Bone Diseases and Fibro-osseous Lesions
Fibro-osseous lesions of the jaw comprise a diverse group of conditions which are characterized by replacement of normal bone by a tissue composed of collagen fibers and fibroblasts that contain varying amounts of mineralized substance which may be bone, cementum or both in appearance. These lesions present a wide range of clinical and radiographic patterns. The precise diagnosis of fibro-osseous lesions depends on good clinical, radiological and histological correlation.
Numerous terminologies have been used to designate these lesions. In 1940s and early 1950s, these lesions were commonly termed as localized osteitis fibrosa, osteofibroma or fibrous osteoma. The lesions in the skull were termed as leontiasis ossea because of its lion-like appearance. With advances in the understanding of these lesions a number of classifications have been proposed by many investigators. Waldron (1985, 1993), Makek (1987), Slootweg (1996), Fowler (2005) are a few among those who have been accepted, although no universally approved classification system has been presented.
The classification system that has been considered to be most useful was given by Waldron in 1993. Waldron suggested that with adequate clinical and radiographic data, most fibro-osseous jaw lesions can be assigned with reasonable certainty into one of the several categories:
The term periapical cemento-osseous dysplasia is used to designate a lesion which occurs in the periapical areas and shows cementum-like and osseous areas on histopathologic examination. The term periapical cemental dysplasia which was used earlier to designate these lesions is somewhat incorrect as the lesion shows both cementum-like and osseous areas. The etiology is unknown, but they appear to originate from the periodontal ligament.
The periapical cemento-osseous dysplasia is a disease which involves the periapical areas of the vital teeth in black female patients who are older than 30 years of age. The lesions are invariably asymptomatic and are discovered on routine radiographic examination.
The early lesions show well-defined, circumscribed radiolucent lesions involving the apices of one or several teeth. Individual lesions are seldom more than 1.0 cm in diameter and most are less than 0.5 cm in size. The lesions show an increasing degree of calcification with time, which may appear as mixed radiopaque and radiolucent lesions. The older lesions show radiopaque masses. These lesions do not show any bone expansion.
Not many reports appear that review the histopathologic findings of periapical cemento-osseous dysplasia. The lesions which are misdiagnosed as inflammatory periapical pathologies and are subjected to histopathologic findings have shown to be composed of cementum-like and/or osseous trabeculae in a fibroblastic stroma. As the lesions become older the calcified component appears to be more prominent.
The diagnosis is done mainly on the basis of radiographic presentation and clinical findings. Surgical intervention is contraindicated. Early lesions showing radiolucent areas are often misdiagnosed as periapical cysts or granulomas. Accurate pulp testing should be done to avoid such errors. Isolated lesions involving the apical areas of vital teeth present greater problems in diagnosis than do multiple lesions, particularly when the solitary lesion is in the pre-molar area and the patient is male or a white female.
The term focal cemento-osseous dysplasia was first suggested by Tomich and Summerlin in 1989. The disease is seen in the edentulous posterior areas of females who are in their 4th and 5th decades of life.
Focal cemento-osseous lesions are invariably asymptomatic and are discovered on routine radiographic examination. There is no swelling associated with it unless the lesions are old and have caused bony expansion. On surgical exploration the tissue occupying the defect is gritty, hemorrhagic and is removed by curettage in small fragments, often with some difficulty. This helps in differentiating the lesion from ossifying fibroma which is well circumscribed and avascular and easy to enucleate.
These are well-demarcated radiolucent or mixed radiolucent/ radiopaque area or highly sclerotic. Most lesions are less than 2 cm but larger lesions may be seen. Simple bone cysts also may occur with focal cemento-osseous dysplasia.
Microscopically areas of cellular fibrous tissue containing numerous small blood vessels, irregular trabeculae of woven bone and/or cementum-like calcifications are seen. Scattered foci of multinucleated giant cells may be seen.
The lesion shows no tendency to recur after removal. Partial removal of the lesion is also advocated in cases where the lesion is very large and limits the total excision. The partial removal does not show any tendency to enlarge or recur and the long-term prognosis seems to be excellent.
