Pathology
Histopathologically, cholesterol granulomas are characterized by cholesterol crystals surrounded by multinucleate giant cells with blood degradation products. The absence of epithelial elements differentiates cholesterol granulomas from similar-appearing cholesteatomas and also excludes epidermoid or dermoid cysts. Additionally, the prominent xanthomatous component serves to differentiate cholesterol granulomas from giant cell granulomas and aneurysmal bone cysts.
Giant Cell Granuloma
Giant cell granulomas (GCG) are benign reactive fibro-osseous proliferations most commonly found in the mandible or maxilla but have also been reported in other bony sites, including the paranasal sinuses, frontal bone, temporal bone, long bones, and cranial vault. GCG of the orbit is extremely rare, with only a handful of cases noted in the literature. Despite their benign nature, GCG may be locally aggressive, resulting in bone damage.13–17
Pathogenesis
The pathogenesis of these lesions is unclear, although inflammation, trauma, and intraosseous hemorrhage are suspected to be causative. These lesions have occasionally been noted in constellation with other syndromes, including Noonan syndrome, Stickler syndrome, neurofibromatosis type 1, and cherubism, perhaps suggestive of an undiscovered chromosomal abnormality.18
Differential Diagnosis and Clinical Features
GCG are most often seen in females during the first two decades of life. Signs and symptoms usually arise from mass effect and include swelling/deformity and occasional pain. The differential diagnosis of GCG, based on histopathologic and radiologic clues, includes osteoclastoma, eosinophilic granuloma, aneurysmal bone cyst, and brown tumor of hyperparathyroidism.
Investigations
The radiographic appearance of GCG demonstrates a well demarcated, multiloculated, expansile, and osteolytic lesion of bone. However, this appearance is highly variable and nonspecific, resulting in easy confusion with other osteolytic and expansile bony lesions such as giant cell tumor, aneurysmal bone cyst, osteosarcoma, and nonossifying fibroma.
Pathology
The gross and histopathologic appearances of these lesions, although still nonspecific, are more characteristic and helpful in differentiating these lesions. Grossly, GCG are usually seen as red or reddish-blue, highly vascular tissue.19,20 Microscopically, the lesions are marked by prominent collections of osteoclast-like giant cells with a tendency to cluster around hemorrhagic foci, an intervening stroma displaying oval-shaped and spindle-shaped fibroblasts with scattered foci of collagen formation, hemosiderin deposition, and osteoid or new bone formation.
Several other lesions of orbital bone also feature multinucleated giant cells. These include giant cell granuloma, giant cell tumor, aneurysmal bone cyst, brown tumor of hyperparathyroidism, and Langerhans cell histiocytosis (LCH). This histologic appearance of giant cell granulomas is shared with “brown tumor” of hyperparathyroidism, which must be excluded by checking serum calcium, phosphorus, and parathyroid hormone. Giant cell tumors (GCT), however, are histologically distinct and lack diffuse hemorrhage, hemosiderin, fibroblasts, and osteoid and instead feature more evenly distributed giant cells containing up to 50 nuclei and prominent mitotic figures. Also noted is a mononuclear cell stromal component, rather than a fibroblastic component. The absence of prominent Langerhans cells and cystic, blood-filled vascular channels helps differentiate giant cell granulomas from Langerhans histiocytosis and aneurysmal bone cysts, respectively.16, ,20,21
Management and Disease Course
Most GCG are benign, with good cure rates achieved by using curettage alone. Differentiating GCG from other similar-appearing lesions may require frozen section evaluation intraoperatively to proceed with the appropriate treatment. Recurrence rates have been variably reported between 10% and 50%. Medical adjuvant therapy with corticosteroids, calcitonin, bisphosphonates, imatinib, and interferon (IFN)-α with variable degrees of success have been reported.18,22 The successful use of adjuvant fractionated radiotherapy has also been reported; however, this has been traditionally avoided, given reports of malignant transformation after radiation therapy.19,18,23
Aneurysmal Bone Cyst
Aneurysmal bone cysts (ABC) are locally expansile osteolytic lesions consisting of blood-filled spaces and surrounding fibro-osseous reactive tissue. They are most commonly seen in the metaphyses of long bones, including the femur, tibia, humerus, and fibula, but can occur throughout the bony skeleton.24 ABC can arise as primary lesions or secondary to existing bony lesions such as giant cell tumor, osteoblastoma, fibrous dysplasia, and others. Both primary and secondary ABC are very rarely seen in the orbit.25
Pathogenesis
The mixed vascular and granulation tissue–like appearance of these lesions led to the traditional belief that ABC are reactive in nature. It has previously been held that ABC arise from altered hemodynamics within bone, perhaps from trauma or an existing arteriovenous anomaly, creating an engorged vascular bed leading to erosion, pressure remodeling, and resorption of the surrounding bone. Secondary osseous reparative processes were thought to result in the formation of giant cells, fibroblastic proliferation, and new bone deposition.
