Osteofibrous Dysplasia Treatment & Management


Background

Osteofibrous dysplasia is a rare, nonneoplastic condition of unknown etiology that affects the long bones. It frequently is asymptomatic. [1]

Frangenheim first described the lesion in 1921 and reported it as a congenital osteitis fibrosa. [2Subsequently, Kempson reported two cases affecting the tibia of young children and named the lesion ossifying fibroma. [3]

In 1981, Campanacci and Laus studied 35 cases and coined the term osteofibrous dysplasia of the tibia and fibula. [4They proposed this term as a replacement for ossifying fibroma because of the supposed congenital origin of the condition, the histologic resemblance to fibrous dysplasia, and the apparent exclusive involvement of the tibia and fibula. [5Osteofibrous dysplasia is occasionally referred to as Campanacci syndrome.

Most lesions of osteofibrous dysplasia affect the cortex of the tibia, predominantly the middle third of the diaphysis. The cortex often is expanded and thinned, with multiple radiolucencies mixed with intervening areas of sclerosis. The second most common site of involvement is the fibula.

Numerous cases of osteofibrous dysplasia affecting the tibia have been reported. Sweet et al reported 30 cases, with ipsilateral fibular involvement in five cases (17%). [6In another study of 10 children with tibial lesions, one case (10%) showed ipsilateral fibular involvement. The tibia was affected in each of the 35 cases reported by Campanacci and Laus; ipsilateral involvement of the fibula was noted in four cases (11%), and 22 lesions (63%) affected the middle third of the tibial diaphysis. [4Ishida et al found 11 of 12 lesions (92%) in the tibia, with one lesion in the ulna. [7Most of these tibial lesions affected the proximal diaphysis.

Bilateral involvement is rare. However, in a study of five children by Ozaki et al, one child presented with bilateral lesions of both ulnae and tibiae. [8The tibia was affected in the remaining four children, with one having ipsilateral fibular involvement.

Wang et al reported one case of a lesion affecting the radius, and Schlitter reported the case of a lesion in the humerus. [910]

Osteofibrous dysplasia of the mandible, which occurs exclusively in adults, commonly is referred to as ossifying fibroma.

Anatomy

The tibia is a tubular long bone with a triangular shape in cross-section. The bone is surrounded by four fascial compartments. The anteromedial surface lies subcutaneously and therefore has no soft-tissue protection. The primary center of ossification appears at 7 weeks' gestation. The proximal ossific nucleus appears soon after birth and fuses with the metaphysis at approximately age 16 years. The distal ossific nucleus appears at age 2 years and fuses at age 15 years. In some, separate centers of ossification exist for the medial malleolus and tibial tubercle.

The vascular supply to the tibia is provided predominantly by the posterior tibial artery, from which the nutrient artery enters the tibia at the origin of the soleus muscle along the oblique line of the tibia. The nutrient artery of the tibia has three ascending branches and one descending branch. The distal aspect of the tibia is supplied by periosteal anastomoses that enter the bone adjacent to the ankle joint.

Etiology

The etiology of osteofibrous dysplasia, as well as the cell of origin, remains to be established. Descriptions of familial osteofibrous dysplasia are rare. [1112]

Osteofibrous dysplasia has been postulated to arise from a fibrovascular abnormality. Johnson proposed a relationship between osteofibrous dysplasia and adamantinoma on the basis of a common causative factor—namely, a fibrovascular defect. [13According to this theory, osteofibrous dysplasia results from an abnormality in the haversian canals, whereas adamantinoma develops secondary to a defect of intramedullary vasculature.

Komiya and Inoue reported similar findings and suggested a deficiency in blood flow within the periosteum as the etiologic factor in osteofibrous dysplasia. [14Bridge et al investigated the cytogenetics of osteofibrous dysplasia. [15They reported trisomy 12 in two distinct specimens from a lesion in an 11-year-old boy and trisomy 7, 8, and 22 in another boy. Studies of adamantinoma have revealed trisomy 7 and 12, suggesting a relation between osteofibrous dysplasia and adamantinoma (see Presentation).

