6.Fibroosseous Lesions 2

Pathology Patterns Reviews

Benign Fibro-osseous Diseases of the Maxillofacial Bones A Review and Differential Diagnosis Faizan Alawi, DDS Key Words: Benign fibro-osseous lesion; Fibrous dysplasia; Ossifying fibroma; Osseous dysplasia; Cementoma DOI: 10.1309/9VB3LGGEPPR7RMAR

Abstract Benign fibro-osseous lesions (BFOLs) of the maxillofacial bones represent a diverse group of pathologic conditions that includes developmental lesions, reactive or dysplastic diseases, and neoplasms. Owing to substantial overlap of the histopathologic findings, subclassification of BFOLs may be problematic. Moreover, this is not merely an academic exercise because the therapeutic management of BFOLs varies depending on the actual disease process. To further complicate matters, a number of other disease processes demonstrate clinical, radiographic, and microscopic features that bear resemblance to those encountered in recognized fibro-osseous conditions. The objective of this article is to review the most current clinicopathologic, radiographic, and molecular studies of BFOLs to aid the surgical pathologist in the recognition and diagnosis of this diverse group of maxillofacial lesions. A discussion of the various disease processes that occasionally may be confused with BFOLs also is included.

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Benign fibro-osseous lesions (BFOLs) of the maxillofacial bones comprise a diverse group of pathologic conditions that includes developmental lesions, reactive or dysplastic diseases, and neoplasms.1 Regardless of subtype, all BFOLs demonstrate replacement of normal bone by fibrous connective tissue with an admixture of mineralized product, including osteoid, mature bone, and/or cementum-like calcifications. Thus, a histologic diagnosis of a BFOL is, in many cases, relatively uncomplicated. The main challenge lies in the subclassification of BFOLs. Moreover, this is not merely an academic exercise because the therapeutic management of BFOLs varies depending on the actual disease process.1 Historically, the nosology of BFOL has been fraught with inconsistency, confusion, and a seemingly endless array of terminology. 1-6 However, a classification of BFOLs proposed by Waldron6 has gained wide recognition over the years and remains, to date, the most accepted. Recently, Brannon and Fowler1 proposed a slightly modified categorization of BFOLs, which, with further study, eventually may become the standard ❚Table 1❚ . Nevertheless, despite advances in our understanding of these conditions, occasional lesions still defy classification.6 From a clinical standpoint, BFOLs may be associated with significant cosmetic and functional disturbances, or they may be completely asymptomatic, localized lesions that are identified only on routine radiographs.1,4,5,7 Furthermore, fibrous dysplasia, a form of BFOL typically diagnosed in children and adolescents, can be associated with a generalized endocrinopathy.2 Moreover, there are pronounced racial and sex predilections for a subset of BFOLs that exclusively affects the jawbones, the osseous dysplasias, of which a hereditary form exists.4 Radiographically, BFOLs may manifest as solitary, multifocal, or multiquadrant disease; they © American Society for Clinical Pathology

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❚Table 1❚❚ Recognized Benign Fibro-osseous Diseases* I. Fibrous dysplasia A. Monostotic B. Craniofacial C. Polyostotic D. McCune-Albright syndrome II. Ossifying fibroma and juvenile ossifying fibroma III. Osseous dysplasia A. Periapical B. Focal C. Florid D. Familial gigantiform cementoma *

Adapted from the classification system proposed by Brannon and Fowler.1

may be ill or well defined; they may have a radiolucent, mixed radiolucent-radiopaque, predominantly radiopaque, or groundglass appearance; they may be monostotic or polyostotic; and they may or may not be associated with the root apices of teeth. 7 The gross appearance of BFOLs also may vary depending on the lesion. Thus, most oral and maxillofacial pathologists would agree that definitive diagnosis of a BFOL requires correlation of the histologic appearance of the lesion with the clinical, radiographic, and intraoperative findings.1,6 The objective of this article is to review the most current clinicopathologic, radiographic, and molecular studies of BFOLs to aid the surgical pathologist in the recognition and diagnosis of this diverse group of maxillofacial lesions. A number of other disease processes demonstrate clinical, radiographic, and microscopic features that bear resemblance to those encountered in recognized fibro-osseous conditions.2 Thus, other entities that may be included in the differential diagnosis of BFOLs also will be discussed ❚Table 2❚ . However, it must be noted that these other lesions do not completely fulfill the histologic criteria for BFOLs as defined by Waldron.6 The interested reader is directed to a number of other articles, including an excellent review by Brannon and Fowler,1 detailing the historic controversies surrounding the putative pathogenesis, diagnosis, and

❚Table 2❚❚ Disease Processes That May Be Included in the Differential Diagnosis of a Benign Fibro-osseous Lesion Paget disease of bone Low-grade osteosarcoma Osteoblastoma Osteoid osteoma Cementoblastoma Central odontogenic fibroma Proliferative periostitis Renal osteodystrophy Central giant cell granuloma Brown tumor Aneurysmal bone cyst Cherubism

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classification of BFOLs.2-6 With respect to nomenclature in the present article, the Brannon and Fowler1 classification system is used.

True BFOLs Fibrous Dysplasia Fibrous dysplasia (FD) is a benign fibro-osseous disease that frequently affects the jawbones. It has been suggested that the diagnosis of FD is overused in clinical practice and should be reserved for only the lesions that manifest as poorly delineated, expanding lesions in children and young adults.2,8 FD is classified as being monostotic when it affects a single bone or, less commonly, polyostotic when it involves multiple bones concomitantly. About 3% to 5% of polyostotic FD may be associated with extraosseous manifestations.9 McCune-Albright syndrome (MAS) is a sporadic disorder that is characterized by the clinical triad of polyostotic FD, skin hyperpigmentation (café au lait spots), and multiple endocrinopathies, including gonadal hyperfunction leading to sexual precocity (especially in females).9 Other less common manifestations of MAS include hyperthyroidism, adenomas of various endocrine glands including the pituitary gland, Cushing syndrome, acromegaly, benign ovarian cysts, linear epidermal nevi, and neonatal cholestasis.9-13 The skin spots often are unilateral and ipsilateral to the FD lesions.14 Mazabraud syndrome is another rare, sporadic disease that is characterized primarily by polyostotic FD and intramuscular myxomas.15 The myxomas tend to appear many years after the initial manifestations of FD. There have been about 40 documented cases of this unusual disorder; however, there seems to be some clinical overlap with MAS, since patients with Mazabraud syndrome also may have café au lait spots, and patients with MAS reportedly have developed soft tissue myxomas.16,17 Although the exact cell of origin remains unclear, it seems that FD is derived from osteoprogenitor, fibroblastlike cells.18,19 It has been determined that monostotic FD, polyostotic FD, MAS, and sporadic pituitary adenomas have the same causal genesis, an activating, somatic mutation in the GNAS1 gene found on chromosome 20q13.9,12,13,20 Two distinct missense mutations in the alpha subunit of a G stimulatory protein have been identified that seem to account for most of the aforementioned disease processes.12 The mutations lead to constitutive activation of adenylyl cyclase, resulting in a persistent elevation of cyclic adenosine monophosphate. This, in turn, induces an alteration in the transcription and expression of several downstream target genes, including c-fos, a proto-oncogene.19,21 Am J Clin Pathol 2002;118(Suppl 1):S50-S70 DOI: 10.1092/9VB3LGGEPPR7RMAR