The term florid cemento-osseous dysplasia (FCOD) was first suggested by Melrose et al in 1976 to describe a condition of exuberant multiquadrant masses of cementum and/or bone in both jaws and in some cases, simple bone cyst-like lesions in affected quadrant. Sometimes familial tendencies have been observed. In past this condition has been designated as sclerosing osteitis, multiple enostoses, diffuse chronic osteomyelitis and gigantiform cementoma. The etiology of florid cemento-osseous dysplasia is unknown. Waldron et al have proposed that reactive or dysplastic changes in the periodontal ligament might be a cause for the disease.
The disease is seen exclusively in middle aged, black female and has a striking tendency for bilateral occurrence, often presenting symmetrically in the jaws. The disease is limited to the tooth bearing areas of the jaws. Many patients are partially or completely edentulous when the conditions are detected. Many cases are completely asymptomatic and the disease is diagnosed during routine radiographic examination. When the lesions are large, jaw expansion may be noted and symptoms of dull pain or drainage are always associated with exposure of the sclerotic calcified mass to the oral cavity as a result of progressive alveolar atrophy after a denture or after extraction. Laboratory investigations show no biochemical abnormalities.
Bilateral densely sclerotic lesions often symmetrically present in various areas of the jaws. These are usually mixed with less well-defined areas of a mixed radiolucent/radiopaque pattern. Majority of the patients are edentulous at initial presentation. If the patient is having remaining anterior teeth, they will often show circumscribed typical lesions of periapical cemento-osseous dysplasia. Well-defined radiolucency representing simple bone cyst is not uncommonly seen with florid cemento-osseous dysplasia.
Microscopically florid cemento-osseous dysplasia shows an admixture of woven bone trabeculae and droplets of cementum-like calcifications in a fibroblastic stroma. The cementum-like calcifications often fuse to form coalescing masses.
The diagnosis of the disease is mainly dependent on the radiographic and clinical presentation. However, the method of treatment is not very satisfactory. In the asymptomatic patient, no treatment should be considered and patient should be kept under observations. In symptomatic patients, where exposure of the sclerotic masses to the oral cavity is seen, biopsy or elective extraction of teeth in the involved area should be avoided. Antibiotic therapy should be instituted. Sequestration of cementum-like masses will occur slowly, followed by healing. Saucerization or surgical excision of the sclerotic masses is not successful.
Gigantiform cementoma is a rare, benign fibro-cemento-osseous disease of the jaws. It is characterized by formation of massive sclerotic masses of disorganized mineralized material. Both sporadic and familial occurrence has been reported. The etiopathogenetic mechanism of gigantiform cementoma is unknown.
The term gigantiform cementoma has been used synonymously with the terms sclerotic cemental masses, florid osseous dysplasia, multiple enostoses and diffuse sclerosing osteomyelitis. It was Norberg in 1930 who first described gigantiform cementoma. In 1971, the World Health Organization (WHO) classified gigantiform cementoma in the category of cemental lesions.
Gigantiform cementoma is an autosomal dominant disorder having high penetrance and variable expressivity. No sex predilection has been observed. It typically presents as a slow-growing, multifocal/multiquadrant and expansile lesions involving both the jaws. The lesions are usually seen in younger age, although older patients have also been reported. The size of the lesions seen in older patients was comparable to those seen in younger individuals. Thus it has been suggested that these lesions may have pla-teaued in their growth, probably after cessation of skeletal growth. The characteristic clinical manifestation is of a painless maxillary and mandibular swelling with associated facial deformity. Tooth impaction, malpositioning of teeth and malocclusion are also seen associated with the swelling. The enlargement of the swelling finally stops during the 5th decade.
Radiographically, gigantiform cementoma exhibits multiple circumscribed, expansile and lobular mixed radiolucent-radiopaque lesions that usually cross the midlines of the jaws. Sometimes large masses are seen in posterior areas of the jaws and the lesions combining in the midline. This suggests that lesions might have started as separate posterior masses; however, with anterior progression they became confluent and crossed the midlines of the jaws.