Sherman et al reported the coexistence of adamantinoma and osteofibrous dysplasia in the same patient, providing additional evidence of a relation between these two entities. [16Several other abnormalities have been found within adamantinoma lesions; consequently, these chromosomal anomalies may not be pathogenetic. [1718On the other hand, Sakamoto et al have shown mutations at the Arg 201 codon in persons with fibrous dysplasia but not in persons with osteofibrous dysplasia, findings that suggest a different pathogenesis for each lesion. [19]

Gray et al identified germline mutations preventing regulated exon skipping in MET. [20They determined that aberrant regulation via the juxtamembrane domain subverted core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone and led to osteofibrous dysplasia.

Epidemiology

Osteofibrous dysplasia usually is diagnosed in children younger than 10 years, with a peak incidence in children aged 1-5 years. Several occurrences in newborns have also been reported. [21222324Adults diagnosed with de-novo osteofibrous dysplasia have been reported, the oldest patient being age 39 years at diagnosis. [6]

The reported mean age at diagnosis has been variable. Sweet et al and Ishida et al reported an average age over 10 years. [67In contrast, Komiya and Inoue, Ozaki et al, and Campanacci and Laus reported an average age younger than 10 years. [4814]

No significant sex preponderance has been reported consistently, though several studies have found a slight male predilection. Sweet et al reported 16 males in their 30 patients. [6Campanacci and Laus noted that 21 of the 35 patients (60%) in their series were male. [4; this represents the largest reported sex preponderance. In contrast, Park et al reported 38 males and 42 females in their series of 80 patients. [25]

Prognosis

The natural history of osteofibrous dysplasia is unpredictable. [26The growth rate can range from slow to rapid, and spontaneous resolution is possible. Campanacci and Laus reported three common clinical courses, as follows:

  • Moderate progression, particularly during the first 5-10 years of life
  • Aggressive growth, with resulting marked deformity
  • Spontaneous resolution

Most commonly, there is continued growth of the lesion until skeletal maturity is reached, with the most rapid period of growth occurring before age 10 years. In most cases, moderate progression is followed by gradual improvement once skeletal maturity is attained.

CLINICAL PRESENTATION


History and Physical Examination

Classically, osteofibrous dysplasia has been described as painless, with a localized, firm swelling of the tibia as the presenting complaint. The tibia frequently is bowed anteriorly or anterolaterally. [27]

Park et al reported that of 80 patients, 25% complained of pain, 12.5% had a pathologic fracture, 8.8% presented with tibial swelling, and 6.2% presented with deformity. [25Sweet et al reported that 18 of 30 patients (60%) presented with complaints of pain, 13 (43%) with swelling, and four (13%) with deformity. [6One lesion was an incidental finding.

Komiya and Inoue reported similar presenting complaints in a series of 10 cases. [14Ishida et al reported a duration of symptoms in 11 of 12 patients ranging from 2 months to 5 years, with an average of 14 months; one lesion was asymptomatic. [7Of three newborns with osteofibrous dysplasia of the tibia, two had swelling and one had pathologic fracture.

Osteofibrous dysplasia vs adamantinoma

Osteofibrous dysplasia and adamantinoma have similar clinical presentations, as well as similar radiologic and pathologic findings. Although adamantinoma can sometimes have the appearance of a low-grade osteogenic sarcoma, osteofibrous dysplasia does not exhibit histologic characteristics of malignancy.

There may be histologic gradations between osteofibrous dysplasia, benign adamantinoma, and the malignant appearance of more aggressive adamantinoma, which usually is encountered in adults. In the latter, osteoid production with cellular mitoses may give the appearance of an osteogenic sarcoma and, indeed, may progress to frank malignancy.

Because the clinical course and radiologic appearance of osteofibrous dysplasia are diagnostic in children, biopsy seldom is indicated and should be avoided, if possible. In patients presenting at skeletal maturity, in whom the incidence of adamantinoma is higher, biopsy of the midportion of the lesion may be necessary for diagnosis. Complete resection of the entire lesion of osteofibrous dysplasia is neither recommended nor necessary.