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In one study, high levels of c-fos were identified in the bone marrow spaces of FD-affected bones, whereas no c-fos expression was detected in bone specimens from healthy subjects or from normal, uninvolved bone obtained from patients with FD.19 In addition, overexpression of c-fos in transgenic mice results in the formation of bone lesions that resemble FD.22 Furthermore, osteosarcomas develop in some cases.23 This latter finding is of particular interest because there is a 0.5% human risk for spontaneous sarcomatous transformation of FD, and osteosarcomas develop in an estimated 4% of patients with MAS.24 Clonal chromosomal aberrations also have been identified in FD; however, the only recurrent changes reported to date include structural 12p13 changes and trisomy 2.25-27 Thus, based on these and other findings, Cohen and Howell13 and others advance the argument that FD should no longer be considered a hamartomatous or developmental disorder of bone (as FD is widely considered to be), but rather a “benign neoplasm with malignant potential.”13,21,24-27 Overall, 25% of all FDs and 35% of patients with MAS exhibit maxillary or mandibular involvement.28 Although mandibular lesions may be monostotic, the term craniofacial FD usually is used to describe FD of the maxillary bone, because often the maxillary sinus and adjacent bones also are involved, such as the zygoma, sphenoid, temporal, orbital, nasal, frontal, and occipital bones.6,28 Although multiple bones are affected, the contiguous distribution of the lesions precludes the classification of craniofacial FD as polyostotic disease. However, regardless of the number of bones affected, FD is almost always a unilateral disease, and lesions rarely cross the midline.14 FD usually arises within the first or second decades of life, manifesting clinically as a slow-growing, painless expansion of the involved bone.28 Facial asymmetry may be apparent. In rare cases, the expansion may be more rapid or begin to accelerate after a period of slow growth, resulting in marked facial deformity and potential nerve entrapment. Many of these latter cases often are attributed to the concomitant development of an aneurysmal bone cyst (ABC) or, less commonly, malignant transformation.1,29,30 Active growth of FD typically slows or ceases around the time of puberty or after skeletal maturation; however, sporadic periods of regrowth may occur in adulthood.2 Patients with polyostotic disease often are younger at the time of diagnosis than those with monostotic FD. In a longitudinal study of 32 patients with MAS, followed up for an average of 10 years, almost all patients exhibited cutaneous café au lait spots at birth; 50% of females manifested precocious puberty by age 4 years; and 50% of patients demonstrated FD by age 8 years, with an increase in the number of affected bones and in the severity of the lesions with advancing age.31 S52 S52

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In general, the radiographic appearance of bone lesions can be very useful and, in some cases, necessary for diagnosing intraosseous pathology. In patients with BFOLs, especially of the maxillofacial bones, radiographs are essential to subclassify a given lesion.7,32 Radiologic methods include panoramic and plain films, computed tomography (CT), magnetic resonance imaging (MRI), and whole-body bone scintigraphy.33 The radiographic appearance of FD varies with the stage of development and amount of bony matrix within the lesion. On a plain or panoramic film, early lesions may appear well defined and radiolucent, whereas later lesions may appear largely sclerotic.7 However, classic FD has a ground-glass or orange-peel appearance, with poorly discernible borders that appear to blend in with the surrounding, unaffected bone ❚Image 1❚.7 The lamina dura surrounding the teeth in the affected area may be completely effaced. These are important features that can be used to differentiate FD from ossifying fibroma (OF), which, unlike FD, appears well-circumscribed and has sharply defined, sclerotic borders.28 FD of the mandible also may displace the inferior alveolar canal superiorly, which is another characteristic feature that may be used to differentiate FD from other BFOLs.7,32 Almost all other BFOLs develop above the canal, in close approximation to the teeth. A lateral skull view of craniofacial FD characteristically demonstrates increased radiodensity of the base of the skull involving the occiput, sella turcica, orbital roof, and frontal bones.6 The maxillary sinus may appear obliterated in a Waters view since FD may displace the floor of the sinus superiorly. CT and MRI scans also may be useful for establishing the full extent of the lesion and for assessing the degree of bony expansion.7 Bone

❚Image 1❚ Periapical radiograph exhibiting a ground-glass appearance of the bone in a patient with craniofacial fibrous dysplasia.

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scintigraphy is a sensitive imaging modality that is useful for detecting early FD, as well as for determining the extent of polyostotic disease.34 FD also may be associated with ABCs and traumatic bone cysts, which may appear radiographically as unilocular or multilocular radiolucencies.29,35 The histologic appearance of FD, as with other BFOLs, varies depending on the stage of the lesion. 1 Early FD usually exhibits a moderately cellular, fibrous stroma containing haphazardly arranged, uniform, benignappearing, spindle-shaped to ovoid fibroblasts. There are typically no mitoses. A variable number of small, ovoid blood vessels are seen within the stroma, and collagen bundles often are scant. Scattered, irregularly shaped trabeculae of woven bone are seen throughout the stroma. The trabeculae tend to be delicate and curvilinear and have been likened to Chinese script-writing.6 Moreover, the lesional bone fuses with the adjacent uninvolved bone—a feature not seen in other BFOLs ❚Image 2❚.1,5 Biopsy specimens that do not demonstrate the relationship of the lesional bone to the adjacent normal bone preclude definitive diagnosis of FD.1,5 Osteoblastic rimming is observed only occasionally; however, osteoblasts may be incorporated within the lesional bone. Focally scattered, small, ovoid calcifications also may be seen. Occasional basophilic reversal lines may be identified, but they are never as prominent as they are in Paget disease of bone.1,3 Artifactual separation of the lesional bone from the surrounding stroma is not unusual. Unlike FD in the long bones, FD of the jaws appears to undergo progressive maturation to lamellar bone, with a concomitant decrease in stromal cellularity.6 The trabeculae in these “older” lesions tend to be arranged parallel to one another.

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Although rare, malignant transformation of FD has been reported in patients with craniognathic disease.30,36-39 Most malignant neoplasms develop in patients who previously have undergone radiation therapy to the affected area; however, de novo sarcomatous transformation has been identified.6,24 Overall, there is a 0.4% to 0.5% incidence of secondary malignant neoplasms in FD, with males and patients with polyostotic disease experiencing a greater risk.36 Osteosarcoma makes up more than half of all the malignant diagnoses, followed by fibrosarcoma and chondrosarcoma.1,30,36,37 Secondary angiosarcomas and a malignant fibrous histiocytoma also have been reported.38,39 The surgical management of a small, monostotic mandibular lesion is much less problematic than treatment of larger, more diffuse lesions or of craniofacial FD.6 It has been suggested that since the growth of FD often tends to stabilize and occasionally stops when skeletal maturity is attained, surgical intervention in children and adolescents with more extensive lesions should be delayed as long as possible.6 However, in some cases, FD may persist into late adult life.40 Conversely, spontaneous regression of FD also has been reported.41 If treatment is necessary, especially in young patients with significant cosmetic or functional deformity, therapy should be limited to a contouring procedure, without complete resection, to minimize morbidity. However, it has been estimated that 25% to 50% of patients will exhibit subsequent regrowth of the lesion and, thus, may require multiple shave-down procedures.6 Complete surgical resection is recommended for patients with rapidly expanding FD, lesions that encroach on the orbit, and lesions secondarily involved with an ABC or a malignancy.6,28-30,42 Radiation

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❚Image 2❚ Fibrous dysplasia. A, Lesional bone fusing with the bony cortex (left side) (H&E, ×40). B, Irregularly shaped bony trabeculae embedded within a moderately cellular fibrous stroma. Artifactual separation of the bony elements from the surrounding fibrous tissue also is seen (H&E, ×100).

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therapy is contraindicated owing to the increased risk of malignant transformation. Long-term clinical and radiographic follow-up is recommended for any patient with FD. Ossifying Fibroma OFs are considered to be true benign fibro-osseous neoplasms that develop mainly within the jawbones.1,3,6 OFs develop more commonly in females than males and have a peak incidence during the third and fourth decades of life.43 The majority of cases arise in the molar-premolar region of the mandible. Unlike focal osseous dysplasia, most OFs do not show close association with the roots of teeth. 44 Although OFs may manifest as small asymptomatic lesions that are noted only on routine dental radiographs, most are slow-growing, expanding lesions that often average more than 3 cm in diameter at the time of diagnosis.44 Pain and paresthesia are rarely associated with OFs. However, occasional tumors may behave more aggressively, reaching massive proportions and causing visible facial deformity.45 A series of 8 female patients with “giant OF” has been reported in which each tumor measured more than 8 cm and involved only the maxillary bone.45 Microscopically, focal areas of ABC were identified in the majority of these lesions. Subsequent reports have documented similar examples of these large tumors.46 Overall, the growth potential of OFs is unpredictable, and there are no clinical or microscopic features that can be used effectively to predict behavior.1 Although the cell of origin remains unknown, OFs are thought to be derived from elements within the periodontal ligament space.2,43 However, since similar-appearing lesions arise in other cranial bones and much less commonly in the long bones, the exact origin of OFs remains unclear.1,6 Cytogenetic study of OFs has been limited; however, molecular changes have been identified.47-49 In one study, 3 orbital OFs exhibited balanced translocations with recurring breakpoints at Xq26 and 2q33.48 Moreover, Dal Cin et al49 also reported a mandibular OF with an interstitial deletion on chromosome 2 between q31-32 and q35-36. The significance of these findings should be confirmed after the analysis of additional tumors. Radiographically, OFs typically appear as unilocular lesions with sharply defined, smooth, corticated borders, a feature that is used to differentiate OFs from FD.7,32,50 Early lesions are largely radiolucent and cyst-like in appearance, whereas later-stage lesions may manifest as central radiopaque masses surrounded by a radiolucent rim, thus resembling an osteoblastoma.50 Approximately 70% of cases develop within the mandible, and large tumors may cause a characteristic downward bowing of the inferior cortex of the mandible ❚Image 3❚.7,32 An OF is a well-circumscribed, occasionally encapsulated mass that may show a variety of different microscopic patterns, depending on the stage of the lesion and S54 S54

