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Fibrous Dysplasia and Related Lesions
Fibrous Dysplasia
This disorder was recognized as a clinical syndrome of disseminated skeletal deformities long before it was given the name fibrous dysplasia by Lichtenstein and Jaffe in two classic publications that appeared in 1938 and 1942. In older literature, it had been discussed under the term osteitis fibrosa or generalized fibrocystic disease of bone, which also included such conditions as renal osteodystrophy and hyperparathyroidism. The craniofacial lesions were classified as leontiasis ossea or cherubism. They were linked to fibrous dysplasia as an underlying condition by Pugh in 1945. Fibrous dysplasia as a solitary lesion was last to be linked to a disseminated polyostotic form of the disease. Albright-McCune syndrome was independently described by two groups in 1937, and the skeletal abnormalities in this condition were originally classified as osteitis fibrosa. They were reclassified as polyostotic fibrous dysplasia in 1942 by Lichtenstein and Jaffe. In 1967, Mazabraud et al. described an association of fibrous dysplasia with soft tissue myxomas.
Fibrous dysplasia is best explained if it is considered as a dysplastic anomaly of bone-forming mesenchymal tissue. The hallmark of this disease is a solitary focal or generalized multifocal inability of bone-forming tissue to produce mature lamellar bone. It is arrested at the level of woven bone. Even if a large amount of osteoid is produced, it cannot mature to lamellar bone. The remarkable consistency of this feature in various clinical forms of fibrous dysplasia ranging from solitary asymptomatic lesions to severe generalized conditions suggests that the underlying molecular mechanism involves the fundamental cell differentiation process. The differences in the extent of skeletal involvement and the coexistence of extraskeletal abnormalities can be related to somatic mosaicism of the defect. The disease is evolutionary conserved; recent evidence indicates that Homo sapiens ' ancestors such as Neanderthals were affected by a similar disorder.
The involvement of a gene or genes playing a fundamental role in modulation of cellular differentiation into mature osteocytes capable of producing lamellar bone can be postulated. In fact, mutations of signal-transducing G proteins have been implicated in the development of multiple endocrinopathies of the Albright-McCune syndrome and fibrous dysplasia. However, not all cases of fibrous dysplasia or Albright-McCune syndrome can be linked to mutations of G proteins, indicating that other molecular mechanisms may be involved. G proteins form heterotrimeric complexes and bind guanine nucleotides. They couple a large number of cell surface receptors to their corresponding intracellular signal transduction pathways. Mutations of G proteins alter these pathways and may disturb the tissue differentiation process ( Fig. 8-1 ). The mutations in fibrous dysplasia involve the α chain of the heterotrimeric G subunit and result in the substitution of histidine, cysteine, or serine for arginine at position 201. These substitutions are caused by single nucleotide mutations involving predominantly exon 8 and less frequently exon 9 of the gene encoding for G sα ( GNAS1 ) located on the long arm of chromosome 20 at 20q13.2-3. These mutations disrupt the inherent guanosine triphosphate activity of the α chain, stimulate adenyl cyclase, and result in independent cell proliferations. Identical mutations are also present in pituitary and other endocrine tumors associated with Albright-McCune syndrome and in the soft tissue myxomas associated with fibrous dysplasia such as Mazabraud's syndrome. They can also be detected in solitary soft tissue myxomas unrelated to fibrous dysplasia. The osteoblastic cells expressing mutant G sα show increased proliferations and inappropriate differentiation that results in overproduction of a disorganized fibrotic bone lesion. In animal studies the implantation of human marrow progenitor cells with mutant G sα admixed with nonmutant cells results in the formation of abnormal ectopic ossicle recapitulating fibrous dysplasia. The mutations of the GNAS1 gene have also been explored as potential biomarkers in the differential diagnosis of fibrous dysplasia and other fibroosseous lesions, including well-differentiated fibroblastic osteosarcoma. Unfortunately, the presence of GNAS1 mutations in well-differentiated fibroblastic osteosarcoma, both parosteal and intramedullary, limits the diagnostic applications of those mutations in the differential diagnosis of fibrous dysplasia and low-grade fibroblastic osteosarcoma. The increased levels of the c-fos and c-jun oncoproteins have been documented in lesions of fibrous dysplasia, but their role in the pathogenesis of this disorder is unclear. The alterations of G sα affect