Several authors have investigated the possible relation between adamantinoma and osteofibrous dysplasia. [2829Dockerty and Meyerding first reported a relation between benign fibro-osseous lesions and adamantinoma. [30Markel was the first to investigate this relation thoroughly. [31Subsequently, three cases of tibial adamantinoma that mimicked osteofibrous dysplasia were reported, two of which occurred in children younger than 10 years. [32]

Several investigators have proposed that osteofibrous dysplasia represents a benign form of adamantinoma or results from a resolved adamantinoma. [33Czerniak et al described an intracortical lesion with pathologic findings similar to those of osteofibrous dysplasia, which they termed differentiated adamantinoma. [34Further, they described differentiated adamantinoma as affecting individuals younger than those with classic adamantinoma. Czerniak et al and Springfield et al reported that differentiated or osteofibrous dysplasia–like adamantinoma can progress to adamantinoma. [3435Thus, these lesions may represent intermediates in a continuum from osteofibrous dysplasia to adamantinoma. [3637]

Hazelbag et al reported several findings that support the connection between the two conditions, as follows [38:

  • First, they noted continuity from epithelial cells in osteofibrous dysplasia to primary epithelioid tumor, as in adamantinoma
  • Second, the mean age at diagnosis of osteofibrous dysplasia and osteofibrous dysplasia–like adamantinoma is younger than the mean age at diagnosis of adamantinoma
  • Third, there are similar radiographic findings
  • Fourth, two patients in their study demonstrated progression from osteofibrous dysplasia to adamantinoma at the time of local recurrence; though it has also been suggested that the sequence may occur in reverse (ie, that adamantinoma may regress to osteofibrous dysplasia), Springfield et al disputed this claim and indicated that such regression is not likely [35]

Findings supporting a relation between the two conditions are in conflict with an investigation by Park et al, who reported no progression from osteofibrous dysplasia to adamantinoma and contended that osteofibrous dysplasia is distinct from adamantinoma. [25 They did, however, suggest that osteofibrous dysplasia might be related to fibrous dysplasia, on the grounds that two cases in their series transformed from osteofibrous dysplasia to monostotic fibrous dysplasia. Subsequent studies have reached similar conclusions. [39]

Several reports on the pathology of adamantinoma have shown that the lesion may have areas resembling osteofibrous dysplasia in appearance. [40This finding suggests the potential for misdiagnosis in cases of inadequate biopsy; such misdiagnosis may explain the reports of progression of osteofibrous dysplasia to adamantinoma.

Thus, Springfield et al suggested that histologic diagnosis of osteofibrous dysplasia should be regarded with caution. [35Hazelbag et al advocated biopsy of the center of the lesion to avoid such an error, whereas Sweet et al suggested examination of the entire specimen to identify areas consistent with adamantinoma.


Diagnostic Considerations

The differential diagnosis of osteofibrous dysplasia includes the following conditions:

  • Monostotic fibrous dysplasia
  • Nonossifying fibroma
  • Adamantinoma

Fibrous dysplasia can be differentiated on the basis of several characteristics. Generally, it occurs in patients older than 10 years, more commonly affects the femur and ribs, and does not resolve spontaneously. [41 Radiographically, it appears as an intramedullary lesion with a ground-glass appearance. [42On histologic examination, fibrous dysplasia is not bordered by active osteoblasts and is cytokeratin-negative. [43Cytogenetically, it is related to anomalies affecting chromosomes 3 and 5. Sakamoto et al found that immunoreactivity for osteonectin in bone matrix is seen more commonly in osteofibrous dysplasia. [44]

Nonossifying fibroma can be distinguished from osteofibrous dysplasia by several typical features. Nonossifying fibroma is predominantly a metaphyseal lesion. Histologically, it is characterized by a storiform pattern of spindle cells with scattered multinucleated giant cells, is not bordered by active osteoblasts, and is cytokeratin-negative.

More challenging is the distinction between osteofibrous dysplasia and adamantinoma [45; these two conditions can appear very similar both clinically and pathologically and are sometimes confused with each other. The distinction between them is important because adamantinoma is a low-grade malignancy that must be managed more aggressively.