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❚Image 3❚ Ossifying fibroma. Panoramic radiograph exhibiting a large, well-circumscribed, mixed, radiolucent-radiopaque lesion in the right mandible.

the degree of calcification. 43 OFs usually consist of a moderately cellular, relatively avascular, dense fibrous stroma. The cells appear spindle-shaped to ovoid and may be haphazardly arranged or organized in a vague storiform pattern. The nuclei are bland appearing and contain single, inconspicuous nucleoli. Focally scattered multinucleated giant cells also may be seen. The calcified material may consist of thin, irregularly shaped trabeculae of woven bone; scattered trabeculae of lamellar bone; deposits of basophilic staining, round or ovoid, cellular or acellular calcified deposits that have been likened to cementum; or any combination thereof ❚Image 4❚.6,43,44 The calcifications occasionally exhibit a peripheral shell of osteoid and may be rimmed by osteoblasts. Owing to the presence of the calcified spherules, OFs also have been designated as “cemento-ossifying fibroma” or “cementifying fibroma.”1,2,6 However, cementum-like calcifications also are seen in similar-appearing cranial and extragnathic bone lesions, thus making their cemental nature unlikely.1,6 Unlike FD, the lesional bone in OFs does not fuse to adjacent uninvolved cortical bone. However, despite the apparent differences in histologic features between OFs and FD, there still is enough microscopic overlap that histologic examination alone is insufficient for differentiating the lesions.1 The therapeutic management of OFs ranges from the observation of small asymptomatic lesions to complete surgical enucleation or local resection of larger lesions.51 Surgical exploration usually reveals a well-demarcated mass that often is easily separated from the surrounding bone, either intact or in several large pieces.43,44,52 On the other © American Society for Clinical Pathology

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❚Image 4❚ Ossifying fibroma. A, Scattered, irregularly shaped bony trabeculae and calcified spherules amid a background of relatively avascular, cellular fibrous tissue (H&E, ×40). B, Round, acellular, cementum-like calcifications (H&E, ×100).

hand, FD and focal osseous dysplasia tend to be excised with greater difficulty and often in multiple, small, gritty fragments.6,44,52 Recurrence rates vary from study to study.43,44 Nevertheless, it can be concluded that OF is a benign neoplasm that seems to have a risk for recurrence, especially if incompletely removed.43 Unusual clinical variations of OF have been reported. In addition to the “giant OF,”45 a number of patients with multiple OFs have been identified, most of whom exhibit solitary, well-circumscribed lesions in both the maxilla and mandible.46,53,54 Multiple OFs also have been identified in association with a clinically and genetically distinct disorder.55-58 Hyperparathyroidism–jaw tumor syndrome is an autosomal dominant disease that is characterized by adenomainduced, primary hyperparathyroidism and well-circumscribed BFOLs of the jawbones that have been characterized as OF.55-58 A variety of renal anomalies also are observed commonly, including renal hamartomas, polycystic kidney disease, and multiple degenerative cysts.55 In addition, affected patients have an increased risk of developing parathyroid carcinoma and Wilms tumor.57 Moreover, in one large kindred traced for 4 generations, family members with pancreatic adenocarcinoma, renal cortical adenoma, papillary renal cell carcinoma, testicular germ cell tumor, and Hürthle cell thyroid adenoma have been identified. 57 In another family, 2 affected females also developed multiple uterine adenomyomatous polyps.58 The gene responsible for this syndrome has been recently mapped to 1q25-q31 and is considered a putative tumor suppressor gene.55 © American Society for Clinical Pathology

Juvenile Ossifying Fibroma There is little agreement on the clinical and histopathologic criteria that currently are used to define juvenile OF (JOF) as a unique benign fibro-osseous neoplasm.1 Nevertheless, there are 2 variants of JOF commonly reported in the literature: a trabecular variant (TJOF) and a psammomatoid variant (PJOF).1,59,60 Whether both types are variations of the same neoplasm or actually represent distinct clinicopathologic entities also remains a subject of debate.60 PJOF is reported more frequently in the literature than TJOF.59 Both variants can occur at any age, but most develop during the first and second decades of life. However, the average age at diagnosis of PJOF seems to be later than that for TJOF.3,59 There is no significant sex predilection for either variant. One of the main arguments used to justify differentiation of these 2 variants as distinct entities is the anatomic site of involvement. Approximately 75% of PJOFs develop in the orbit, paranasal sinuses, and calvaria, whereas only about 25% of all cases involve the maxilla or mandible.59 In contrast, about 95% of the documented cases of TJOF have developed within the jawbones, with maxillary lesions occurring more frequently.59 Only occasional examples of TJOF have arisen within the fronto-ethmoid complex and sinonasal bones. The clinical signs and symptoms are related to the anatomic site of involvement. Although tumors in young children may expand rapidly, overall, the growth rate is variable. The radiographic appearance is nonspecific. Both tumors may manifest as well-demarcated, unilocular or multilocular radiolucencies with a variable amount of radiopacity, usually manifesting as fine specks or as Am J Clin Pathol 2002;118(Suppl 1):S50-S70 DOI: 10.1092/9VB3LGGEPPR7RMAR

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ground-glass opacification.7,59 Maxillary tumors often fill and obliterate the maxillary sinus, whereas mandibular tumors usually involve the ramus and angle. A biopsy reveals significant histologic overlap between the variants.1,60 Microscopic examination typically shows an unencapsulated lesion composed of a cell-rich stroma, usually with little collagen. However, later-stage lesions may demonstrate some collagenization. Reactive bone may be seen at the periphery of the lesion, but the lesional tissue often is seen infiltrating the surrounding normal bone. The cells are spindle-shaped to ovoid, contain bland-appearing nuclei and inconspicuous nucleoli, and may be arranged in a storiform pattern. Focally scattered, typical mitotic figures may be seen; however, they are never numerous. In TJOF, delicate “seams” of osteoid rimmed by osteoblasts seem to arise from within the stroma. 3 Plump, eosinophilic osteoblasts often are incorporated within the osteoid. Scattered, irregularly shaped trabeculae of woven bone and occasional calcified spherules also are seen. On the other hand, the calcifications in PJOF usually are basophilic, acellular, and round or ovoid and may resemble psammoma bodies ❚Image 5❚.59 In some cases, the calcified spherules may be closely packed to one another with little intervening stroma. Occasional trabeculae of woven bone also may be seen; however, they usually are more numerous in TJOF. Crescentic or thorn-shaped calcifications also may be observed.1 Myxoid degeneration and ABC-like areas that are characterized by large, blood-filled sinusoidal spaces surrounded by multinucleated giant cells may be seen in both variants. However, these features are identified more commonly in PJOF than in TJOF.59

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A limited number of ultrastructural studies have been performed on BFOLs.61,62 In one study of a JOF of the orbit, fibroblasts, myofibroblasts, and “undifferentiated” cells with numerous cytoplasmic processes were seen extending between irregularly arranged collagen bundles.61 The psammomatous calcifications were composed of dense, amorphous material, and they appeared to be deposited on top of the collagen fibers. The calcified spherules bore a superficial resemblance to psammoma bodies of meningiomas and some papillary carcinomas. Conservative surgical excision is the treatment of choice for PJOF and TJOF; however, recurrences are seen in 30% to 50% of cases. 59 Multiple recurrences also have been reported; however, local excision is still recommended.1 The extent of surgical resection should be dictated by the age of the patient, anatomic location of the tumor, and the effect of the tumor on surrounding vital structures.59 Malignant transformation has not been reported for either variant. Osseous Dysplasia Osseous dysplasias are the most common form of BFOL in the jawbones, yet they are probably the least recognized by surgical pathologists.6 Osseous dysplasias include hereditary and nonhereditary diseases. Since osseous dysplasias develop only in tooth-bearing regions, it is theorized that this unique group of lesions is derived from elements within the periodontal ligament space or is related to the unique presence of teeth and periodontium within the jawbones.2,4,6 Similar lesions have yet to be characterized in any other bones apart from the maxilla and mandible.