The mineralized component is present as admixture of small and large psammomatoid and spherical hematox-ylinophilic, cementum-like calcified deposits and irregular bony trabeculae in a fibroblastic proliferative background. The fibrous stroma may show fascicular or storiform patterns with spindle-shaped or stellate-shaped fibroblasts. The lesions are generally hypovascular, with occasionally focally rich vascular areas exhibiting aggregates of thick-walled small blood vessels. Mitoses, hyperchromatism and pleomorphism are not seen.
The surgical management of gigantiform cementoma is usually difficult because of the extensive involvement of the jaws with these tumors. Surgical inaccessibility, particularly in the posterior regions of the jaws seems to be responsible for recurrence of the tumors. These lesions seem to have a tendency toward recurrence when they are treated with incomplete surgical removal. It is therefore recommended that these lesions should be managed with conservative but complete surgical excision whenever feasible.
Ossifying fibroma is the most common fibro-osseous neoplasm of the jaw. It is a bone producing, slow growing, asymptomatic, well demarcated, benign lesion common in maxilla and mandible. The tumor is defined as a demarcated and occasionally capsulated lesion consisting of fibrous tissue containing variable amounts of mineralized material resembling bone and/or cementum or both. The term ossifying fibroma is used if the predominant component is bone, while cementifying fibroma is defined by the presence of cementum-like spherical calcifications. The lesions characterized by the presence of bone and cementum are referred to as cemento-ossifying fibroma.
The 1972 WHO classification separated the cementifying fibroma which was considered to represent odontogenic tumors, from ossifying fibroma, which was considered to be osseous tumors. However, it has been agreed by all that the two represent the same pathological condition with different histological presentation. Thus, in 1992, WHO classified the lesion as cemento-ossifying fibroma. The origin of the amorphous cementum-like calcifications commonly seen in these lesions is still uncertain. Many of the fibro-osseous lesions of the skull which were excised from the regions far away from the jaws showed cementum-like calcifications which make their cemental origin very unlikely. It is also known that bone and cementum cannot be distinguished histologically. Thus, the nomenclature represents only a variation in the histologic presentation. The prognosis and course of the lesion remains the same.
Ossifying fibroma shows a definite female predilection, with the mandible (premolar-molar area) involved more than maxilla in most of the cases. These occur mostly in the 3rd and 4th decades of life. The lesions are restricted to the tooth-bearing areas of the jaws, although posterior mandibular lesions may extend upward into the ascending ramus. The lesion appears as hard, localized and slow growing, painless mass that may displace adjacent structures and cause root resorption. Exfoliation of teeth may also be seen. Expansion is seen commonly in the inferior border of the mandible, followed by buccal plate expansion. On surgical exploration, the tumor is found to be relatively hypovascular and well demarcated from the surrounding tissue, permitting relatively easy separation from the surrounding bone. This demarcation from the surrounding structure is not seen in fibrous dysplasia and thus can be used to distinguish the two.
The lesion appears well circumscribed in contrast to fibrous dysplasia, the borders of which are ill-defined. Initial lesions are radiolucent representing an osteolytic image followed by gradual transformation into a mixed lesion and eventually becoming radiopaque. The periodontal ligament space of the involved teeth is clearly seen unlike fibrous dysplasia. Eversole et al have described two basic radiological patterns: a unilocular radiolucency with or without radi-opaque foci, and a multilocular radiolucency. The former presentation is found to be more common. Expansion of the cortical plates is a common finding. Teeth displacement and root resorption may be seen (Figure 1).
Ossifying fibroma shows a range of histologic appearances. It shows fibrous and osseous tissues with the former tissue predominating. The fibrous stroma is highly cellular, with spindle-shaped fibroblastic cells arranged in whorls. A fibrous capsule may be seen in some cases. The osseous tissue consists of rounded or lobulated basophilic masses (cementum-like), trabeculae of osteoid, woven or lamellar bone, or combination of the two. Osteoblastic rimming around the trabeculae can be seen. Focal clusters of giant cells (osteoclasts) can be seen to be arranged haphazardly or adjacent to the mineralized material.