downstream regulatory pathways, playing an important role in the proliferation of cells involved in the development of the skeleton, neuroendocrine sites, and skin melanocytes as the most frequently affected tissues. Transcriptional activation of the c-fos- and c-jun protooncogenes as well as Runx2 and Wnt/β-catenin, which play important roles in skeletal development, is caused by activating mutations of G sα protein. The human GNAS locus is maternally and paternally imprinted and encodes multiple transcripts and alternative isoforms. The genetic imprinting of both maternal and paternal alleles and of different alternative isoforms produces a mosaic of transcripts with restricted expressions to specific tissues. This complexity, coupled with a background of somatic mutations and a mixture of mutant and nonmutant alleles, is responsible for the variable phenotypic presentations of GNAS related disorders. In individual skeletal progenitors, the transcriptional activity of two G sα alleles can be different and each allele can be selectively expressed or completely silenced. This is believed to be responsible for the highly variable clinical manifestations of GNAS related disorders ranging from a single focus to widespread skeletal involvement as well as distinctive alterations in predominantly neuroendocrine sites and skin melanocytes but also affecting soft tissue, including cardiac muscle, among others. The presence of clonal structural alterations involving chromosomes 3, 8, 10, 12, and 15 suggests that fibrous dysplasia may represent a neoplastic condition with a predisposition to somatic mutations of skeleton-forming mesenchymal tissue. Extremely rare cases of familial association between multiple endocrine neoplasia type 1 and Albright-McCune syndrome have been described, and this suggests a possible pathogenetic link between these two conditions. Deletions involving chromosome 9q37.3 were found in several individuals with Albright-McCune syndrome, suggesting the possible involvement of this chromosome region in the development of the syndrome. Rare familial transmission of fibrous dysplasia has also been reported.
Definition
Fibrous dysplasia represents a dysplastic disorder of bone characterized by solitary or multifocal polyostotic intramedullary lesions composed of proliferations of fibroblast-like spindle cells with a characteristic whorled pattern in which trabeculae of immature woven bone may be present. The latter are typically not bordered by palisading osteoblasts.
Clinical Symptoms
Fibrous dysplasia can occur in several distinct clinical settings ( Table 8-1 ). It has two basic clinical forms: monostotic and polyostotic ( Figs. 8-2 and 8-3 ). It can be associated with extraskeletal symptoms, which occur more frequently in patients with the polyostotic form. The most common extraskeletal symptom is hyperpigmentation of the skin (café au lait spots)( Fig. 8-4 ). More severe forms of polyostotic fibrous dysplasia may be associated with endocrine abnormalities, such as precocious puberty in female subjects (Albright-McCune syndrome). Other less frequent endocrine dysfunctions include acromegaly, hyperthyroidism, hyperparathyroidism, and Cushing's syndrome. Association of fibrous dysplasia, typically of the polyostotic form, with soft tissue myxomas (Mazabraud's syndrome) is the rarest form of clinical manifestation of this disease ( Fig. 8-5 ).
TABLE 8-1
Summary of Clinicoradiographic Features of Fibrous Dysplasia
| Variant of Fibrous Dysplasia | Distribution of Lesions and Clinical Features |
|---|---|
| Monostotic | Single focus in one bone |
| Polyostotic | Multiple foci in several bones |
| Monomelic | Predominant or exclusive unilateral involvement of one extremity and of homolateral pelvis or scapula |
| Polymelic | Widespread skeletal involvement |
| Albright-McCune syndrome | Polyostotic (typically polymelic) fibrous dysplasia with endocrine abnormalities (most frequently precocious puberty in female patients); less frequent anomalies include acromegaly, hyperthyroidism, hyperparathyroidism, and Cushing's syndrome |
| Mazabraud's syndrome | Polyostotic fibrous dysplasia associated with soft tissue myxomas |
Monostotic fibrous dysplasia occurs more frequently than the polyostotic variant. The ratio between the monostotic and polyostotic forms varies among series from 8 : 1 to 10 : 1. Monostotic fibrous dysplasia affects a single bone, and typically one focus of involvement is identified. Polyostotic fibrous dysplasia is characterized by multiple foci involving several bones. The polyostotic form is further subdivided into monomelic and polymelic subtypes. The lesions in polyostotic fibrous dysplasia tend to be unilateral and to involve the bones of one extremity (monomelic polyostotic fibrous dysplasia). More severe forms can exhibit widespread skeletal involvement (polymelic polyostotic fibrous dysplasia).
