PRIMARY LESIONS OF THE BONY ORBIT

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2 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 1 Tatyana Milman, MD Pathology Department Hospital of the University of Pennsylvania milmant@uphs.upenn.edu PRIMARY LESIONS OF THE BONY ORBIT Introduction Primary lesions of the bony orbit are relatively rare, comprising 0.6% to 2% of all orbital tumors. While uncommon, the lesions arising within the walls of the bony orbit are quite diverse, and include a variety of reactive processes, benign neoplasms, and malignant tumors. The heterogeneity of these lesions is highlighted in a review by Selva et al, which summarizes the authors experience over the course of 3 decades (Table 1). Selva D1, White VA, O'Connell JX, Rootman J. Primary bone tumors of the orbit. Surv Ophthalmol 2004;49: Fibro-osseous and osseous tumors account for approximately one half of all primary orbital bone lesions. These tumors share clinical, radiologic, and pathologic features causing potential difficulties in diagnosis. In contrast to similar lesions of long bones, orbital lesions are frequently curetted, limiting contribution of gross evaluation to pathologic assessment. This session will focus on the site-specific features of fibro-osseous and osseous lesions of the bony orbit and on the clinical, radiographic, and pathologic criteria that may assist in differentiating these lesions from one another.

3 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 2 Benign Fibro-Osseous Lesions of the Bony Orbit Fibrous dysplasia Definition Fibrous dysplasia is a dysplastic skeletal anomaly in which normal medullary bone is distorted and replaced by structurally weak, poorly organized and inadequately mineralized immature woven bone and fibrous tissue. The disease may affect a single bone (monostotic) or multiple bones (polyostotic). Notably, the pathologic process in the craniofacial skeleton is not always strictly limited to one bone, but may extend by continuity across suture lines to involve adjacent bones, thus the commonly used notation monostotic in these cases is not always accurate, and the term craniofacial fibrous dysplasia is preferred. Rarely, polyostotic fibrous dysplasia can be associated with skin pigmentation and endocrine abnormalities, a condition known as the McCune-Albright syndrome. Clinical Presentation Fibrous dysplasia is a disease of growing bones, thus the majority of patients affected are under 30 years of age, and usually present in the first two decades of life. Males and females are equally affected. While monostotic fibrous dysplasia is much more frequent overall in the entire skeleton, including craniofacial region, up to 50% of polyostotic fibrous dysplasia lesions involve craniofacial bones. Specifically to the orbital region, the majority of patients have monostotic fibrous dysplasia involving the frontal bone, followed by the sphenoid and ethmoid bones being most frequently affected. The patients typically present with long-standing facial asymmetry, proptosis, and globe displacement, frequently associated with either localized orbital pain or diffuse ipsilateral headache. Less commonly, double vision, cranial nerve palsies, nasolacrimal duct obstruction, and elevated intracranial pressure can occur. Gradual visual loss can result from chronic optic nerve compression, while acute loss of vision can be precipitated by the intralesional hemorrhage or by an associated mucocele or aneurysmal bone cyst. Rapid progression and increasing pain may herald the rare occurrence of malignant transformation to osteosarcoma, chondrosarcoma, and fibrosarcoma. Radiographic Features Computed tomography (CT) classically demonstrates an expansion of the involved bone with an intact thin cortex and a characteristic heterogeneous radiolucent/radiopaque pattern ( ground glass appearance ), with lesional bone blending imperceptibly with the surrounding normal-appearing bone. However, radiographic appearance may vary depending on the stage of disease and the amount of bony matrix within the lesion. Early lesions tend to be radiolucent and become more opaque as the lesion progressively calcifies. On magnetic resonance imaging (MRI), fibrous dysplasia has an intermediate signal on T1-weighted images and heterogeneous hypointense signal on T2-weighted images. Pathologic Features Grossly, the affected bone is rubbery, compressible, and grayish white to pink tissue with frequent blood- or serous-filled cysts and a gritty texture when cut with a scalpel. Microscopically, the normal bone is replaced with a variably cellular fibrous stroma, which contains variable amounts of randomly dispersed irregular, usually delicate, immature (woven) bone trabeculae that lack osteoblastic rimming, forming odd geometric patterns, including C or S shaped configurations (so-called Chinese characters). Multinucleated giant cells, macrophages, nodules of hyaline cartilage, and increased vascularity may be seen. Infiltration of surrounding tissues, including normal bone, associated with areas

