Fibrous Dysplasia Pathology 

Fibrous dysplasia is a noninherited developmental anomaly of bone in which normal bone marrow is replaced by fibro-osseous tissue.^{[1, 2]} This condition was first described in 1942 by Lichtenstein and Jaffe^[3] ; hence, fibrous dysplasia is sometimes referred to as Lichtenstein-Jaffe disease. The disease process may be localized to a single bone (monostotic fibrous dysplasia) or multiple bones (polyostotic fibrous dysplasia).^[4]

Polyostotic fibrous dysplasia can occur as a part of McCune-Albright syndrome (unilateral polyostotic fibrous dysplasia, ipsilateral café-au-lait spots on the skin, and endocrine disturbances such as precocious puberty) or Mazabraud syndrome (polyostotic fibrous dysplasia and soft-tissue myxomas). Fibrous dysplasia has also been reported in association with other endocrine dysfunctions,^[4] such as hyperthyroidism, hyperparathyroidism, acromegaly, diabetes mellitus, and Cushing syndrome.

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.

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Fibrous dysplasia represents about 5% of benign bone lesions^[3] ; however, the true incidence is unknown, as many patients are asymptomatic. Monostotic fibrous dysplasia accounts for 75-80% of the cases.

Fibrous dysplasia is a slowly growing lesion that usually appears during periods of bone growth and is thus seen in those in early teen and adolescent years. Polyostotic fibrous dysplasia accounts for 20-25% of cases, and patients tend to present at a slightly earlier age (mean age, 8 y).^[5]

Pregnancy can cause increased growth of the lesion as well as secondary changes of aneurysmal bone cyst formation. However, males and females are equally affected, although the polyostotic variant associated with McCune-Albright syndrome is seen more frequently in females.^[3]

Patients with small, monostotic lesions may be asymptomatic, with the osseous abnormality identified incidentally on radiologic studies obtained for unrelated reasons. However, bone pain, swelling, and tenderness are common presentations in symptomatic patients.^[4]

Endocrine disturbances may be the initial presentation in some patients.

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, 5]} The lesion may involve only a small segment of bone or it may occupy its entire length.

In polyostotic fibrous dysplasia, the spectrum of involvement varies from 2 bones to more than 75% of the skeleton. Polyostotic fibrous dysplasia is most commonly found in the femur, tibia, pelvis, and foot. Other sites less commonly affected include the ribs, skull, and bones of the upper extremity. Uncommonly affected bones include the lumbar spine, clavicle, and the cervical spine.

Deformity and fracture

The most common physical deformities are leg-length discrepancy, facial asymmetry due to hemicranial involvement, and rib deformities.

Fracture is the most common complication in fibrous dysplasia.^[6] It is seen in more than half of the 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, with reported prevalences ranging from 0.4% to 4%.^[6] Previous irradiation has been documented in more than half of the cases with malignant transformation.

The most common malignant tumors are osteosarcoma, fibrosarcoma, and chondrosarcoma, and the majority of patients are older than thirty years when the sarcoma is diagnosed. The craniofacial region is the most common site of involvement, followed by the femur, tibia, and pelvis. The rate of malignant transformation is higher for polyostotic lesions than for monostotic lesions.

On plain films, fibrous dysplasia is 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.

Endosteal scalloping of the overlying cortex may also be seen.^[6] 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."

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At the patient's initial presentation, scintigraphy may be used to demonstrate the extent of disease. Active fibrous dysplasia lesions in younger patients have greatly increased isotope uptake; the uptake becomes less intense as the lesions mature.

The extent of the lesion is best demonstrated on computed tomography (CT) scans. 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.^[7] Because fibrous dysplasia is composed mainly of fibrous tissue and bone, T1-weighted images have a low-intensity signal.^[6] T2-weighted images have a higher intensity signal that is not as bright as the signal of malignant tissue, fat, or fluid.

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Incidentally discovered, asymptomatic, radiographically characteristic fibrous dysplasia lesions do not require further assessment and require only clinical observation.^[8] 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.^[8]

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.^[9]

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.

The macroscopic appearance of fibrous dysplasia is that of a centrally located, tan to gray white, gritty-feeling lesion (see the image below). Areas of cyst formation or hemorrhage may be identified. The lesion can be easily peeled away from the encircling shell of reactive bone by blunt dissection. Occasionally, small islands of cartilage that undergo calcification and enchondral ossification may be observed in the lesional tissue. This phenomenon is most frequently encountered in the proximal femur and is sometimes referred to as fibrocartilaginous dysplasia.

Histologically, fibrous dysplasia is composed of fibrous tissue with randomly oriented bony trabeculae that are thought to be formed by osseous metaplasia of the fibrous stroma (see the following image).^[6]

The fibrous stroma is usually of low cellularity and contains variable amounts of myxoid material to dense collagenous matrix (see the first image below).^{[10, 11]} The fibroblasts usually have plump, ovoid nuclei, although elongated, narrow nuclei may also be seen. A storiform pattern of the fibroblasts may also be identified (see the second and third images below).^[12]

The osseous trabeculae are composed of immature woven bone and are typically not lined by osteoblasts, although focal osteoblastic rimming may be seen. Osteoclasts are frequently observed, especially on the concave side of the trabeculae. The outline of the trabeculae varies from solid, round islands to short, irregular, curvilinear or serpiginous shapes, giving the characteristic "Chinese character" or "alphabet soup" appearance.^[12] The ratio of fibrous tissue to bone ranges from fields that are totally fibrous to those filled with dysplastic trabeculae.^{[3, 6]}

Multiple, delicate capillaries are found throughout the lesion and, when injured, incite a giant-cell reactive process. A cartilagenous component, composed of lobules of mature hyaline cartilage (fibrocartilaginous dysplasia), may be encountered, most often in the proximal femur. Hemorrhage and cystic change may be occasionally found. Secondary aneurysmal bone cyst formation can also occur.

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.^[13] 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, by 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.^[13] This abnormal growth leads to the formation of a disorganized fibrotic bone matrix with primitive bone formation, and lack of maturation to lamellar bone. Mineralization is also abnormal. There is a failure of the bone to align in response to mechanical stress. 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. 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.^[14]

The recurrence rate of fibrous dysplasia after curettage and bone grafting is high. However, the majority of the monostotic lesions stabilize with skeletal maturity.^[11] As a rule, the monostotic form does not convert to the polyostotic form.

Although the manifestations of the polyostotic form may be severe, it does not proliferate and generally becomes quiescent at puberty. However, the existing deformities may progress.