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❚Image 5❚ Juvenile ossifying fibroma. A, Trabecular variant. Hypercellular stroma with strands of osteoid and scattered multinucleated giant cells (H&E, ×40). B, Psammomatoid variant. Numerous round calcifications embedded in a hypercellular background (H&E, ×20).

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The term dysplasia refers to the abnormal production and disordered development of bone and cementum-like material.1,6 Because these lesions have a distinct predilection for females, it also has been suggested that osseous dysplasias may represent a dysplastic process related to a hormonal imbalance that influences bone remodeling.63 There are 3 nonhereditary subtypes of osseous dysplasias that are believed to represent variants of the same basic disease process: periapical osseous dysplasia, focal osseous dysplasia, and florid osseous dysplasia.4 The distinction is based solely on the clinical and radiographic manifestations of the lesions. The histologic appearance of osseous dysplasias varies depending on the stage of the lesion ❚Image 6❚.4,6 Early

lesions may demonstrate hypercellular, fibrous connective tissue containing numerous small, round or ovoid, vascular channels. A variable mixture of calcified spherules and osteoblast-rimmed, irregularly shaped trabeculae of woven bone are scattered throughout the stroma. Focally scattered multinucleated giant cells also may be seen. In more advanced cases, the calcifications may coalesce at the expense of the surrounding stroma, forming large aggregates of acellular, poorly vascularized sclerotic tissue. Prominent basophilic reversal lines may be seen within the sclerotic bone, resembling those seen in Paget disease of bone.4 Inflammation often is minimal. However, if the overlying oral mucosa becomes ulcerated and the lesional bone comes

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❚Image 6❚ Osseous dysplasia. A, Predominantly hypercellular fibrous stroma with few calcifications (H&E, ×20). B, Numerous irregularly shaped trabeculae of woven bone embedded within a fibrous stroma containing numerous small blood vessels (H&E, ×40). C, Round, cementum-like calcifications (H&E, ×100). D, Large aggregate of acellular bone that has coalesced in a patient with florid osseous dysplasia (H&E, ×40).

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into contact with the oral flora, a low-grade osteomyelitis may ensue, with eventual sequestration of a sclerotic mass.1,4 This complication more commonly arises in patients with late-stage florid osseous dysplasia. Periapical Osseous Dysplasia Periapical osseous dysplasia has a distinct predilection for black females and develops almost exclusively after the age of 30 years.4,64 Up to 6% of black females may manifest this disease, whereas periapical osseous dysplasia occurs in up to 0.29% of the general population.64,65 Periapical osseous dysplasia is almost always asymptomatic and nonexpanding and usually is discovered only on routine dental radiographs.4 Periapical osseous dysplasia usually is found in intimate association with the root apices of the mandibular anterior teeth ❚Image 7❚.7 However, in occasional cases, periapical osseous dysplasia may be associated with a single tooth, in which case it often is mistaken for inflammatory periapical disease.7,66 Vitality testing of the tooth should avoid any errors in diagnosis, since periapical osseous dysplasia–affected teeth remain vital. Serial radiographs have demonstrated that periapical osseous dysplasia initially manifests as multiple, circumscribed, noncorticated radiolucencies, which may, over time, exhibit increasing radiopacity.7,32,67 Moreover, bone scintigraphy may demonstrate intense isotope accumulation within the lesions.68 Although each individual lesion exhibits little tendency to enlarge, often adjacent lesions coalesce to form a larger, irregularly shaped, mixed radiolucent-radiopaque mass.6 However, the progression of calcification is not always predictable, because occasional lesions may remain static over time or regress spontaneously.67 In most cases, the characteristic clinical and radiographic features of periapical osseous dysplasia usually preclude the need for any surgical intervention. However, regular follow-up visits are needed to gauge the progression of the disease, since periapical osseous dysplasia may be mistaken for other neoplastic and nonneoplastic lesions.66 Although periapical osseous dysplasia is a sporadic disorder, the classic radiographic features have been identified in multiple individuals of one family.69 However, it has been suggested that this family probably demonstrates a minimally expressed variant of familial gigantiform cementoma (also known as familial florid osseous dysplasia).69 Focal Osseous Dysplasia Waldron6 suggested that focal osseous dysplasia likely represents the most common BFOL of the jawbones. However, many cases probably are misdiagnosed as OF.6 Like periapical osseous dysplasia, focal osseous dysplasia is much more common in females than males, and most lesions are recognized during the fourth and fifth decades of life.4,52,70 Focal osseous dysplasia is much more common in S58 S58

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❚Image 7❚ Periapical osseous dysplasia. Periapical radiograph demonstrating multiple, relatively well-circumscribed radiolucencies involving the apices of the mandibular anterior teeth. This is an example of an early-stage lesion.

blacks than whites; however, a number of cases also have been reported in Asian patients.4,70,71 In all reports, females outnumber males by almost 9:1.70,71 Like periapical osseous dysplasia, focal osseous dysplasia is invariably asymptomatic, manifesting most commonly as a small, solitary, relatively well-demarcated lesion in the posterior mandible, either in close association with the apices of teeth or in areas where a tooth has been extracted previously ❚Image 8❚.44,52,70 In contrast, most OFs cause jaw expansion and are not intimately associated with teeth or with extraction sites.43,44 Moreover, OFs demonstrate no significant sex predilection. In one study examining 221 cases of focal osseous dysplasia70 and in another study comparing 241 cases of focal osseous dysplasia with 75 cases of OF,44 it was determined that radiographically focal osseous dysplasia tends to manifest as an irregularly shaped, mixed radiolucent-radiopaque lesion, occasionally with well-defined borders. On the other hand, OF typically manifests as a well-circumscribed, unilocular lesion with sharply defined, corticated borders.7,43 Most focal osseous dysplasia lesions are no greater than 2 cm, whereas the average OF tends to be up to 4 cm in diameter at the time of diagnosis.43,44 In occasional cases, concomitant traumatic bone cysts also may develop.52,70 On surgical exploration, focal osseous dysplasia tends to be adherent to the surrounding normal bone and, thus, usually is removed piecemeal, in multiple, small, hemorrhagic, gritty fragments.52 In contrast, OFs tend to enucleate from the surrounding bone either intact or in several large pieces.6,52 Unlike in OFs, serial radiographs demonstrate that © American Society for Clinical Pathology

Pathology Patterns Reviews

❚Image 8❚ Focal osseous dysplasia. Periapical radiograph showing a relatively well-circumscribed radiolucency with a central nidus of calcification. Note the close association of the lesion with the root apex of the molar tooth.