Adamantinoma has a similar predilection for the cortex of long bones, particularly the tibia, and may have radiologic and histologic findings similar to those of osteofibrous dysplasia. [464748However, adamantinoma can be distinguished from osteofibrous dysplasia by the presence of soft-tissue extension, intramedullary involvement, periosteal reaction in the absence of pathologic fracture, and the histologic finding of hyperchromatic epithelial islands. Adamantinoma typically manifests with a larger, more painful lesion and is usually found in patients older than 10 years.

As suggested by Kuruvilla and Steiner, however, it is likely that osteofibrous dysplasia is part of the morphologic spectrum of adamantinoma. [49Kanamori et al found that extra copies of chromosomes 7, 8, 12, 19, and 21 recur in adamantinoma. [50These aneuploidies may be useful in differentiating adamantinoma from osteofibrous dysplasia.

A review article by Most et al [51on the similarities and differences between the two entities described immunohistochemical and ultrastructural evidence demonstrating that the neoplastic cell in adamantinoma derives from an epithelial lineage. Subsequently, published reports [495253described another clinical entity—differentiated or osteofibrous dysplasia–like adamantinoma—that appears to lie between osteofibrous dysplasia and adamantinoma along a spectrum of disease.



Imaging Studies

Radiography

In children, osteofibrous dysplasia initially engenders tremendous concern among clinicians and parents regarding the possibility of malignancy. However, the appearance usually is typical, and radiologic diagnosis generally proves sufficient.

The characteristic radiographic appearance of osteofibrous dysplasia (see the images below) has been well reported. Lesions are eccentric, intracortical, and osteolytic. Variable expansion of the external cortical surface is present, with sclerosis of the internal cortical surface. Frequently, a multilocular lesion gives rise to a bubbled appearance. Soft-tissue extension is absent, and periosteal reaction is rare, unless there is an associated pathologic fracture. The size of the lesion is variable. Usually, it affects the diaphysis, though metaphyseal encroachment has been reported.

Characteristic radiographic findings of osteofibroCharacteristic radiographic findings of osteofibrous dysplasia. Note eccentric intracortical lesion with sclerosis of internal surface, bubbled appearance of lesion, and anterior tibial bowing.
Radiograph of osteofibrous dysplasia of tibia in 5Radiograph of osteofibrous dysplasia of tibia in 5-year-old girl.

CT and MRI

To date,the  diagnostic characteristics of osteofibrous dysplasia on computed tomography (CT) or magnetic resonance imaging (MRI) have not been well established. [54However, Jung et al reviewed MRI scans of 24 pathologically proven cases and concluded that osteofibrous dysplasia showed a range of features from limited to aggressive lesions. [55]

Biopsy

Because the clinical course and the radiologic appearance of osteofibrous dysplasia are diagnostic in children, biopsy is seldom indicated and should be avoided if possible. In patients presenting at skeletal maturity, in whom the incidence of adamantinoma is higher, biopsy of the midportion of the lesion may be necessary for diagnosis. If a biopsy is performed, histologic examination is generally definitive.

If biopsy is necessary to confirm the diagnosis, consult with a radiologist and a pathologist to ensure an adequate specimen. Adhere to strict biopsy principles; a malignant process has not yet been excluded.

Biopsy the tibia away from the apex of the tibial curvature to minimize the development of a fatigue fracture, which is common after biopsy in osteofibrous dysplasia. Incise the skin longitudinally and minimize dissection to the greatest extent possible. Disrupt as few compartments as possible; dissect through, rather than adjacent to, muscle; fill bone defects; and strictly maintain hemostasis.

Biopsy material should include periosteum, cortical bone, and medullary material, both central and peripheral to the lesion. Tissue obtained must be representative of the lesion and adequate for histologic grading. Obtain a frozen section to ensure the specimen is sufficient. Avoid leaving sharp edges that may act as stress risers, leading to postbiopsy fracture.

After biopsy, protect the limb in a cast or splint for 3-6 weeks.