The disease usually manifests during the first three decades of life (approximately 70% of cases). Monostotic fibrous dysplasia may be asymptomatic and is discovered incidentally on radiographs obtained for other reasons. The most common clinical symptom is swelling or deformity of the affected site. In fact, severe deformities of the affected sites represent a major problem in the clinical management of fibrous dysplasia ( Fig. 8-6 ). The lesion may occasionally be heralded by mild to moderate pain of long duration. Pathologic fracture, particularly in the long tubular bones, may also be a presenting symptom. Often, the growth of the lesion stabilizes at a certain point. This usually occurs during puberty. Skin pigmentations may correspond to sites of skeletal involvement.
The more extensive the disease, the earlier the onset of symptoms. In the monostotic form, the most frequent sites of involvement are the ribs, craniofacial bones, proximal femur, and tibia. The monomelic variant of the polyostotic form frequently affects the lower extremity and the homolateral hemipelvis. The polymelic form (the most severe generalized variant) shows widespread involvement of both extremities, the trunk, and craniofacial bones. Even in this form, the disease may predominantly involve one side. Involvement of the vertebral column is extremely rare in fibrous dysplasia.
Albright-McCune syndrome is clinically defined by the triad of fibrous dysplasia, café au lait spots, and precocious puberty. Clinical manifestations of Albright-McCune syndrome relative to age and their clinical behavior are summarized in Figure 8-7 . It is a rare syndrome with estimated prevalence of 1/100,000 to 1/1,000,000. Typically, the signs of precocious puberty or symptoms related to skeletal involvement by fibrous dysplasia as well as early onset of café au lait spots are the initial presentations. In girls, precocious puberty usually presents as vaginal bleeding or spotting accompanied by the premature development of breast tissue and pubic hair. In boys, it is associated with testicular and penile enlargement and premature development of pubic and axillary hair. The café au lait spots are usually present at birth or develop shortly thereafter. They are classically described as having jagged outlines referred to as a coast of Maine outline. They show some respect to the midline but there are frequent exceptions to this rule. The development of café au lait spots with midline lateralism in the adjacent skin regions may produce a harlequin pattern of hyperpigmentation. The prevalence of major clinical findings in fibrous dysplasia/Albright-McCune syndrome is described in Table 8-2 . Less common clinical findings are summarized in Table 8-3 . Two thirds of patients show involvement of the thyroid with hyperparathyroidism. Some patients with extensive fibrous dysplasia may have hypophosphatemia due to the overproduction of a circulating phosphaturic hormone caused by overproduction of FGF23 in the fibrous dysplasia tissue. Overproduction of growth hormone is caused by the presence of GNAS mutations in the anterior pituitary causing hyperplasia manifesting as adenomas. Cushing's syndrome is one of the rarest endocrine abnormalities found in Albright-McCune syndrome and typically occurs in the neonatal period. Other extraskeletal manifestations include gastrointestinal reflux, gastrointestinal polyps, pancreatitis, and cardiac abnormalities potentially resulting in tachycardia and sudden death.
TABLE 8-2
Prevalence of Major Findings in the NIH Cohort of Patients with Fibrous Dysplasia/Albright-McCune Syndrome
Collins MT, et al: Orphanet J Rare Dis 7:S4, 2012.
| Clinical Finding | % Patients * |
|---|---|
| Fibrous dysplasia | 98 |
| Café au lait spots | 66 |
| Gonadal abnormalities | |
| Male: (ultrasound) † | 70 |
| Female: precocious puberty | 50 |
| Thyroid abnormalities | |
| Abnormal ultrasound (U/S) | 66 |
| Hyperthyroid + abnormal U/S | 28 |
| Renal phosphate wasting | 43 |
| Hypophosphatemia | 10 |
| Growth hormone excess | 21 |
| Cushing's syndrome | 4 |
TABLE 8-3
Prevalence of Less Common Findings in the NIH Cohort of Patients with Fibrous Dysplasia/Albright-McCune Syndrome
Collins MT, et al: Orphanet J Rare Dis 7:S4, 2012.