4 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 3 of reactive bone formation, correlates with the poorly defined lesion seen radiographically. Notably, lamellar bone and osteoblastic rimming can be present in fibrous dysplasia, contributing to the challenges in its histologic distinction from ossifying fibroma. Thus, the pathologic diagnosis rests on careful clinical-radiographic-histologic correlation. Young age at presentation, radiographic evidence of expansile heterogeneously intense bony lesion with poorly defined borders, which blends gradually with the surrounding bone, are the findings that support histologic diagnosis of fibrous dysplasia. Genetics Fibrous dysplasia is a nonhereditary condition, caused by a post-zygotic somatic gain of function mutation in GNAS1 gene located at 20q, which encodes G protein subunit alpha (GS alpha). GS alpha regulates adenylate cyclase, an enzyme involved in bone development and endocrine gland regulation. Post-zygotic GNAS1 mutation results in mosaic distribution of cells bearing constitutively active adenylate cyclase. This leads to increased cell proliferation and inappropriate differentiation, culminating in multifocal overproduction of disorganized immature fibrotic bone in polyostotic fibrous dysplasia and in the hormonal hyperproduction and skin pigmentation in McCune-Albight Syndrome. The same mutation has been identified in the monostotic fibrous dysplasia. Management and Prognosis Craniofacial fibrous dysplasia typically becomes quiescent after puberty. However, persistent growth in later life has also been described. Surgery in the form of resection or curettage has traditionally been reserved for functional deficits, pain, gross deformity, or malignant change. Contouring of the affected bone back to normal dimension can be a viable option, although retreatment may be required in a small percentage of the patients. Partial excision followed by grafting with normal autologous bone or acrylic implants may achieve reduction in the rate of recurrence. Aggressive surgery, including optic nerve decompression and radical resections are reserved for the lesions causing optic neuropathy or in a setting of malignant transformation. Malignant transformation, most commonly into osteosarcoma and less frequently, into chondrosarcoma and fibrosarcoma, has been rarely seen in fibrous dysplasia, classically in a context of prior radiation therapy. For that reason, radiation is currently strictly contraindicated in management of fibrous dysplasia. Ossifyng fibroma Definition Ossifying fibroma is a benign bone-producing fibrous neoplasm. In craniofacial skeleton, ossifying fibromas are separated into two main clinicopathologic entities: 1) ossifying fibroma of odontogenic origin, also known as cemento-ossifying fibroma and 2) juvenile ossifying fibroma, which is further subdivided into trabecular and psammomatoid variants. Cemento-ossifying fibroma affects the tooth bearing areas of the mandible and maxilla, and is believed to be derived from the progenitor cells of the periodontal membrane. Clinical evidence and recent molecular genetic data suggest that cementoossifying fibroma is a distinctive jaw lesion that should not be confused with extragnathic craniofacial ossifying fibromas. Further, some experts endorse that the published histology of the cementoossifying fibromas of the orbit is more compatible with psammomatoid juvenile ossifying fibroma. Similarly, trabecular juvenile ossifying fibroma is extremely uncommon in extragnathic location, and is not well-documented in the orbital region.