focal osseous dysplasia exhibits little tendency to enlarge over time; thus, further treatment usually is unnecessary.4,70,71 However, periodic, long-term follow-up is recommended, because patients with focal osseous dysplasia may develop additional lesions in other parts of the jaws, leading to the suggestion that focal osseous dysplasia may represent the initial manifestation of florid osseous dysplasia.70 Florid Osseous Dysplasia Florid osseous dysplasia is the most clinically extensive form of osseous dysplasia.1 However, florid osseous dysplasia is, in most cases, an innocuous, self-limiting disease. Like the other 2 forms of osseous dysplasia, florid osseous dysplasia arises mainly in black females during the fourth and fifth decades of life.4,72 However, there are numerous documented cases of florid osseous dysplasia in Asian females as well.71 Florid osseous dysplasia commonly involves the posterior regions of the mandible, manifesting as bilateral, relatively symmetrical lesions. Moreover, simultaneous, bilateral involvement of both jaws is very common.4,6 In most cases affected patients are asymptomatic, and the disease is detected only on routine dental radiographs. However, occasional patients may have dull, intermittent, poorly localized pain, especially in lesions that are infected secondarily.4,72 Unlike patients with periapical osseous dysplasia and focal osseous dysplasia, patients with florid osseous dysplasia may have limited bony expansion, especially of the mandible.4 Radiographs often demonstrate numerous, irregularly shaped, sclerotic radiopacities admixed with diffuse, ill-defined, © American Society for Clinical Pathology

radiolucent-radiopaque areas ❚Image 9❚.7,32,72 The disease is limited exclusively to the tooth-bearing areas of the jaws, thus sparing the inferior cortex and ascending ramus of the mandible. Both dentulous and edentulous areas may be affected. Anterior mandibular involvement typically manifests radiographically as periapical osseous dysplasia, which reinforces the concept that both florid osseous dysplasia and periapical osseous dysplasia are part of the same disease spectrum.4 Concomitant multiple traumatic bone cysts commonly develop in association with florid osseous dysplasia, manifesting as well-delineated, cystlike radiolucencies.6,72 In occasional cases, these cysts may represent the initial manifestation of florid osseous dysplasia.72 Florid osseous dysplasia is a clinical and radiographic diagnosis in which at least 2 quadrants must be involved to make the diagnosis.4 Although a biopsy may be performed for diagnostic purposes, it usually is unnecessary in asymptomatic patients and, in most cases, not recommended. This is because the densely sclerotic, calcified masses are avascular and, thus, are susceptible to infection if exposed to the oral flora. The subsequent development of an acute or chronic osteomyelitis may lead to substantial bone loss, sequestration of the sclerotic masses, and fistula formation ❚Image 10❚.4,72 As a result, in typical cases, therapeutic management for asymptomatic patients consists of long-term follow-up, maintenance of excellent oral hygiene, preventive dental care, and elimination of any inflammatory stimuli that may predispose to infection.1 In symptomatic patients, treatment often is more challenging and not always successful.6 Antibiotic therapy and surgical debridement of the infected sclerotic bone usually are necessary. To date, there has been only 1 documented case of sarcomatous transformation in a patient with florid osseous dysplasia of the mandible.73 However, this latter case may represent a coincidental finding since osseous dysplasias do not demonstrate an appreciable risk for malignant transformation.4 Florid osseous dysplasia–like lesions have been identified in other disorders. A rare osteogenesis imperfecta–like syndrome, also termed gnathodiaphyseal dysplasia and hereditary gnathodiaphyseal sclerosis, has been recognized.74,75 In addition to bone fragility and modeling defects of the tubular bones, multiple BFOLs involving the toothbearing regions of the jawbones also have been noted.74 Both the maxilla and mandible typically are involved, and, in the few cases reported, multiquadrant disease is not unusual.3,74,75 Although not completely characterized, radiographically, the lesions seem to resemble those seen in florid osseous dysplasia. Moreover, affected patients seem to have a propensity for jaw infection.74 The microscopic appearance of the jaw lesions is consistent with that of a BFOL. Familial Gigantiform Cementoma Another genetic disorder that is characterized by florid osseous dysplasia–like lesions of the jawbones also has been Am J Clin Pathol 2002;118(Suppl 1):S50-S70 DOI: 10.1092/9VB3LGGEPPR7RMAR

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❚Image 9❚ Florid osseous dysplasia. Panoramic radiograph demonstrating diffuse, ill-defined, radiolucent-radiopaque lesions of the mandible, extending bilaterally. Maxillary involvement was not noted.

❚Image 10❚ Florid osseous dysplasia with secondary osteomyelitis. A bony sequestrum is seen extruding through the overlying alveolar mucosa.

identified. This condition, labeled familial gigantiform cementoma (FGC) or familial florid osseous dysplasia, is an autosomal dominant disorder with variable phenotypic expressivity.76,77 A number of affected families have been identified, including a large pedigree of 55 individuals spanning 3 generations.76 The radiographic appearance is identical to that of florid osseous dysplasia, ie, multiquadrant, dense lobular radiopacities with ill-defined radiolucentradiopaque areas. Like florid osseous dysplasia, there is no clinical or radiographic evidence of disease in other parts of the skeleton. However, unlike florid osseous dysplasia, there is no sex, age, or racial predilection for FGC.76,77 Lesions often manifest at an early age and may cause substantial rapid bony expansion and facial asymmetry. Sporadic cases of FGC also have been reported with features analogous to the familial form.78 Moreover, the clinical features differentiate the sporadic form of FGC from florid osseous dysplasia. In addition, the clinicoradiographic manifestations of sporadic FGC resemble those seen in patients with multiple OFs. Thus, it has been suggested that cases previously reported as “multiple ossifying fibromas” should more appropriately be characterized as sporadic FGC.78 Based on the clinical manifestations, it seems that FGC is a benign heritable or sporadic neoplastic process demonstrating a multifocal growth pattern. Moreover, given the often synchronous involvement of both jawbones, FGC may be viewed as a polyostotic benign fibro-osseous disease.78 Owing to the often rapid expansion of the lesions, surgical

intervention usually is necessary. If clinically feasible, conservative but complete surgical excision is recommended. Recurrence has been reported.

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Lesions That May Resemble BFOLs A number of neoplastic, nonneoplastic, and metabolic disease processes may manifest with clinical, radiographic, and histopathologic features that closely resemble those seen in BFOLs. However, these diseases do not completely satisfy the histologic criteria required for a diagnosis of a BFOL, as outlined by Waldron.6 Nevertheless, owing to the wide array of lesions that may be included in the differential diagnosis of a BFOL, an accurate diagnosis may be challenging, especially when evaluating small, fragmented tissue specimens in the absence of adequate clinical and radiographic data. Paget Disease of Bone Paget disease of bone (PDB) is a chronic, focal disease of the bones that affects 3% to 5% of the population older than 40 years.79 Males are more commonly affected than females and whites more often than blacks. PDB is characterized by excessive bone resorption owing to increased osteoclastic activity, coupled with rapid, disorganized bone remodeling.79,80 Although the exact cause remains unclear, a number of studies have identified a substantial genetic component, with evidence of linkage to 4 distinct loci.80-82 Furthermore, a familial, autosomal dominant form of PDB © American Society for Clinical Pathology

Pathology Patterns Reviews

also has been recognized.83 Thus, it appears that PDB is a genetically heterogeneous disease. A persistent paramyxoviral infection also has been suggested to have a role in the development of PDB.3,84 A number of molecular studies support a role for virus in the pathogenesis of PDB; however, other studies do not.84,85 Nevertheless, recent data suggest a trend toward a decreased clinical severity of PDB.86,87 Thus, environmental factors also may have a role in the development of PDB.3 PDB may be a monostotic or a polyostotic disease. The jawbones are affected in up to 20% of patients.88 Moreover, the jaw findings may represent the initial manifestation of the disease.3 Clinically, PDB is characterized by a slow but progressive symmetrical expansion of the affected bone. The maxilla is involved more commonly than the mandible. Thus, enlargement of the midface often is observed.3 Associated nasal obstruction and sinus obliteration also are typically seen. Edentulous patients who wear complete dentures may complain that their denture no longer fits. For dentulous patients, the initial complaint may be that spaces are developing between their teeth, due to expansion of the alveolar bone.3 The radiographic appearance of PDB resembles that of a BFOL.89 In the early stages of the disease, PDB may manifest as an ill-defined, radiolucent lesion with poorly defined borders that blend into the surrounding bone.84,89 The lesion may exhibit ground-glass opacification, thus resembling FD.89 As the disease progresses, confluent radiolucentradiopaque areas often are seen, thereby resembling osseous dysplasias.3 These affected areas often are described as having a “cotton-wool” appearance. Teeth in the affected regions usually demonstrate hypercementosis, a finding only rarely encountered in BFOL.3,4 Microscopically, a benign fibro-osseous pattern typically is seen.3 Irregularly shaped trabeculae of woven bone are scattered throughout the stroma. The bone often is lined by osteoblasts and osteoclasts, indicating simultaneous resorption and formation of the bone. Characteristically, numerous basophilic reversal lines are noted throughout many of the bony trabeculae ❚Image 11❚. The lines may give the pagetoid bone somewhat of a jigsaw or mosaic pattern.3 Although occasional reversal lines may be seen in the bony trabeculae of BFOLs, they are never as numerous as they are in PDB.1,3 Although the microscopic appearance of PDB often can be used to distinguish this disease from a BFOL, occasional difficulties may be encountered. In these latter cases, the clinical and laboratory findings may be needed to establish the correct diagnosis. Owing to the high turnover rate of pagetoid bone, patients often demonstrate high serum levels of alkaline phosphatase.90 Furthermore, urinary hydroxyproline levels usually are elevated as well. In contrast, the biochemical profiles in patients with BFOL usually remain unaffected.2 More sensitive markers of bone turnover have © American Society for Clinical Pathology