| Other Clinical Findings | % Patients a |
|---|---|
| Gastrointestinal | 7 |
| History of hepatitis b | 4 |
| Reflux b | 5 |
| Pancreatitis b | 3 |
| Polyps c | 5 |
| Cardiac | 6 |
| Tachycardia d | 4 |
| Aortic root dilatation (GH excess) e | 2 |
| Hematologic | 1 |
| Platelet dysfunction | 1 |
| Cancer | 4 |
| Thyroid f | 1 |
| Breast f | 2 |
| Bone f | 1 |
| Testicular f | 1 |
| Hyperparathyroid | 1 |
| Neuropsychiatric | 9 |
a N = 140; 58 males, 82 females.
b Appeared in childhood, common causes excluded.
c Atypical, upper GI tract polyps, myxomatoid pathology more common.
d Unexplained/not associated with hyperthyroidism.
e Only seen in patients with growth hormone excess.
f All tumors bear GNAS1 mutation, adjacent normal tissue mutation negative.
Radiographic Imaging
On radiographs, fibrous dysplasia appears as a medullary lesion with the so-called ground-glass appearance ( Figs. 8-8 and 8-9 ). The radiographic density of the lesion varies and depends on the relative proportions of bone and fibrous elements. Lesions with abundant bone elements are more radiopaque ( Figs. 8-10 and 8-11 ). On the other hand, the predominance of fibrous tissue is associated with a more lucent radiographic appearance ( Fig. 8-12 ). Predominantly radiopaque lesions occur more frequently in the craniofacial bones than in other parts of the skeleton. This is related to the particular prevalence of well-mineralized bone trabeculae in fibrous dysplasia of craniofacial bones. The bone contour is usually expanded. This feature is particularly evident in bones with small diameter (ribs and fibulas) and in flat bones but can also be seen in the major long tubular bones ( Figs. 8-8 and 8-9 ). In the femur, tibia, or humerus, fibrous dysplasia may cause expansion of the bone contour with cortical thinning and endosteal scalloping ( Figs. 8-9 and 8-13 ). In the long tubular bones, the shaft is typically involved, but the metaphyses are also frequently affected. Lesions extending to the epiphyseal end of a bone are unusual. Foci of punctate and ringlike calcification may be present and represent the areas of cartilaginous differentiation that may be found in fibrous dysplasia. When cartilaginous differentiation is extensive, the radiographic appearance is similar to that seen in cartilage lesions. This variant of fibrous dysplasia is sometimes referred to as fibrocartilaginous dysplasia.
The lesions in fibrous dysplasia are often well circumscribed and are typically surrounded by a relatively wide rim of sclerotic bone sometimes referred to as a rind ( Figs. 8-10 , 8-11 and 8-12 ). This feature is often seen in long-standing asymptomatic solitary lesions. Even the expansile lesions are usually delineated by a thin rim of newly formed bone. Bony deformities, particularly of the weight-bearing bones, are associated with more extensive involvement ( Figs. 8-9 and 8-14 to 8-16 ). An example is the shepherd's crook deformity of the proximal femur ( Figs. 8-14 and 8-15 ). In extremely rare cases, fibrous dysplasia can form an exophytic extraosseous mass or can grow on the surface of bone ( Figs. 8-17 and 8-18 ). This rare form typically occurs in smaller bones, such as the ribs or short tubular bones of the hands and feet. These lesions are sometimes attached to the adjacent bone by a bony stalk or form exophytic sessile masses. This unusual variant of fibrous dysplasia is also referred to as fibrous dysplasia protuberans.
Gross Findings
When a focus of fibrous dysplasia is examined in situ, as in a resected rib or fibula, it presents as a centrally located lesion composed of fibrous tan to gray gritty tissue ( Fig. 8-19 ). Lesions that are more heavily ossified may be yellow to white focally. Fibrous dysplasia usually has sharp borders, and the bone contour is expanded with a thinned cortex. Areas of cartilaginous tissue are sometimes recognized as discrete translucent blue-white nodules. Hemorrhage and cystic change may be present, and areas of prominent xanthogranulomatous reaction have a yellow appearance. Some lesions may develop extensive cystic change. Hemorrhagic, blowout areas usually signify secondary aneurysmal bone cyst formation.