5 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 4 Clinical Presentation The demographics and clinical presentation of patients with orbital ossifying fibroma overlap with those of fibrous dysplasia, contributing to the diagnostic challenge. Unlike gnathic ossifying fibroma, which has female predilection and the peak incidence in a third and fourth decades of life, orbital ossifying fibroma demonstrates no gender predilection, and typically occurs in a younger age group (average 16 to 33 years), although the age can range widely from 3 months to 72 years. The patients typically present with a slow painless displacement of the eye, visual disturbances, and nasal obstruction, related to the involvement of the frontal bones and, less frequently, ethmoidal and maxillary bones. Radiographic Features On CT scans, orbital ossifying fibroma typically presents as a well-circumscribed, round or ovoid, expansile 2 to 8 cm (average 5 cm) bony mass with a thin or thick sclerotic rim and central mixed pattern of osteoblastic and osteolytic areas. Early lesions may have more lytic or cyst-like appearance. Later sclerotic changes may impart a ground glass appearance. Radiographic areas of invasion with bone erosion may be occasionally seen in locally aggressive lesions. On MRI, ossifying fibromas are heterogeneous and usually show intermediate signal on T1-weighted and hypointense signal on T2- weighted images. Pathologic Features Grossly, the tumor is yellowish-white to red and gritty. Microscopically, the cardinal feature is presence of randomly distributed mature (lamellar) bone spicules, rimmed by osteoblasts admixed with a dense fibrous stroma. Secondary changes, including hemorrhage, inflammation, and giant cells may be seen. While the osseous component is generally described as mature, the central portions may be woven bone with lamellar bone at the periphery ( zonation phenomenon ), leading to the histologic overlap with fibrous dysplasia. In a psammomatoid variant of ossifying fibroma, the characteristic finding is the presence of mineralized or calcified psammomatoid bodies ( ossicles ), which vary from very few to innumerable. These ossicles have a blue-to-black center and a pink-appearing rim with concentric laminations that contain osteoclasts and osteoblasts. The psammomatoid ossicles vary in shape from round and oval in the center of the lesion to larger, irregularly shaped ossicle pattern within the bony trabeculae in the periphery of the lesion. Cystic degeneration and aneurysmal bone cyst formation may occur, and may be in part accountable for the reported sudden aggressive growth in psammomatoid juvenile ossifying fibroma. Genetics The genetics of ossifying fibroma are still not well elucidated, although these lesions appear to lack the GNAS mutation of fibrous dysplasia. Non-random chromosome break points at Xq26 and 2q33 resulting in (X;2) translocations have been described in ossifying fibromas of the orbit. Additionally MDM2 gene amplifications, not associated with MDM2 protein overexpression, have been described in psammomatoid ossifying fibroma. Management and Prognosis

6 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 5 Complete surgical excision is the treatment of choice, since incompletely excised orbital ossifying fibromas have propensity for multiple recurrences, which can occur after prolonged follow up periods. Malignant transformation has not been reported. Osteoma Definition Osteomas are benign bone-forming tumors of uncertain etiology, which are almost exclusively identified in the craniofacial skeleton. Traumatic, infectious and developmental theories have been proposed, but the origin of these lesions remains elusive. Clinical Presentation Orbital osteomas generally present in in 4th to 5th decades (range years) with an equal malefemale distribution. Most commonly, osteomas originate in the frontal and ethmoid sinuses with secondary involvement of the orbit. These lesions are usually asymptomatic and are found incidentally on radiographic studies. Symptomatic osteomas manifest with gradually progressive, typically painless proptosis or eye displacement. Location in the sphenoid sinus may lead to compression of orbital apex structures. Additionally, osteomas can lead to sinusitis and mucocele formation. Rare complications include acquired Brown syndrome, orbital emphysema and cerebrospinal fluid rhinorrhea. Gardner s syndrome, an autosomal dominant cancer syndrome characterized by familial polyposis, soft tissue and bone tumors, and pigmented ocular fundus lesions, while uncommon, should always be considered when evaluating a patient with osteoma, particularly when multiple osteomas are identified. Radiographic Features On CT scan, the radiographic appearance is that of a sharply delineated radiopaque lesion arising in and confined to bone or protruding into a sinus. Bone window settings often reveal a trabecular central area with a dense periphery. Pathologic Features When removed en block, osteomas have a glistening white-to-pink, smooth or bosselated surface, which may be covered by mucoperiosteum or periorbita. Microscopically, osteomas are well circumscribed lesions which demonstrate a consistent zonation pattern: outer compact bone surrounding an intermediate zone of cancellous bone with increased osteoblastic activity, and a central loose fibrous stroma with increased vascularity, plump osteoblasts, and few trabeculae of immature bone. The predominance of a specific zone within the osteoma, has led to the histological subtyping of the lesions into the compact (ivory), cancellous (trabecular) and fibrous (spongy). Interosseous spaces may also contain fatty tissue with occasional hematopoietic elements. Management and Prognosis If asymptomatic, osteomas should be treated conservatively with observation. Surgical resection may be required for symptomatic osteomas, or for sphenoid sinus lesions that threaten the optic canal or orbital apex. Complete surgical excision is generally curative.