More recently, however, oncogenetic studies have suggested that ABC may, in fact, be clonal neoplastic lesions with a specific genetic rearrangement resulting in the upregulation of the Ubiquitin protease USP6 gene within spindle cells.26,27 Further studies are ongoing, and genetic testing in the future may help differentiate ABC from similar pathologies that do not show USP6 rearrangements, including osteosarcoma, chondroblastoma, giant cell tumor, and simple bone cyst.27
Clinical Features
ABC commonly manifest in the first two decades of life and have no known gender predilection. Lesions in the orbit have been reported to grow slowly for weeks to months, followed by a period of rapid growth, resulting in painful exophthalmos, ptosis, diplopia, and other ophthalmic symptoms.28
Investigations
The radiographic features of ABC are highly characteristic. CT imaging classically demonstrates a multiloculated interdiploic lesion, with cystic spaces containing fluid–fluid levels corresponding to the layering of uncoagulated blood. The inner and outer cortical bone tables are usually thinned but intact. The peripheral capsule and internal septations of the lesion are enhanced strongly with intravenous iodinated contrast. MRI studies are similarly characteristic: the fibrous capsule and internal septations are seen with hypointense signal intensity in all sequences. Cystic spaces with fluid–fluid level are also seen, with variable signal intensity. Both the peripheral capsule and internal septations similarly are enhanced intensely with intravenous gadolinium. Although orbital ABC may extend intracranially, they typically do not violate the dura.
Ultrasonography has also been used to detect the characteristic fluid–fluid levels and is a safe alternative in young children who may require sedation for CT or MRI.29 Angiography may sometimes reveal the blood supply to these vascular lesions and also arteriovenous shunts.30,31
Pathology
Histopathologic examination reveals a highly vascular lesion that is composed of numerous blood-filled cysts without endothelial lining. The cysts are separated by septa composed of spindle-shaped fibroblasts with scattered multinucleated giant cells, hemosiderin-laden macrophages, granulation tissue, and extravasated red blood cells. The septa also usually contain trabeculae of new bone formation. A variety of benign and malignant bone and soft tissue neoplasms – including giant cell tumor of bone, chondroblastoma, osteoblastoma, fibrous dysplasia, and osteosarcoma – may contain areas histologically indistinguishable from ABC.32–34
Management and Disease Course
The treatment of orbital ABC is total resection and bony defect repair, where needed. Radiotherapy and systemic steroids have been used as adjuvant therapy, although radiation therapy should only be used in cases not suitable for surgery.35 Recurrence is common within the first 2 years, with a 10% to 50% recurrence rate noted in the literature.24 Malignant transformation has also been described but is exceedingly rare.27 Close follow-up after resection of orbital ABC is recommended.
Bony Tumor of Hyperparathyroidism – “Brown Tumors”
“Brown tumors” (osteitis fibrosa cystica) are localized bony accumulations of fibrous tissue and giant cells that occur as a direct result of the effect of parathyroid hormone (PTH) on bone tissue in patients with primary and secondary hyperparathyroidism.36 Craniofacial brown tumors are uncommon, typically involving the mandible or the maxilla, with orbital involvement being even more infrequent.37,38 Very rare orbital involvement has been reported in all walls of the orbit, usually secondary to invasive lesions arising from the maxilla, frontal bone, and paranasal sinuses.39
Pathogenesis
The pathogenesis of these lesions is directly attributable to the effects of PTH on bone, and the diagnosis of hyperparathyroidism is imperative to differentiate these lesions from other giant cell lesions. The diagnosis is made by checking PTH levels, and by elevation of alkaline phosphatase, high calcium levels, and low phosphate levels. Primary hyperparathyroidism causes an elevation in PTH usually from primary secreting gland tissue, whereas secondary hyperparathyroidism is most commonly a sequela of renal failure.19,40
Differential Diagnosis and Clinical Features
“Brown tumors” may manifest at any age but are more commonly seen in adults over the age of 50 years and are up to three times more common in women.41 Patients with brown tumors involving the orbit may present with a mass, proptosis, pain, diplopia, decreased extra ocular motility, or decreased visual acuity.40,42 The differential diagnosis, based on clinical, radiographic, and histopathologic evidence, should include giant cell tumor, giant cell reparative granulomas, aneurysmal bone cyst, fibrous dysplasia (FD), osteoblastoma, ossifying fibroma (OF), Paget disease of bone, and metastasis.