Microscopic Findings
Fibrous dysplasia is composed of spindle cells that have a whorled or storiform arrangement with interspersed trabeculae of immature woven bone devoid of rimming osteoblasts ( Fig. 8-20 ). The number and distribution of bone trabeculae and their level of maturation may vary among different lesions and in different areas of the same lesion ( Figs. 8-21 to 8-23 ). The most common and characteristic pattern of bone produced in fibrous dysplasia consists of slender, curved, and branching trabeculae of bone without surface osteoblasts. These are frequently described as resembling Chinese characters ( Fig. 8-22 ), although no such characters actually exist in written Chinese. In some cases, the trabeculae of bone are sparsely distributed with a predominance of cellular fibrous tissue. At the other end of the spectrum are heavily ossified lesions in which relatively mature bone trabeculae overshadow the fibrous component of the lesion ( Figs. 8-23 and 8-24 ). The lesions with abundant bony components frequently contain foci of matrix mineralization that resemble cementoid bodies ( Fig. 8-24 ). These concentrically laminated calcified structures are most frequently seen in fibrous dysplasia involving craniofacial bones but may also be present in other sites. In the past, lesions with prominent cementoid structures were designated, especially in oral pathology literature, as fibrocementomas or cementifying fibromas.
Examination under polarized light reveals a very characteristic and diagnostically important feature: All bone trabeculae in fibrous dysplasia, despite their mature appearance, show a polarization pattern that forms disorganized, haphazard deposits characteristic of woven bone ( Fig. 8-25 ). Secondary changes in fibrous dysplasia may alter the typical microscopic appearance and make it difficult to diagnose. Hemorrhage and secondary fibrohistiocytic reaction may be present focally. Occasionally a diffuse infiltrate of foamy histiocytes may obscure the characteristic microscopic features of the lesion. Such lesions may be incorrectly designated as xanthomas of bone. Intralesional hemorrhage in fibrous dysplasia can provoke extensive giant cell reaction, which leads to confusion with giant cell tumor ( Figs. 8-26 and 8-27 ). Myxoid change of stromal tissue can be focal or quite extensive in some lesions. These secondary changes are more likely to be found in the older lesions of fibrous dysplasia.
Reactive bone with prominent osteoblastic rimming may be seen focally in fibrous dysplasia complicated by pathologic fracture. Small fractures of the thinned cortex may not be clinically and radiographically evident; therefore the stimulus to reactive bone formation remains unrecognized. Secondary aneurysmal bone cyst with radiographic evidence of an expansile lesion is a common complication ( Figs. 8-26 to 8-28 ). Cystic change with accumulation of serous fluid in fibrous dysplastic tissue is a distinct phenomenon and should not be automatically interpreted as a secondary aneurysmal bone cyst. The underlying fibrous dysplasia can be almost completely obliterated by either type of secondary cystic change. Microscopic foci of cartilaginous differentiation are frequently present in fibrous dysplasia, but in rare cases the cartilage matrix may dominate the microscopic and radiographic pictures. These rare cases are referred to as fibrous dysplasia with massive cartilaginous differentiation or fibrocartilaginous dysplasia. This peculiar variant of fibrous dysplasia is separately described in further detail.