7 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 6 Osteoid Osteoma and Osteoblastoma Definition Osteoid osteoma and osteoblastoma are benign osteoblastic tumors, which share overlapping clinical, radiographic and histologic findings. It is a matter of controversy whether these lesions are a part of the same continuum, or represent distinct entities. By current definition, osteoid osteomas measure <1.5 cm in greatest dimension; lesions with the same radiographic and microscopic appearance but larger than 1.5 cm are classified as osteoblastomas. Clinical Presentation Osteoid osteomas typically affect the long bones, while osteoblastoma are frequent both in the long bones and in the axial skeleton. The gender and age distribution of both neoplasms are similar, with a distinct predilection for males between 10 and 20 years. Classically, both lesions present with nocturnal pain which usually responds to NSAIDs in osteomas, but not in osteoblastomas. Osteoblastoma of the orbit is rare, with approximately 10 cases reported in the last 4 decades. Primary orbital osteoid osteomas are rarer still. Similarly to their extraorbital counterparts, orbital osteoblastomas and osteoid osteomas have predilection for young males, and present as slow-growing tumors arising from the orbital roof or ethmoid sinuses, resulting in gradual globe displacement and proptosis. Radiographic Features On CT scan, osteoblastomas and osteoid osteomas appear as osteolytic masses with sclerotic margin and a central lucency, called nidus. Occasionally, central calcification of nidus results in a targetoid appearance of the lesion. The classic radionuclide bone scan appearance of double density is specific. Pathologic Features Grossly, osteoblastoma and osteoid osteoma appear as gritty, reddish-brown tumors with a red granular appearance of the nidus. Microscopically, the nidus consists of an interlacing network of woven bone trabeculae with variable mineralization and prominent plump osteoblastic rimming in a loose fibrovascular stroma, which may contain reactive osteoclast-like giant cells. The histologic diagnosis rests on documentation of a nidus. If the clinical information and radiologic impressions are consistent with osteoid osteoma or osteoblastoma, but microscopic appearance is not typical of these entities, it is advisable to resample the gross specimen to ensure that the nidus can be visualized. An epithelioid variant of osteoblastoma has been described, characterized by the presence of large epithelioid osteoblasts with abundant eosinophilic cytoplasm, frequently forming clusters and sheets. Epithelioid osteoblastoma has a tendency to local recurrence, but not to metastases. Importantly, the advancing border of osteoblastoma should not show evidence of permeative growth and the finding of definite itnraosseous infiltration, particularly in a setting of cytologic atypia, should instead raise concern for osteoblastoma-like osteosarcoma. Genetics The genetics of osteoid osteoma and osteoblastoma are still not well understood. While some studies suggest a genetic overlap, others speak to the distinct genetic origin of these lesions. Common clonal chromosomal abnormality has been identified in osteoid osteomas and osteoblastomas. Conversely,

8 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 7 structural chromosomal alterations involving 22q13 have been described in osteoid osteoma, which may affect critical genes involved in the regulation of cell proliferation, while unique three-way translocations involving chromosomes 1, 2 and 14, and rearrangement of 1q42 have been reported in osteoblastomas. Management and prognosis Osteoid osteoma has been traditionally treated with surgical resection. However, the possibility of spontaneous regression during the course of several years has led to a wider acceptance of conservative medical management (NSAIDs) and newer minimally invasive techniques (CT-guided core drill excision, percutaneous radiofrequency ablation, cryoablation, and laser photocoagulation). Despite these advances, the few tumors described in the orbital location have been removed with a conservative surgical approach. Osteoblastomas are typically managed by surgical removal either by curettage or by en block resection. The recurrences following piecemeal removal of an orbital tumor have been reported, and complete excision is, therefore, recommended. The malignant transformation of osteoblastoma into osteosarcoma is extremely rare, and is disputed by some experts, who believe that osteosarcomas arising in osteoblastoma were, in all likelihood, osteoblastoma-like osteosarcomas from the beginning. Osteosarcoma Definition Osteosarcoma is a mesenchymal malignancy that is characterized by production of osteoid matrix, variable additional components of chondroid material, and fibrous tissue. The WHO has divided osteosarcoma into eight categories: conventional, secondary, telangiectatic, small-cell, low-grade central, parosteal, periosteal, and high-grade surface types. Clinical Presentation Primary orbital involvement by osteosarcoma is rare, and usually has a maxillary focus. Most patients present in the fourth or fifth decades with a several month history of progressive mass effect, frequently associated with pain, diplopia and decreased vision. While most orbital osteosarcomas arise de novo, some are secondary to prior radiotherapy (particularly in a setting of treatment for retinoblastoma), or occur in a setting of preexistent fibrous dysplasia or Paget s disease. Familial osteosarcomas can be observed in a setting of various cancer syndromes, such as Li Fraumeni syndrome and hereditary retinoblastoma, and typically present at a younger age. Radiographic Features The usual radiographic appearance is that of an irregular lytic and sclerotic mass, often with an infiltrating soft tissue component, which is best visualized on MRI. Pathologic Features Grossly, osteosarcoma appears as a poorly circumscribed, infiltrative white-to-tan tumor with a texture varying from soft to firm and gritty, depending on the degree of mineralization and the extent of stromal component. Histologically, orbital osteosarcomas are characterized by the presence of epithelioid,