Investigations
Radiologic studies usually show a moth-eaten appearance of bony demineralization, with erosion of the inner and outer cortical layers and fractures. The lesions are usually well-defined osteolytic lesions with cystic, expansile, and aggressive aspects. As with ABC, fluid–fluid levels may be present.38 Variable degrees of calcification and reactionary bone formation may also be present, depending on the underlying disease stage and treatment. Diffuse bilateral widening of all bones of the facial skeleton, called facial leontiasis (lion face), can also rarely be seen.37
Pathology
Histopathologically, brown tumors have no pathognomonic findings and are indistinguishable from other giant cell lesions of bone such as giant cell granulomas and GCT. The lesions arise in areas of intense bone resorption, where bony defects become filled with cysts of reactive fibroblastic tissue.41 Examination reveals cystic degeneration, osteoid, macrophages with hemosiderin, and multinuclear osteoclastic giant cells in a fibroblastic stroma.37 The term “brown tumor” comes from the gross appearance of the lesion resulting from blood pigments that are both free and within hemosiderin-laden macrophages.
Management and Disease Course
After controlling the underlying metabolic disorder (sometimes requiring parathyroid surgery), most brown tumors regress spontaneously. Surgical resection or debulking may be necessary in unresponsive cases or in cases presenting with serious functional problems, including loss of vision. The lesions can recur if hyperparathyroidism persists or recurs.40
Benign Fibro-Osseous and Cartilaginous Lesions
Fibrous Dysplasia
Fibrous dysplasia (FD) is a disease of bone characterized by expansion and replacement of normal medullary bone by disorganized fibro-osseous tissue.43–46 These lesions are usually found as isolated skeletal findings in a single location (monostotic) but may also occur in multiple locations (polyostotic) in isolation or in association with cutaneous and endocrine abnormalities known as the McCune-Albright syndrome.45,46 Craniofacial bones are involved in approximately 10% to 20% of cases of FD.44,47 When observed in the orbit, FD is typically monostotic and crosses suture lines to involve multiple orbital walls.44,47–49 The term monostotic is somewhat of a misnomer in its use in FD, as it refers to one region rather than one bone.
Pathogenesis
Recent advances have improved our understanding of the pathogenesis underlying FD. Lesions are now believed to arise secondary to a somatic mutation in osteoblastic cells, resulting in increased intracellular cyclic adenosine monophosphate. This accumulation may induce cell proliferation, inappropriate cell differentiation, and overproduction of a disorganized fibrotic bone matrix.43,50
Clinical Features
FD commonly presents in childhood, although symptoms may progress into adulthood; it may be slightly more common in females.44,45 Patients with orbital involvement may present with facial asymmetry, visual loss, proptosis, or globe displacement44,49,51 (Fig. 16.2). Incapacitating pain is not uncommon. These symptoms may be the first clinical manifestations of the disease. Additional ophthalmic symptoms, including epiphora, dacryocystitis, ptosis, trigeminal neuralgia, and strabismus, have been reported.43,44,47,49,51 Visual impairment is thought to be the most common neurologic complication of craniofacial FD, although the etiology of this is unclear. Aneurysmal bone cysts and mucoceles occurring in association with FD have previously been shown to cause compressive optic neuropathy. Additionally, encasement of the optic canal by fibrous dysplastic changes was thought to result invariably in optic neuropathy, although recent evidence suggests otherwise.43,44,47,51
Investigations and Differential Diagnosis
The radiologic features of FD vary from lucent zones to large areas of sclerosis, depending on the developmental stage of the lesion. In the early stages, CT imaging reveals a well-defined and radiolucent lesion. In the later stages, the lesion becomes more opaque with ill-defined borders. It is common to see radiolucent areas of fibrous tissue adjacent to radiodense or sclerotic areas that are predominantly osseous. As mentioned previously, lesions in the orbit are typically seen as monostotic lesions that cross suture lines and involve multiple cranial bones. MRI typically exhibits areas of low-to-intermediate signal intensity, with moderate-to-marked enhancement with contrast administration (Fig. 16.2). Soft tissue involvement is generally absent.44 Importantly, radiologic evidence of apical involvement does not correlate well with visual function. Patients may continue to have normal visual function despite severe optic canal and superior orbital fissure involvement.43 The radiographic differential diagnosis varies by anatomic location but includes nonossifying fibroma, osteofibrous dysplasia, aneurysmal bone cyst, giant cell tumor, and low-grade osteosarcoma.46 Biopsy specimens can be tested for nerve growth factor receptor Trk A, which, when present, portends good response to intravenous tocilizumab treatment.