Differential Diagnosis
Fibrous dysplasia is most frequently confused histologically with other benign fibroosseous lesions, in particular with osteofibrous dysplasia . This entity is composed of a mixture of fibrous tissue and mature bone trabeculae that exhibit classic osteoblastic rimming. Osteofibrous dysplasia is an intracortical lesion that occurs in children, whereas fibrous dysplasia tends to be more centrally located in the medullary cavity and is often first diagnosed in adults. It affects the tibia and fibula almost exclusively, whereas fibrous dysplasia can occur in any bone. Desmoplastic fibroma, because it can mimic the fibrous component of fibrous dysplasia, is sometimes considered when a small biopsy sample does not include the osteoid and woven bone elements found in fibrous dysplasia. Reactive bone formation in desmoplastic fibroma at the edge of the lesion can usually be recognized by the prominent osteoblastic rimming. It is most important to distinguish between fibrous dysplasia and low-grade intramedullary osteosarcoma . The latter lesion can be difficult to diagnose when the bone trabeculae of the tumor forms the branching or interconnected pattern usually associated with fibrous dysplasia. However, the spindle-cell areas in this entity usually show nuclear atypia and larger nuclei with a coarser chromatin pattern than those found in fibrous dysplasia. As opposed to the circumscribed expansile growth pattern of fibrous dysplasia with peripheral bone sclerosis, low-grade intramedullary osteosarcoma permeates cancellous bone trabeculae with an infiltrative growth pattern. Preliminary evidence indicates that the presence of mutations involving a gene coding for G sα subunit in fibrous dysplasia may be a useful marker in differential diagnosis of this disorder and other fibroosseous lesions, including well-differentiated fibroblastic osteosarcoma.
Polyostotic fibrous dysplasia may mimic enchondromatosis on radiographs because of the multiplicity of lesions in both conditions, but enchondromatosis tends to show a much greater unilateral predominance. Histologically, these lesions may be confused when fibrous dysplasia contains an abundance of cartilage. In these cases, attention to the radiographic features and careful study of the histologic material for evidence of fibroosseous elements usually resolves the dilemma. In more florid examples of massive chondroid differentiation in fibrous dysplasia, there is also the danger of confusion with conventional chondrosarcoma. This can be excluded by the absence of chondrocyte atypia and the presence of enchondral ossification at the borders of the dysplastic chondroid foci.
Treatment and Behavior
In fibrous dysplasia the multifocal skeletal lesions develop more or less synchronously. Therefore the initially diagnosed monostotic forms typically do not progress to polyostotic generalized forms. However, additional foci of fibrous dysplasia occasionally develop in an affected bone. A solitary focus may enlarge in size, and the extent of involvement can progress over time. In rare instances, such locally progressive lesions may expand beyond the bone contour into the soft tissue. This occurs most frequently during the skeletal growth period. The lesions have a tendency to stabilize after puberty, and new foci rarely develop during adulthood. The enlargement of lesions of fibrous dysplasia after puberty is more frequently related to secondary aneurysmal bone cyst and simple cystic degeneration rather than to actual proliferative activity of the lesion. Superimposition of aneurysmal bone cyst and rapid enlargement of the lesion may prompt surgical intervention. Pregnancy seems to promote enlargement of the lesions, but the mechanism of this phenomenon is unclear. It is unknown whether it is related to increased proliferative activity or simply to secondary changes such as hyperemia and hemorrhage.
Bone deformities in fibrous dysplasia are treated by corrective surgery. A solitary focus that is prone to pathologic fracture, especially in the long bones, is treated by curettage and bone grafting with or without internal fixation. Lesions of small-diameter expendable bones, such as the ribs or fibula, are usually treated by segmental resection.
The development of secondary sarcoma in fibrous dysplasia is an extremely rare but well-established phenomenon. It occurs in less than 1% of patients during adult life in long-standing lesions. Lesions treated with radiation therapy are more likely to develop sarcomatous transformation, but rare cases of spontaneous malignant transformation also have been reported. Malignant transformation is related to the extent of involvement, and patients with polyostotic fibrous dysplasia have a greater risk of the development of sarcomatous transformation than those with monostotic forms. The average lag between the diagnosis and the development of a malignancy is 13.5 years, and patients are generally in the third and fourth decades of life. The types of sarcoma that complicate fibrous dysplasia are most frequently malignant fibrous histiocytoma (fibrosarcoma) or osteosarcoma of high histologic grade. Chondrosarcoma that develops in association with fibrous dysplasia has also been reported. An extremely rare case of association between desmoplastic fibroma and fibrous dysplasia was documented in one report. The craniofacial skeleton and femur are the most common sites of malignant transformation. This generally correlates with the frequency of distribution of bones involved in fibrous dysplasia. The prognosis for patients who develop sarcomatous transformation is poor. Pulmonary metastasis develops in most patients, and the mean survival period is 3.4 years. Alterations in the clinical course in patients older than age 40 years with known fibrous dysplasia, such as pain and swelling, should be carefully evaluated.
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