The histologic differentiation of ossifying fibroma from osteogenic sarcoma may occasionally cause difficulty for the pathologist. Ossifying fibroma shows osseous tissue which is relatively uniform and regularly arranged. On the other hand, in osteogenic sarcoma, the bone spicules and osteoid usually demonstrate irregularity and haphazard arrangement along with significant cellular anaplasia.
Juvenile ossifying fibroma is an uncommon lesion that affects the jaw of children under 15 years of age. Histologically it is composed of cell-rich fibrous tissue containing bands of cellular osteoid, trabeculae of bone and aggregates of giant cells. There are two histologic variants of juvenile ossifying fibroma: psammomatoid and trabecular variants. The lesion is characterized by the early age of onset, the bone pattern, the high tendency to recurrence and the aggressive local behavior. The lesion has been variously described as juvenile ossifying fibroma, active juvenile ossifying fibroma, aggressive ossifying fibroma, reticular desmo-osteoblastoma or active fibrous dysplasia.
The term juvenile (aggressive) ossifying fibroma was used in the second edition of the WHO classification of odontogenic tumors to describe a lesion affecting the jaws of children under the age of 15 years. This term is used to describe two distinct histopathologic variants of ossifying fibroma of the craniofacial skeleton. These are referred to here as psammomatoid juvenile ossifying fibroma and trabecular juvenile ossifying fibroma. Psammomatoid juvenile ossifying fibroma was first reported by Benjamins, in 1938, who gave it the designation osteoid fibroma with atypical ossification of the frontal sinus. It was later termed psammomatoid ossifying fibroma of the nose and paranasal sinuses by Gögl, in 1949. The same lesion was later termed juvenile active ossifying fibroma by Johnson et al in 1952. Makek considered the lesion to be a variant of osteoblastoma and termed it psammous desmo-osteoblastoma.
The lesion characteristically occurs under the age of 15 years in 79% of cases. The psammomatoid variant occurs exclusively in the extragnathic craniofacial region especially in the orbital bones and paranasal sinuses (61.6%), and less commonly in the jaws, maxilla (19.7%) and mandible (7%). Few cases have been reported to occur in calvarium, parietal, temporal and frontal bones. In mandible, the tumor occurs more commonly in the ramus than in the body of the mandible. There seems to be no predilection for either sex. Patients often present with symptoms such as exophthalmus, bulbar displacement and proptosis when affecting the orbital bones and paranasal sinuses. In the jaws, the affected region shows a painless expansive swelling of several months. Development of aneurysmal bone cyst in psammomatoid juvenile ossifying fibroma is commonly reported. The cyst tends to occur more commonly in the younger patients in the 1st and 2nd decades of life.
The trabecular variant is characterized by a progressive and sometimes rapid aggressive growth. The tumor expands the affected bone, leading to facial asymmetry. It occurs more commonly in maxilla as compared to mandible. Few cases have also been reported in sinonasal region. Slight male predominance has been observed with an average age range of 8.5–12 years. In maxilla, tumor may lead to nasal obstruction, epistaxis and eye displacement. The duration of the lesion is usually a few months.
Radiographically, the psammomatoid variant shows well-defined expansion of the affected bone having mixed radiolucent, radiodense and ground-glass appearance. The lesion is partially or completely surrounded with thin, corrugated margins. Sometime multilocular appearance may be seen representing the small cystic spaces.
The trabecular variant is expansive, well-defined and unilocular or multilocular with cortical thinning and perforation. The tumor mass is radiolucent with variable calcification-induced radiopacities, occasionally demonstrating fine specks and occasionally producing a ‘ground-glass’ appearance. Increase in radiodensity may be observed over time. Root resorption and displacement of involved teeth are also observed.