❚Image 11❚ Paget disease of bone. A fibro-osseous pattern typically is seen. However, prominent basophilic reversal lines usually are observed within many of the bony trabeculae (H&E, ×40).

been identified that may be used to gauge disease activity and treatment response in patients with PDB. These markers include urinary deoxypyridinolines and N-telopeptides.90 The risk for sarcomatous transformation in patients with PDB is several thousand-fold more than that for the general population.91,92 Reports state that 0.1% to 5.5% of affected patients may develop a malignant neoplasm, the most common of which is an osteosarcoma.91,92 Osteosarcomas in patients with PDB account for a substantial proportion of osteosarcomas in people older than 60 years.91 Interestingly, a subset of osteosarcomas exhibits loss of heterozygosity at 18q21-23, a region genetically linked to PDB.93 Secondary osteosarcoma in a pagetoid jawbone is extremely rare.94 There have been fewer than 15 documented cases, and almost all of the tumors have involved the mandible.94 These secondary malignant neoplasms have been shown to be uniformly and rapidly fatal and have a much poorer prognosis than osteosarcomas in nonpagetoid mandibles.93 Benign and malignant giant cell tumors also may develop in pagetoid bones, including the jawbones.95 In slowly evolving PDB or in asymptomatic patients, treatment often is unnecessary or is delayed until the level of alkaline phosphatase is more than 25% to 50% above normal.3,84 Parathyroid hormone antagonists, including calcitonin and bisphosphonates, usually are used to reduce the rate of bone turnover.84 Surgery is not usually indicated. Low-Grade Osteosarcoma Osteosarcoma is made up of a heterogeneous family of tumors with variable biologic behavior.96 Osteosarcoma of Am J Clin Pathol 2002;118(Suppl 1):S50-S70 DOI: 10.1092/9VB3LGGEPPR7RMAR

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the jaws represents fewer than 10% of all osteosarcomas, and most are high-grade, aggressive neoplasms.97,98 Low-grade central osteosarcoma is an uncommon form of osteosarcoma that is characterized by a protracted clinical progression and prolonged survival.96 Most cases arise in the lower limbs; however, a number of cases have been documented in the jawbones.97,99-102 Low-grade osteosarcoma may demonstrate striking similarities to FD.99,101,103 Radiographically, the tumors may be predominantly radiolucent or demonstrate a mixed radiolucent-radiopaque appearance. They also may manifest as a ground-glass, expanding lesion with poorly defined borders that blend in with the surrounding bone.102,103 However, cortical thinning and local destruction also may be seen, a feature not observed in FD.99,101 Occasional patients may have pain, paresthesia, or both. Microscopically, low-grade osteosarcoma is characterized by minimal cytologic atypia, thus making it difficult to distinguish it from a BFOL.100,103 In occasional cases, the neoplastic cells may be arranged in short fascicles, a feature usually not identified in BFOLs.101 Moreover, lace-like osteoid often is more prominent in low-grade osteosarcoma. Scattered trabeculae of woven bone and rare, calcified spherules also may be seen. Owing to the striking microscopic resemblance to BFOLs, FD in particular, Franceschina et al103 recommend a large representative sample of tissue for diagnostic purposes. Treatment of choice for low-grade osteosarcoma is surgical excision with wide margins. Recurrence has been reported; however, overall, the prognosis is very good.96 Dedifferentiation of low-grade osteosarcoma has been reported.96,104 Moreover it has been suggested that some cases of FD that reportedly have transformed into osteosarcoma actually may represent examples of low-grade osteosarcoma with dedifferentiation.104 A recent study by Pollandt et al105 suggests that mutational analysis may be helpful in distinguishing low-grade osteosarcoma from FD. In their study, 9 of 9 cases of monostotic FD exhibited a GNAS1 mutation, whereas only 1 of 5 low-grade osteosarcomas demonstrated the mutation.105 Osteoblastoma, Osteoid Osteoma, Cementoblastoma Osteoblastoma and osteoid osteoma are solitary, benign neoplasms that may clinically, radiographically, and histologically resemble BFOLs.3,106 Osteoblastoma and osteoid osteoma cannot be differentiated reliably based on histologic examination alone; thus, the 2 neoplasms may be variants of the same tumor.106-108 However, studies have shown that osteoblastoma may have a different clinical potential because of the propensity for recurrence, locally aggressive behavior, and, in rare cases, malignant transformation.107,108 Osteoblastomas tend to develop more commonly in males than females. They may occur over a wide age range, S62 S62

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but most arise during the third decade of life. The vertebra is the most common site, but an estimated 10% of all cases develop within the jawbones, usually the mandible.108,109 The radiographic appearance of osteoblastoma often is characterized by a well-circumscribed, lytic lesion that measures more than 2 cm, with varying amounts of calcification.106 Bone scintigraphy identifies these lesions as hot spots. Cortical expansion often is noted, occasionally resulting in facial asymmetry. Of the 59 reported jaw lesions, spontaneous pain and/or tenderness were identified in the majority of patients.109 However, pain is associated more commonly with osteoid osteoma, which is a self-limiting tumor that classically manifests with severe nocturnal pain that is relieved substantially by nonsteroidal anti-inflammatory medications.106 Osteoid osteoma typically manifests as a small (less than 2 cm), well-circumscribed, radiolucent nidus, with or without a central area of opacification, and surrounding bone sclerosis.7,106 A biopsy or excision of an osteoblastoma often is received as multiple, red to tan, gritty, friable fragments.108 Although osteoblastomas have numerous histologic variants, classic osteoblastoma occasionally may be mistaken for a BFOL.3 Microscopically, osteoblastomas are composed of long, interanastomosing, irregularly shaped trabeculae of osteoid or immature woven bone rimmed by osteoblasts and embedded within a fibrovascular stroma. 108,110 The neoplastic cells often are polygonal, with round to oval nuclei and a prominent nucleolus. About 10% of cases may exhibit a moderate number of typical mitoses.108 Foci of delicate, lace-like osteoid sometimes may be observed. In occasional cases, mature bone and calcified spherules or acellular, psammomatous-type calcifications also may be seen. 108 Numerous small-caliber blood vessels and extravasated hemorrhage are commonly noted. A peripheral rim of reactive bone is not unusual, and there often is a sharp interface between tumor and the adjacent normal bone. Focally scattered multinucleated giant cells may be seen, and up to 10% of cases may exhibit ABC-like areas.108,111 Cytogenetic changes have been identified in osteoblastoma and osteoid osteoma; however, recurrent alterations have not been noted.112,113 In addition, recent studies have demonstrated that neoplastic osteoblasts in osteoid osteoma express high levels of cyclooxygenase-2 (COX-2), whereas COX-2 is expressed minimally by cells in the surrounding uninvolved bone.114 Moreover, very limited amounts of COX-2 are detected in osteoblastoma and FD.114 Local surgical excision is the treatment of choice for both tumors; however, up to 20% of osteoblastomas may recur.108,110 Cementoblastoma is an odontogenic neoplasm that is thought to represent a true tumor composed of cementum.3 This unusual neoplasm develops most commonly during the second and third decades of life. Most cases arise within the © American Society for Clinical Pathology