Pathology
FD exhibits a classic histology of low to moderately cellular fibrous stroma surrounding irregular trabeculae of immature bone. The stroma may be variably collagenized, and the ratio of fibrous tissue to bone can range from being completely fibrous to being densely packed with dysplastic trabeculae. Unlike OF, the immature trabeculae are usually not lined with osteoblasts. Cytologic atypia is not seen, whereas secondary changes such as the formation of a metaplastic chondroid component or aneurysmal bone cyst-like changes are occasionally observed. The histologic differential diagnosis is similar to the radiographic differential diagnosis.
Management and Disease Course
Treatment strategies for orbital lesions should prioritize the restoration of ocular function, relief of pain, improvement of structural deformity, and long-term monitoring of visual function (Fig. 16.3). Pain may be unresponsive to traditional medications (opioids, gabapentin), but successful pain management with bisphosphonates and parathyroid hormone analogues in extraorbital lesions has been reported.45,46 Tumors that test positive for the Trk A receptor can be managed with monoclonal antibodies such as tocilizumab or denosumab. However, complete resection and simultaneous bony reconstruction, if necessary, remain the definitive treatment. Some authors have recommended watchful expectancy of these lesions as their growth may slow after puberty.49 Additionally, current evidence suggests that prophylactic transcranial decompression of the optic canal should not be performed but be reserved for those instances in which there is documented visual loss.51 The potential role of endoscopic transsphenoidal optic canal decompression is less clear. In addition, the presence of intralesional cysts near the orbital apex may be an indication for early surgery as these expansile lesions are responsible for the majority of cases of acute vision loss in FD.43 Lastly, any rapid progression or abrupt change of symptoms should raise the rare possibility of malignant transformation (most commonly to osteosarcoma).47
Ossifying Fibroma
Ossifying fibromas (OF) are benign fibro-osseous tumors consisting of highly cellular fibrous tissue with varying amounts of osseous tissue replacing normal bone.52,53 The nomenclature of these lesions has varied over time and includes the terms juvenile ossifying fibroma, psammomatoid ossifying fibroma, and cementifying fibroma.52,54 These entities are thought to encompass clinical and histologic variants of the same underlying pathology.55,56 OF are usually solitary and are almost exclusively found in the craniofacial bones, predominantly in the mandible and the maxilla.52,53 Orbital involvement usually occurs secondarily from lesions originating in the paranasal sinuses, affecting the medial or inferior orbital wall.55 Primary OF of the orbit involving other orbital walls have also been rarely described.53,57
Differential Diagnosis and Clinical Features
OF is most commonly seen in children and young adults, with some authors reporting a female preponderance.54,57 Despite their benign and often asymptomatic nature, OF can exhibit locally aggressive behavior, particularly in children.52 Symptoms develop in response to lesion expansion, resulting in significant facial asymmetry, pain, and local destruction.52,58 When present in the orbit, these lesions commonly present with globe displacement and diplopia, although eyelid edema, erythema, ptosis, chemosis, extraocular motility restriction, and other signs of orbital inflammation have been reported.53,55,58,59 These lesions may present similar to other bony lesions in the orbit, including FD, aneurysmal bone cyst, GCG, osteoma, and osteoblastoma.1
Investigations
CT imaging characteristically demonstrates a well-defined, monostotic, round, or ovoid mass that produces expansion of the involved bone (Fig. 16.4). Bony expansion occurs as a result of combined osteoblast and osteoclast activity in the central matrix seen radiographically as reduced internal density.60 The lesions are commonly separated from the surrounding bone by an outer sclerotic shell,55 which may enhance with contrast administration.1,55 The well-circumscribed nature of these lesions on imaging studies helps differentiate them from FD, which usually shows an intimate continuity between the lesion and normal bone.56 On MRI, the bony walls are isointense with grey matter on T1-weighted images and display variable signal intensity on T2-weighted images. High technetium-99 radioisotope uptake can also be seen as a result of high osteoblastic activity.53
Pathology
