This clinical photograph shows the distinctive pigmentation in patients with endocrine abnormalities associated with fibrous dysplasia.
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Fibrous Dysplasia Pathology. This photomicrograph of fibrous dysplasia demonstrates irregularly shaped islands of woven bone with a bland mononuclear background stroma.
-
Fibrous Dysplasia Pathology. A medium-power view of a microscopic field of fibrous dysplasia is shown. The segments of bone demonstrate an intensely pink osseous matrix that is part of the woven bone formation process.
-
Fibrous Dysplasia Pathology. A low-power photomicrograph of a more mature lesion than that observed in the previous image is demonstrating maturation and coalescence of the woven bone. There is a more noticeable hyalinization of the stroma that can be seen in older lesions. Inflammation can also be noted.
-
Fibrous Dysplasia Pathology. An examination of fields of fibrous dysplasia with polarized light demonstrates the woven nature of the collagen deposition characteristic of this tumor.
-
Fibrous Dysplasia Pathology. This plain film shows a lytic lesion of the femoral neck with surrounding sclerosis and a hazy or "ground glass" appearance (red arrow).
-
Fibrous Dysplasia Pathology. This plain film is that of a larger lesion of the femoral neck than shown in the previous image. It demonstrates the physical distortion that can accompany fibrous dysplasia (red arrow).
-
Fibrous Dysplasia Pathology. This is a low-power histologic section that shows a stroma-predominant fibrous dysplasia.
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Fibrous Dysplasia Pathology. This gross specimen displays fibrous dysplasia of the mandible, cross-section. The cut surface of the tumor is firm, tan, and densely fibrous.