Microscopic examination of psammomatoid juvenile ossifying fibroma shows well demarcated but unencapsulated lesion composed of numerous small rounded mineralized collagenous bodies (psammomatoid ossicles) uniformly distributed within a cellular fibroblastic stroma. The cellularity of the fibroblastic stroma varies in different tumors and at different sites within the same lesion. Occasional shrunken cells, representing nuclei of osteocytes, are embedded within the ossicles, and there is usually a collagen outer band to these mineralized bodies. Some of the ossicles may show a basophilic center and eosinophilic fringe. In the periphery of the lesions, some of the ossicles show a transition into small bone trabeculae. The tumor infiltrates and destroys the adjacent bone with focal induction of reactive bone formation. Development of aneurysmal cyst is followed by focal myxoid change in the stroma with hemorrhage and osteoclastic giant cells, with gradual expansion and formation of cysts with thin fibrous walls. The differential diagnosis with other fibro-osseous lesions of the jaw, such as cemento-ossifying fibroma, osteoid osteoma or bone dysplasia, should be made with a mandatory pathological study, and is largely based on the nature of the calcified products of the tumor. The mineralized tissue of central ossifying fibroma is composed of a variable combination of mature and immature bony trabeculae and lobulated basophilic masses of cementum-like material. There may be occasional concentrically laminated particles, called cementicles, but these are not a prominent feature of psammomatoid entity.
Microscopic features of trabecular variant of juvenile ossifying fibroma shows an unencapsulated tumor mass infiltrating into the surrounding bone and reactive bone formation at the periphery. The tumors show a characteristic loose structure with cell-rich stroma composed of fibroblastic spindle cells that produce little collagen. Anastomosing trabeculae of osteoid is seen in a pattern that resembles ‘paintbrush’ strokes. The osteoid areas mature into woven bone trabeculae that are rimmed with osteoblasts and show osteocytes embedded in it. Aggregates of osteoclastic giant cells are commonly present and seen in association with the bony trabeculae and in separate foci in the fibrous stroma, usually—but not always—at sites of hemorrhage. Mitotic figures may be observed in the stroma but are never numerous. Cystic degeneration and aneurysmal bone cyst formation have been described in a few cases.
Recurrence after surgical management is common and is reported to range from 30 to 56% in psammomatoid juvenile ossifying fibroma. Recurrence may be attributed to difficulty in proper resection caused by the location of the lesion and the infiltrative nature of tumor borders. Malignant change has not been reported. Fatal consequences are extremely rare and usually caused by complications arising from direct intracranial extension with resultant encephalitis and meningitis.
Trabecular juvenile ossifying fibroma should be conservatively excised in its entirety. Recurrences are seen in 30–50% of cases. More than one excision may be required to achieve cure. No malignant transformation has been reported.
Fibrous dysplasia of bone is an uncommon congenital skeletal disorder. It is characterized by the replacement of normal bone and marrow by fibrous tissue, within which irregular trabeculae of woven bone are haphazardly distributed. The maturation of bone is arrested at the woven bone stage. It may affect single (monostotic) or multiple bones (polyostotic) and may be associated with endocrinopathies.
A paper by von Recklinghausen in 1891 was probably the first citation of the disease. Albright pointed out two cases that were described by von Recklinghausen as examples of osteitis fibrosa generalisata due to hyperparathyroidism were almost certainly examples of fibrous dysplasia. The term fibrous dysplasia was first suggested by Lichtenstein in 1938 as a designation for multiple bone lesions that were described by Albright et al as osteitis fibrosa generalisata. The lesions of fibrous dysplasia were initially considered to be primarily polyostotic. Lichtenstein and Jaffe later expanded this concept and noted that isolated (monostotic) form of disease also occurred and was by far more common than the polyostotic. McCune and Albright in 1936 and 1937 respectively showed an association of polyostotic fibrous dysplasia with abnormal skin pigmentation, and precocious puberty because of which this association has been termed as McCune–Albright’s syndrome. Jaffe–Lichtenstein described the association of polyostotic fibrous dysplasia with abnormal skin pigmentation; thus it was named as Jaffe–Lichtenstein syndrome.