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mandible, usually in the premolar-molar regions. About half of all reported cases involve the mandibular first molar.115 Radiographically, the tumor manifests as a well-circumscribed, radiopaque mass surrounded by a radiolucent rim. The mass appears fused to one or more tooth roots.3,115 Although OFs may radiographically appear predominantly radiopaque, they usually are not associated with the apices of teeth.43 Cementoblastomas are identical histologically to osteoblastomas.115,116 The only difference is that a cementoblastoma is fused to the root of the tooth.115 The treatment of choice is surgical excision of the mass with a root amputation or a tooth extraction. Recurrences have been reported, especially in cases that were treated incompletely.116 Central Odontogenic Fibroma Central odontogenic fibroma (COF) is an unusual benign neoplasm that typically manifests as a slow-growing, potentially expanding lesion. Its cause remains unclear; however, it is believed that COFs are mesenchymal neoplasms that are derived from remnants of the odontogenic apparatus. 3 COFs demonstrate a 2:1 female predilection.117,118 Approximately half of all cases develop in the tooth-bearing regions of the maxilla, usually anterior to the molars.118 Mandibular tumors often arise posterior to the molars. Radiographically, COFs may manifest as solitary, unilocular or multilocular radiolucencies with well-defined borders. About 10% to 15% of tumors may be speckled with small radiopacities.3,117,118 There are 2 histologic subtypes of COF; however, the distinction is purely academic.118 The clinicoradiographic features of both microscopic variants are identical.3,118 Moreover, there is no correlation between the histologic pattern and clinical behavior of the tumors.3 A COF, simple type, is characterized by a myxoid to densely hyalinized stroma composed of scattered oval to spindle-shaped fibroblasts.117 Foci of odontogenic epithelial rests often are noted. Small, round calcifications also are seen frequently. On the other hand, a COF, World Health Organization type, is characterized by a more cellular and collagenous stroma that contains sparse cords and islands of odontogenic epithelium ❚Image 12❚.117 Acellular, round or ovoid, cementum-like calcifications usually are seen. In addition, droplet-like calcifications also are observed commonly.3 Odontogenic epithelial rests are rarely, if ever, seen in BFOLs.3 Overall, COF tends to have a limited growth potential with little tendency to recur after surgical enucleation and curettage. However, rare lesions have been reported with the combined features of a COF and a central giant cell granuloma.119,120 It is unclear whether this entity represents a “collision” of the 2 lesions or whether it is a unique form of COF. Nevertheless, this unusual combination seems to © American Society for Clinical Pathology

❚Image 12❚ Central odontogenic fibroma, World Health Organization type. Relatively cellular stroma with scattered circular calcifications and rests of odontogenic epithelium (H&E, ×100).

impart an increased risk of recurrence after simple curettage.119 In addition, the recurrences tend to exhibit both components.119,120 Proliferative Periostitis Proliferative periostitis, also known as Garré osteomyelitis, represents a periosteal reaction to bony irritants, including infection, neoplasia, and trauma.121,122 In the jawbones, the most common cause of proliferative periostitis is periapical inflammation.3 Most affected patients are diagnosed between the first and third decades of life. There is no significant sex predilection. Typical cases are unilateral, and the vast majority of lesions are restricted to the mandible, usually in the premolar and molar regions.121 However, rare examples of multiquadrant disease also have been reported.122 Proliferative periostitis is best observed on a CT scan; however, panoramic, lateral oblique or occlusal plain films also may be used.3 Radiographs often demonstrate a variable number of parallel, radiopaque laminations separated from one another by radiolucent areas. This gives rise to the classic “onion-skin” appearance of the lesion.121 Microscopically, a fibro-osseous–like pattern often is observed.121 The tissue usually is characterized by parallel trabeculae of cellular, reactive, woven bone in which the individual trabeculae often are arranged perpendicular to the surface ❚Image 13❚.3,121 On occasion, the bony trabeculae may be more widely scattered or interconnect to form a meshwork of bone, thus resembling an early BFOL.3 The intertrabecular Am J Clin Pathol 2002;118(Suppl 1):S50-S70 DOI: 10.1092/9VB3LGGEPPR7RMAR

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fibrous tissue usually is minimally inflamed and may contain a variable number of small ovoid blood vessels. In most cases, a biopsy is unnecessary because the radiographic appearance often is characteristic.121,122 Treatment of proliferative periostitis is aimed at removing the source of the bony irritant. In cases related to odontogenic infection or periapical inflammation, extraction or endodontic treatment of the offending tooth often is sufficient. Subsequent bone remodeling over a period of 6 to 12 months usually results in complete resolution of proliferative periostitis.3,121 Renal Osteodystrophy Clinical and radiographic alterations of the jawbones in patients with chronic renal disease are not uncommon and may represent one of the earliest signs of disease.123 Renal osteodystrophy is a universal complication of renal failure and is a major cause of morbidity in patients undergoing dialysis treatment.124,125 In a study by Maxwell et al,123 73% of dialysis patients had radiographic evidence of renal osteodystrophy, and 17% of these lesions were identified in the jawbones. Moreover, 50% of children and 25% of adults exhibited maxillofacial disease.123 Patients also typically have a constellation of other signs and symptoms related to secondary hyperparathyroidism.124 For reasons that remain unclear, a small number of patients undergoing long-term dialysis may have significant enlargement of one or both jawbones.124-126 The expansion often is painless but may result in marked facial asymmetry. The radiographic and microscopic appearance of one of these enlarging lesions usually demonstrates features that resemble a BFOL (in particular, FD) or PDB.124,126 Occasional lesions may show features of both BFOL and PDB. Thus, Damm et al124 concluded that “any fibro-osseous enlargement of the jaws in a dialysis patient must be considered renal osteodystrophy until proven otherwise.” A diagnosis of renal osteodystrophy is based on the clinical, radiographic, microscopic, and laboratory findings.124 Patients with chronic renal failure usually exhibit other systemic signs and symptoms, in addition to elevated levels of parathyroid hormone, phosphate, alkaline phosphatase, and urea.123,124 Although patients with PDB may demonstrate increased alkaline phosphatase levels, most other laboratory findings usually are within normal limits.90 Furthermore, the biochemical profiles in patients with BFOL usually remain unchanged as well.1,4 Treatment of patients with renal osteodystrophy is initially directed at controlling the serum phosphate and parathyroid hormone concentrations.123-125 Nadimi et al127 state that a dramatic reduction in the size of the jaws may occur within 3 to 6 months, provided the patient remains compliant during therapy. If the bone remains enlarged, surgical recontouring may be needed. S64 S64

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❚Image 13❚ Proliferative periostitis. Parallel rows of cellular, reactive woven bone. The intervening fibrous stroma is uninflamed and contains scattered blood vessels (H&E, ×40).

Central Giant Cell Granuloma Central giant cell granuloma (CGCG) is a giant cell lesion that commonly develops within the jawbones.128,129 CGCGs often demonstrate clinical, radiographic, and microscopic features that are similar to those seen in BFOLs.3,8,128 Histologically, a number of giant cell lesions contain fibrous tissue and bone.129 Conversely, scattered multinucleated giant cells are seen occasionally in BFOLs.43,45,52 Therefore, it has been proposed that the 2 groups of lesions may share a common histogenesis.129 CGCGs occur over a wide age range; however, the majority of cases develop before the age of 30 years.3,128 A CGCG that arises in a patient older than 30 years usually warrants further clinical evaluation to rule out hyperparathyroidism.129 Females are affected more often than males. The most common clinical manifestation is an asymptomatic, localized swelling that occasionally may be associated with mild discomfort. Occasional CGCGs may behave more aggressively, resulting in local destruction, pain, and/or paresthesia.129,130 Although CGCGs may develop within the maxilla, most cases manifest within the mandible as solitary, unilocular or multilocular radiolucencies, with or without well-demarcated borders.8,32 The lesions often are anterior to the molar teeth and may cross the midline. In some cases, cortical perforation may be seen. Unlike BFOLs, discrete radiopacities are rarely observed in CGCGs.8,129 In most instances, microscopy can easily distinguish a CGCG from a BFOL. However, in a biopsy specimen consisting of multiple small tissue fragments, the diagnosis may be somewhat more challenging. CGCGs are made up of © American Society for Clinical Pathology