The histologic features of OF can be difficult to distinguish from those of other fibro-osseous lesions. In general, OF consists of a fibrous stroma, as well as a bony element showing various degrees of maturation. The trabeculae are often interconnected, and surrounded by osteoblasts, resulting in the formation of an osseous capsule – features not observed in FD.56 Several distinct histologic variants of OF have been distinguished on the basis of the characteristics of the osteoid component. These distinctions may be clinically significant, as the overwhelming majority of cases with orbital involvement belong to the “psammomatoid” variant.55 This variant is characterized by the presence of a large number of round hypocellular ossicles (psammoma-like) embedded in a stroma of spindle cells.55,56
The molecular mechanisms underlying the pathogenesis of these benign lesions remain unknown, and investigations into possible culprit somatic mutations are ongoing.50
Management and Disease Course
Most authors recommend complete surgical excision because of the tumor’s aggressive local behavior and a 0% to 28% recurrence rate when simple curettage with incomplete resection is performed.52,55 For smaller lesions, an orbitotomy may suffice, but larger lesions will likely require a combined approach.1 Significant bony debridement may require reconstruction with bone grafts or other alloplastic materials.56 These patients require long-term surveillance to monitor for recurrence and to ensure normal development of the affected craniofacial skeleton.
Osteoma
Osteomas are benign, slow-growing tumors of bone. They are the most common tumor of the paranasal sinuses, of which the frontal sinus is the most frequently involved.61,62 Most orbital osteomas occur as extensions of paranasal sinus lesions, with an incidence ranging from 0.9% to 24%,1,62,63 although primary orbital lesions have also been reported.64 Osteomas are usually found incidentally on imaging and rarely cause serious complications.65
Pathogenesis
The etiology of osteomas remains unknown, although developmental abnormality, trauma, infection, and chronic inflammation have all been proposed as possible mechanisms. Although most osteomas are sporadic, they may be associated with Gardner syndrome, an inherited colonic adenomatosis, in which the incidence of colon adenocarcinoma is 100%. Patients with osteoma and suspicion of Gardner syndrome (positive family history, gastrointestinal symptoms, and/or extracolonic manifestations) should undergo further evaluation to exclude this potentially fatal disease.63
Differential Diagnosis
The differential diagnosis for orbital osteoma includes benign fibro-osseous entities such as OF, FD, and osteoblastoma and malignant neoplasms such as osteosarcoma.
Clinical Presentation
Orbital osteomas most commonly present in the fourth and fifth decades and more often in males.61 Signs and symptoms of orbital osteomas include headaches, diplopia, globe displacement, epiphora, metamorphopsia, dacryocystitis, orbital cellulitis, and vision loss.63,64,66,67 On examination, a bony mass may be palpable.1
Investigations
CT imaging with thin (1 mm) slices is preferred to MRI, given the small and bony nature of these lesions. On CT imaging, osteomas characteristically appear as highly circumscribed, dense, sclerotic masses, which can be sessile or pedunculated.1,63 They often feature a central area of lucency, surrounded by homogeneously calcified and lobulated bone. This radiographic appearance mirrors the zonal appearance of osteomas noted on histologic examination.
Classification
There are several classification schemes to describe the histologic features of osteomas, although these distinctions may have limited clinical relevance.63 Osteomas characteristically exhibit concentric and histologically distinct zones of bone maturation. This zonal pattern suggests outward growth from the center and may explain why partial excision with removal of the central core typically prevents recurrence.1 Centrally, loose fibrovascular tissue with active osteoblasts and immature Paget-like bone are seen.61 The osteoid is often organized into trabecular arrays lined by osteoblasts, a key finding in distinguishing osteoma from osteosarcoma.68 External to this inner zone is a middle area of cancellous bone with increased osteoblastic activity, surrounded by an outer zone of compact bone resembling normal cortical bone. Importantly, the diameter of osteomas rarely exceeds 1 cm. The term osteoblastoma, implying greater growth potential, is applied when a lesion of identical histology exceeds 1 cm.68
Prognosis and Management
Indications for surgical intervention include vision loss, optic neuropathy, eye pain, globe displacement, diplopia, sinus obstruction, headaches, or cosmetic deformity.63 Given the benign nature of osteomas and minimal risk of malignant transformation, subtotal resection targeting the central core of the lesion is a valid alternative when complete excision would result in significant disfiguration or morbidity. Although recurrence is extremely rare,63 patients with orbital involvement should be periodically monitored for recurrence or residual growth of the tumor.