9 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 8 plasmocytoid, fusiform, ovoid, or small-round-cell type stromal cells with variable anaplasia intimately admixed and giving rise to osteoid, which appears as eosinophilic, hyalinlike material with irregular contours that tends to be deposited on preexisting bony trabeculae in a process known as scaffolding. Mononuclear histiocyte-like cells or multinucleated giant cells may be prominent, and can sometimes imitate giant cell tumor. Presence of epithelioid osteoblast-like cells may lead to a misdiagnosis of osteoblastoma (see above). In addition to forming osteoid, osteosarcomas can produce variable amounts of cartilage and fibrous tissue, leading to subdivision according to the predominant matrix into chondroblastic osteosarcoma and fibroblastic osteosarcoma. Genetics Conventional osteosarcomas demonstrate numerical and structural chromosomal alterations. While no single mutation or chromosomal alteration is pathognomonic for osteosarcomas, amplifications of MDM2, CDK4, TOP2A, and MACC1, overexpression of MET and FOS, and loss of heterozygosity for chromosomes 3q, 13q, 17p, and 18q have been described. Patients with hereditary retinoblastoma and Li-Fraumeni syndromes have an increased propensity for the development of osteosarcoma with loss of heterozygosity at 13q and 17p compounding the RB1 and TP53 mutations. Management and prognosis Though 5 year survival rates approach 70% for peripheral osteosarcomas, patients with craniofacial tumors have poorer survival (approximately 35% at 5 years), potentially reflecting the delay in diagnosis and difficulties in obtaining a complete resection. Osteosarcoma arising in Paget s disease has an especially dismal prognosis. Treatment regiments include preoperative chemotherapy, resection, followed by postoperative chemotherapy and radiotherapy for residual disease. Postradiation osteosarcomas have been shown to demonstrate the expression of c-kit (without associated c-kit gene mutations), leading to treatment of some patients with KIT inhibitors. Summary In summary, the primary tumors of the orbit comprise a heterogeneous group of disorders, with firbroosseous and osseous benign and malignant neoplasms most commonly encountered. Some of these lesions, such as osteoma, have a particular predilection for the craniofacial region, while others, such as osteoid osteoma, are almost never seen in the orbital location. Regional differences in the clinical presentation, including the age of onset and patient demographics, are exemplified by the orbital ossifying fibroma. Site-specific differences in management and prognosis exist, mostly related to the challenges of complete surgical excision in the skull base region. The frequent fragmented nature of the specimens from the orbital location contributes to the histologic diagnostic challenges, emphasizing the need for careful clinical and radiographic correlation. References 1. Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients with orbital tumors and simulating lesions: The 2002 Montgomery Lecture, part 1. Ophthalmology 2004;111:

10 USCAP 2016 Companion Meeting Primary Lesions of the Bony Orbit Milman 9 2. Selva D, White VA, O'Connell JX, Rootman J. Primary bone tumors of the orbit. Surv Ophthalmol 2004;49: Wenig BM, Mafee MF, Ghosh L. Fibro-osseous, osseous, and cartilaginous lesions of the orbit and paraorbital region. Correlative clinicopathologic and radiographic features, including the diagnostic role of CT and MR imaging. Radiol Clin North Am 1998;36: El-Mofty SK. Fibro-osseous lesions of the craniofacial skeleton: an update. Head Neck Pathol 2014;8: Hakim DN, Pelly T, Kulendran M, Caris JA. Benign tumours of the bone: A review. J Bone Oncol. 2015;4: Chung EM, Murphey MD, Specht CS, Cube R, Smirniotopoulos JG. From the Archives of the AFIP. Pediatric orbit tumors and tumorlike lesions: osseous lesions of the orbit. Radiographics. 2008: Green JT, Mills AM. Osteogenic tumors of bone. Semin Diagn Pathol. 2014;31: Garcia RA, Inwards CY, Unni KK. Benign bone tumors--recent developments. Semin Diagn Pathol. 2011;73-85.

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