Histologic Findings

Despite the characteristic radiographic appearance, Wang et al recommended that diagnosis should be based on biopsy and pathologic examination. [9At the time of surgery, inspection reveals an intact periosteum. The cortex is thinned and may be perforated. The lesion itself is composed of soft, granular tissue that is whitish-yellow in color.

The histologic characteristics of osteofibrous dysplasia are well described. The overall appearance is that of zonal architecture (see the first image below). The lesion is fibrous at its center, with immature woven bone trabeculae. Vascular channels have been described within the lesion (see the second image below). At the periphery, a prominent border of active osteoblasts rims the bony trabeculae. The presence of such a border helps differentiate osteofibrous dysplasia from fibrous dysplasia, in which there is no border of active osteoblasts (see the third image below).

Typical histologic appearance of osteofibrous dyspTypical histologic appearance of osteofibrous dysplasia lesion (×100). Note zonal architecture with periphery of active osteoblasts surrounding bone trabeculae.
Histologic section (×100) demonstrating vascular cHistologic section (×100) demonstrating vascular channels within osteofibrous dysplasia lesion, which has been proposed as etiologic factor in development.
Histologic appearance of fibrous dysplasia, revealHistologic appearance of fibrous dysplasia, revealing appearance similar to osteofibrous dysplasia but lacking periphery of active osteoblasts.

As examination proceeds from the center of the lesion to the periphery, the bone trabeculae become larger and more lamellar in appearance. Fibroblasts in the lesion have been noted to be well differentiated. Several studies have reported cytokeratin-positive elements on immunohistochemical staining. Occasional hemorrhagic zones, cysts, or foci of cartilaginous differentiation have been reported. Multinucleated giant cells have also been observed.


Medical Therapy

Nonoperative treatment usually is recommended until skeletal maturity is reached. [56Recurrent pathologic fractures may be an ongoing problem in some active children. Using a tibial brace similar to those used for congenital pseudarthrosis of the tibia may minimize recurrent pathologic fractures. A lace-up leather support from just below the knee to the ankle may be used. Fractures usually are nondisplaced and can be treated in a walking patellar tendon-bearing cast. Cast immobilization is sufficient for fracture healing, though healing is slower than normal.

Surgical Therapy

There are no absolute contraindications for surgical intervention in children, with the exception of any underlying medical or anesthetic issues. Operative management is not recommended in patients who are skeletally immature, because of the high recurrence rate after resection and curettage [57and because of the predisposition to fracturing after the bone has been weakened by biopsy.

Once skeletal maturity has been reached, marginal resection and bone grafting may be performed without increased risk of recurrence. [5859Pathologic fracture does not necessarily require surgical management, because cast immobilization frequently results in good healing.

For patients of any age, surgical correction of associated deformities may be required. Campanacci and Laus recommended wide resection with extensive bone grafting in children who are skeletally immature if the lesion is aggressive, with marked expansion and bone destruction or multiple pathologic fractures. [460Intramedullary prophylactic rodding of the tibia may also be an option in children who frequently present with fractures; this approach is similar to that used in osteogenesis imperfecta. Resection of large portions of the lesion usually is not necessary and only increases susceptibility to recurrent fractures.

Complications

The recurrence rate after resection and curettage has been reported to be 64-100%. [61Goergen et al reported multiple recurrences in a 3-year-old boy and a 6-month-old boy after attempts at resection. [62Wang et al also reported multiple recurrences after surgical intervention. [9Campanacci and Laus indicated that recurrence does not develop in patients older than 10 years. [4]

Malignant transformation of the lesion is very rare. Ben Arush et al described the course of a boy diagnosed at age 4 years with osteofibrous dysplasia of the tibia who subsequently presented at age 14 years with synovial sarcoma of the peroneal muscles of the same leg. [63At the time of the latter diagnosis, computed tomography (CT) confirmed multiple pulmonary metastases.

Malignant transformation to soft-tissue sarcoma has been reported in fibrous dysplasia, most commonly in the polyostotic variation. [646566However, the case reported by Ben Arush et al is the only report of sarcomatous degeneration of osteofibrous dysplasia.



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