The molecular mechanism responsible for fibrous dysplasia is a postzygotic activating mutation of the GNAS1 gene that encodes for the Gsα subunit of the heterotrimeric G protein complex. The result is constitutive activation of the adenylyl cyclase enzyme and overproduction of 3′,5′-cyclic adenosine monophosphate. The most common GNAS1 gene mutations are a replacement of arginine by either cysteine or histidine at codon 201 (R201C or R201H), but other mutations have also been identified. The severity of the disease phenotype is thought to depend on when the mutation occurs during embryogenesis. If the mutation occurs during the formation of the inner cell mass, all three germ cell layers will be affected and the phenotype will be McCune–Albright’s syndrome. If it occurs later in development, only one or two germ cell layers will be affected and the phenotype is less severe. Fibrous dysplasia is considered a disease of cells of the mesenchymal stem cell/osteoblastic lineage in which excess cyclic adenosine monophosphate impairs the ability of the stem cell to differentiate into a mature functioning osteoblast.
Fibrous dysplasia is mainly diagnosed before the age of 30 years and is equally seen in both the sexes. It occurs both in polyostotic and monostotic forms. Monostotic form is at least six times more common than polyostotic form.
In polyostotic form of disease two or more bones are affected generally the long bones, ribs and skull, although any bone may be affected. The lesions are often found unilaterally. Painless expansion of the affected area is most common complaint of the patient. Pathological fracture with resultant pain and bone deformity are other symptoms.
Presence of abnormal skin pigmentation with polyostotic fibrous dysplasia is termed as Jaffe–Lichtenstein syndrome. The abnormal hyperpigmentation seen resembles cafe´-au-lait spots which mean coffee with milk. The hyper-pigmentation tends to be present on the same side and on the skin overlying the lesions of fibrous dysplasia. The hyperpigmented macules are well-defined and have irregular borders which sometimes distinguish them from the lesions associated with neurofibromatosis. The color can be medium to dark brown.
Association of endocrine abnormalities with skin hyperpigmentation and polyostotic fibrous dysplasia is termed as McCune–Albright’s syndrome. A variety of endocrine abnormalities such as accelerated skeletal growth, acromegaly, gigantism, hyperprolactinemia, Cushing’s syndrome, hyperthyroidism, hyperparathyroidism, diabetes mellitus, hypothalamic hypogonadism and hypophosphatemic rickets, gynecomastia, spermatogenesis in young boys and sexual precocity in girls have been associated with the disease. Sexual precocity is the most common endocrine abnormality seen in the affected individual. Male children exhibit enlarged genitalia and advanced secondary sex characteristics. Female children manifest estrogen excess.
Monostotic form of the disease is seen in 80–85% of cases. The jaws are the most common areas affected, with the maxillary jaw being more common than the mandibular jaw. The maxillary lesions frequently involve a group of contiguous bones separated by sutures (i.e. maxilla, zygoma, sphenoid and occiput) and thus are not strictly monostotic lesions. Such lesions are more appropriately classified as craniofacial fibrous dysplasia. The craniofacial region is involved in up to 25% of the patients with monostotic fibrous dysplasia, and in approximately 40–60% of those with the polyostotic fibrous dysplasia. Similarly, maxillofacial fibrous dysplasia is the term recently described by Mahajan et al for the lesions which are limited to the facial bones. Painless enlargement of the affected bone is most commonly seen. The patient usually is not able to recall the onset of the swelling. Maxillary and mandibular fibrous dysplasia is associated with significant facial and palatal asymmetries, heterogeneous dental anomalies (rotation, oligodontia, displacement, enamel hypoplasia and hypomineralization, taurodontism, and others), malocclusion, and a high caries index score.
The diagnosis of fibrous dysplasia can be made by radiographs although it is not unusual for bone biopsies to be required because of uncertainty based on radiographs alone. The characteristics, which are somewhat variable, include a ground-glass appearance, which occurs due to sup/>