Pathology Patterns Reviews

a hypervascular, hypercellular, collagenous stroma exhibiting a variable number of osteoclast-like multinucleated giant cells.128,129 The giant cells may aggregate in focal areas or they may be diffusely scattered throughout the stroma. The stromal cells are bland appearing and spindle-shaped to ovoid and often are arranged in a haphazard manner. Occasionally, the stromal cells may be arranged in short, intersecting fascicles that are organized in a storiform or herringbone pattern. A small number of typical mitoses may be seen. Extravasated hemorrhage, hemosiderin deposits, and a mild chronic inflammatory infiltrate are seen throughout the stroma. Osteoid or thin trabeculae of bone are identified in about 50% of cases.129 However, unlike BFOLs, the bony deposits usually do not make up a substantial component of the lesion. Furthermore, the giant cells are much more numerous in a CGCG. Treatment of a CGCG usually is by curettage; however, more aggressive lesions may require peripheral ostectomy or en bloc resection.129 Although CGCGs are thought to be nonneoplastic, these lesions may recur.128 Moreover, aggressive lesions have a higher tendency to recur. However, there are no histologic or clinical criteria that can reliably predict the recurrence of a CGCG.128,129 Systemic and intralesional calcitonin therapy has been used to successfully treat patients with CGCGs.131 Intralesional steroid injections also have been used in a limited number of cases.132 Brown Tumor (Hyperparathyroidism) Bone lesions develop in an estimated 10% to 15% of patients with hyperparathyroidism.133 Furthermore, multiple lesions may be identified simultaneously. Although renal osteodystrophy may develop in a small number of patients,124 the most characteristic jaw lesion associated with hyperparathyroidism is a brown tumor, so named because its gross appearance is characterized by a red-brown color.129,133 Unlike renal osteodystrophy, brown tumors may be seen in patients with either primary or secondary hyperparathyroidism.129 The clinical, radiographic, and microscopic appearances of a brown tumor are indistinguishable from those of a CGCG.3,129 Spontaneous resolution of a brown tumor may occur after treatment of the underlying source of the lesion. Aneurysmal Bone Cyst About 10% of ABCs develop in the maxillofacial bones.3 Furthermore, ABCs may develop in association with a number of other osseous lesions, including FD, OF, JOF, osteoblastoma, and osteosarcoma.29,45,59,111 Rapid expansion of an otherwise slow-growing BFOL should alert the clinician to the possibility of a newly formed ABC.29 In a study examining ABCs of the jawbones, 22% of ABCs were seen in association with other osseous pathology.134 © American Society for Clinical Pathology

ABCs may occur over a wide age range; however, most develop before the age of 30 years.3 Lesions may be asymptomatic or cause substantial enlargement, resulting in facial asymmetry and pain. Radiographically, most lesions manifest as solitary, multilocular radiolucencies in the posterior mandible. Bony expansion may be evident. There is considerable histologic overlap between ABCs and CGCGs.3,129,134 The only significant difference is that ABCs exhibit numerous large, blood-filled, sinusoidal spaces that are surrounded by multinucleated giant cells ❚Image 14❚.129 In cases that develop in association with a BFOL, the ABC component may be adjacent to the BFOL component or it may be intermingled with the fibro-osseous tissue.29,59 Cytogenetic studies have demonstrated that at least some ABCs exhibit recurrent changes involving 16q22 and/or 17p11-13.135,136 Moreover, there have been at least 4 reported cases showing a recurrent (16;17)(q22;p13) translocation.136 Treatment of an ABC includes enucleation, curettage, cryotherapy, or resection. Jaw lesions seem to have a lower tendency to recur than do ABCs of the long bones. 129 BFOLs secondarily involved by an ABC often require complete resection. Cherubism Cherubism formerly was described as familial fibrous dysplasia.2 Although it now is clear that cherubism is not a subtype of BFOL, let alone related to FD, reports continue to make use of this outdated terminology.137 Cherubism is a rare, autosomal dominant, self-limiting disorder that exhibits

❚Image 14❚ Aneurysmal bone cyst. Large sinusoidal spaces filled with blood and surrounded by numerous multinucleated giant cells. Extravasated hemorrhage and hemosiderin deposits also are seen. This lesion was associated with a benign fibro-osseous lesion (not shown) (H&E, ×40).

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100% male and 50% to 70% female penetrance. 129,138 Sporadic cases also have been reported. Unlike FD, the clinical manifestations of cherubism are restricted to the jawbones.138 However, cherubism also has been identified in association with other disorders, including Noonan syndrome, Ramon syndrome, Jaffe-Campanacci syndrome, and fragile X syndrome.139-142 Mutations in the SH3BP2 gene, found on chromosome 4p16, have been identified in a series of unrelated families with cherubism.143 Furthermore, all known mutations seem to be confined within a 6–amino acid sequence in exon 9 of the gene.143 Cherubism usually is identified during early childhood. Patients typically have painless, bilateral, symmetric jaw enlargement resulting in marked facial expansion.137,138 The expansion often is gradual and usually continues until puberty, after which the lesions tend to undergo spontaneous resolution.138 In most cases, cherubism is confined to the mandible. However, simultaneous, diffuse involvement of the maxilla also may occur.137,138 If so, the midface may become expanded, resulting in exposure of the inferior portion of the sclerae. As a result, the patient’s eyes may appear to be looking upward. It is this latter feature that gives this disorder its name.138 An intraoral examination may reveal numerous missing teeth.137 CT, MRI scans, and panoramic radiographs are useful in the evaluation of patients suspected of having cherubism.137 Radiographically, the lesions usually manifest as bilateral, multilocular radiolucencies with concomitant bony expansion. Numerous impacted or displaced teeth may be identified. Bone scintigraphy is not recommended because normal scintigrams may be obtained in patients with radiographic evidence of cherubism.137,138 Microscopically, the features of cherubism are almost identical to those of a CGCG.129 The only difference is that the blood vessels may exhibit an acellular, eosinophilic, perivascular cuff of dense collagen.129,137 This is a feature that is unique to cherubism; however, this finding is not seen in all cases.3 Therefore, the diagnosis of cherubism often is based on a clinicopathologic correlation in conjunction with the radiographic findings.138 Laboratory findings in patients with cherubism usually are within normal limits.144 In most cases, cherubism is a self-limiting disease that often undergoes spontaneous resolution after puberty.137,138 Thus, surgical intervention usually is unnecessary. However, patients may experience functional and psychological disturbances, in which case treatment may be needed.138 Studies suggest that intralesional calcitonin injection or systemic calcitonin administration may induce complete remission of lesions in affected children, with minimal adverse effects.131 Longterm follow-up has shown that the multilocular radiolucencies gradually fill in with normal bone.138 However, in some cases, radiographic evidence of disease may persist for decades after S66 S66

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clinical resolution.137 Furthermore, a biopsy of a persistent or healing lesion occasionally may resemble a BFOL, since the giant cell component eventually becomes replaced by fibrous tissue and bone.129 Thus, in these cases, a good clinical history is necessary to establish the proper diagnosis.

Conclusion Benign fibro-osseous diseases of the maxillofacial bones make up a diverse collection of disorders that include neoplastic and nonneoplastic diseases and hereditary and nonhereditary conditions. BFOLs share many similar histopathologic features. Furthermore, a number of other non–fibro-osseous disease processes that develop within the jawbones exhibit findings that may closely mimic those seen in BFOLs. Thus, a definitive diagnosis of a BFOL requires correlation of the histologic features with the clinical, radiographic, and intraoperative findings. Although subclassification of BFOLs occasionally can be challenging, a proper diagnosis is essential to ensure adequate and appropriate treatment. The wide array of terminology used to describe the various BFOLs has contributed to much of the confusion surrounding these lesions. However, classification schemes proposed initially by Waldron 6 and more recently by Brannon and Fowler1 provide a foundation on which the results of future clinical, microscopic, and molecular studies can be added to further define and understand this unique group of bone lesions. From the Department of Pathology, School of Dental Medicine, University of Pennsylvania, and the Section of Dermatopathology, Department of Dermatology and Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia. Address reprint requests to Dr Alawi: Dept of Pathology, School of Dental Medicine, University of Pennsylvania, 4010 Locust St, 3rd floor, Philadelphia, PA 19104-6002. Acknowledgments: I thank Paul Freedman, DDS, for reviewing the manuscript and supplying the clinical picture and cases for photomicrographing and Linda Otis, DDS, MS, for providing radiographs for reproduction.

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