Osteoblastoma
Osteoblastoma is a rare, benign, osteogenic neoplasm that is usually seen in the spinal column69–72 Skull involvement is estimated at less than 20% of cases, with orbital involvement being even less frequent.69 In most cases, lesions in the orbit involve the anterior skull base69 and should be differentiated from similar tumors such as osteoma, osteosarcoma, giant cell tumor, aneurysmal bone cyst, and FD.
Clinical Features
Osteoblastoma usually occurs in children and young adults but has been described in all age groups with possible male predilection.68,70 The tumor typically grows slowly but can exhibit rapid growth simulating infectious or malignant process.69 When present in the orbit, common clinical features include exophthalmos, periorbital swelling, frontal headache, and vision loss69,71–74 (Fig. 16.5). Variable cranial nerve deficits may also be seen with skull base involvement.69,72,74
Investigations
CT imaging demonstrates a well-circumscribed lesion with high bone density but less dense and homogeneous than seen in osteoma69 (Fig. 16.5). The tumor can often be visualized displacing surrounding bone, but without true cortical erosion, and is surrounded by a thin shell of new bone.69 Young lesions tend to appear lucent with progressive ossification over time. MRI studies, if performed, generally reveal a nonenhancing mass with low signal in both T1- and T2-weighted scans, corresponding to diffuse mineralization and osteoid production.72,73 Additional imaging modalities such as nuclear technetium scanning and angiography may enhance visualization of new bone growth and increased tumor vascularity.61 Differentiating osteoblastoma from osteosarcoma radiographically can be challenging because no established radiologic criteria exist.72
Pathology
On gross examination, osteoblastoma appears as a well-circumscribed but nonencapsulated tumor, 1 cm or more in diameter and with marked vascularity and a gritty texture. Microscopically, the tumor is composed of small bony trabeculae and osteoid separated by a highly vascular stroma. Multinucleated giant cells mimicking giant cell tumor can be seen, but no atypia and few mitotic figures are present.68,70 This histologic appearance cannot be reliably distinguished from that of osteoma, although these lesions are thought to be more vascular and may result in severe bleeding during surgical procedures.69 An important distinction must be made between osteoblastoma and osteosarcoma. Unlike osteosarcoma, osteoblastoma does not infiltrate and isolate pre-existing lamellar bone structures.68 Additionally, osteosarcoma can be distinguished by the presence of cellular atypia, mitotic activity, and cartilaginous proliferation.72
Management and Disease Course
Total surgical resection remains the treatment of choice for orbital osteoblastoma (Fig. 16.5). Removal can be challenging because of high vascularity and skull base extension. A multidisciplinary approach is often required, with some authors recommending preoperative embolization to improve intraoperative hemostasis.69 Although malignant transformation is extremely rare, adjuvant radiotherapy should be reserved for unresectable, or partially resected, lesions. Long-term surveillance is recommended, as recurrence after incomplete resection has been reported.1
Bony Neoplasms
Osteosarcoma
Osteosarcoma is the most common primary malignant neoplasm of bone and is typically seen in in the long bones.1,68 These lesions have been described by several names in the literature, including conventional osteosarcoma, classic osteosarcoma, osteogenic sarcoma, osteoblastic carcinoma, and medullary osteosarcoma.68 Involvement of the orbit is rare and is thought to have a maxillary focus.1 Orbital osteosarcomas have been reported as primary de novo lesions, as metastatic lesions, in association with predisposing disease such as Paget disease of bone, secondary to prior chemoradiation, and even as extraskeletal lesions.75–81
Pathogenesis
The etiology of osteosarcoma remains unknown. Most, if not all, osteosarcomas contain clonal chromosomal abnormalities, although no diagnostically unique alteration has been identified.68 Paget disease of bone and prior chemoradiation exposure have long been associated with an increased incidence of osteosarcoma.68,81 Additionally, the development of radiation-induced osteosarcoma after treatment of retinoblastoma is well established, with a 500-fold increase in hereditary retinoblastoma.81
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