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Orbital osteoclastoma of apparent extraskeletal origin in a pagetic patient: A case report
CASE STUDIES
ORBITAL OSTEOCLASTOMA OF APPARENT EXTRASKELETAL ORIGIN IN A PAGETIC PATIENT: A CASE REPORT IRENE PECORELLA, MD, ANTONIO CIARDI, MD, GIORGIO AMADEO, MD, ANDREA BAIOCCHINI, MD, ANGELA MARASCO, MD, AND UGO DI TONDO A large mass in the right orbit, causing proptosis, ptosis of the right upper eyelid, and limitation to eye movements, was surgically removed from a 51-year-old woman suffering from Paget’s bone disease (PBD). Histologically, a giant cell tumor of the bone (osteoclastoma) was diagnosed. No bony involvement was apparent either operatively, microscopically, or on preoperative computed tomographic scans. The neoplasm has not recurred in a 3-year follow-up.
In addition to the fact that osteoclastoma complicating PBD is rare, the extraskeletal origin of the tumor is a matter of interest and can be tentatively explained by an unusually powerful systemic stimulus acting on circulating osteoclast precursors. HUM PATHOL 31: 1527-1531. Copyright © 2000 by W.B. Saunders Company Key words: osteoclastoma, orbit, soft tissue, Paget’s disease. Abbreviations: PBD, Paget’s disease of bone; TRAP, tartrateresistant acid phosphatase.
Osteoclastoma (giant cell tumor) is a rare complication of Paget’s disease of bone (PBD) and, in contrast to the conventional type of giant cell tumor, most commonly affects the skull and facial bones or other anatomic sites involved in PBD; the orbit, however, appears to be affected very seldomly, because there are only few reports of osteoclastoma of PBD arising from the orbital bones in the literature.1 The rarity of such an involvement is, furthermore, highlighted by the results of a large combined series of 4,563 orbital lesions diagnosed in the United States,2 which includes 8 cases (0.17%) of PBD, but none of osteoclastoma. The tumor is found very rarely elsewhere in the body, with Paget’s sarcoma being from 10 to 30 times more frequent, and conventional giant cell tumor of epiphysis about 50 to 100 times more common than osteoclastoma of PBD.3 In a combined series of 340 neoplasms arising in PBD, osteoclastoma accounted for only 3.5% of the cases.4
Here we describe a woman with polyostotic PBD who developed an orbital osteoclastoma with neither apparent changes of PBD in the orbital bones, nor evidence of bone origin. The possibility that this tumor may have arisen from the orbital soft tissues is discussed.
From the Dipartimento di Medicina Sperimentale e Patologia, Universita` degli Studi “La Sapienza,” Presidio Ospedaliero “Villa Betania,” Via Nicolo` Piccolomini, and Istituto di Anatomia Patologica, Ospedale S. Spirito, Lungotevere in Sassia, Roma, Italy. Address correspondence and reprint requests to Irene Pecorella, MD, Dipartimento di Medicina Sperimentale e Patologia, Universita` degli Studi “La Sapienza,” Viale Regina Elena, 324-00161 Roma, Italy. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3112-0013$10.00/0 doi:10.1053/hupa.2000.20411
CASE REPORT A 51-year-old woman, who was born in Avellino, Italy, and had been suffering from Paget’s disease of the pelvis, hips, and proximal femur (Fig 1) for 10 years, presented with a unilateral right proptosis, ptosis of the right upper eyelid and limitations to eye movements in all directions. The symptoms had been present for 3 months and had gradually worsened. The left orbit and eye were normal. Routine laboratory work-up showed high levels of serum alkaline phosphatase (1513 U/L; normal level, 50-136), increased erithrocyte sedimentation rate (57 mm/h, normal level, 10), and mild anemia. White cell blood count and serum calcium, phosphorous, and parathormone levels were within normal range. Computed tomographic (CT) scans of the right orbit showed a large, homogeneous, solid mass in the upper quadrant, which appeared to be adherent inferiorly to the superior rectus and oblique muscles (Fig 2). The tumor extended anteriorly into the inner part of the upper eyelid and posteriorly up to the orbital apex. The lacrimal gland appeared to be infiltrated, and the eyeball was compressed and displaced to the down-and-out position. The mass was isodense to the orbital muscles and showed homogeneous intravenous con-
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normal bone were observed separate from the tumor (Fig 6), but the tumor itself displayed no osteoid or new bone formation. Extensive recent or old hemorrhages and xanthomatous foci were also absent, as well as any muscle tissue, which was most probably not sampled. Abundant tartrate-resistant acid phosphatase (TRAP) activity was shown in the multinucleated giant cells, which is consistent with the osteoclastic origin of the cells. Immunohistochemical stains showed positivity to CD68 (Dako, Glostrup, Denmark) and negativity to MIB-1 and p53 (Dako) antibodies in the giant cells; focal positivity to CD68 and to smooth-muscle actin (Dako) was observed in the mononuclear stromal cells. The histopathological, histochemical, and immunohistochemical findings were consistent with a giant cell tumor of bone. DISCUSSION
FIGURE 1. Plain radiographs of the patient’s pelvis, hips, and proximal femur, showing diffuse abnormalities of the bone structure, with a “cotton-wool” appearance.
trast enhancement. The frontal bone was compressed and markedly thinned nasally but not disrupted. No bony defect was seen in the remainder of the orbit. The skull showed marked enlargement of the calvarium with thickening of the diploic space and changes of a “cotton-wool” appearance. These findings are typical of PDB. Magnetic resonance imaging (MRI) in the axial, sagittal, and coronal planes confirmed the presence of an extraconal solid mass located in between the superior rectus muscle and the orbit roof, which did not show contrast enhancement after injection of gadolinium (Figs 3A,B,C). The optic nerve was essentially normal, whereas in the paranasal, fronto-ethmoidal, and maxillary cavities a polipoid, inflammatory thickening of the mucosal layer was seen. The general clinical examination disclosed no other tumors. A malignant neoplasm of the lacrimal gland was diagnosed, and the patient underwent a lateral orbitotomy. During surgery, the mass appeared to be adherent to the periorbital tissue of the supero-temporal quadrant, the lacrimal gland, and the superior rectus. Isolation from the former 2 structures was possible, whereas a partial resection of the superior rectus muscle was deemed necessary to free it from the tumor. No bony attachment was present. The surgical excision appeared complete. The postoperative course was uneventful, with resolution of the ocular signs. Repeated MRI studies, performed 15 months later, did not uncover any evidence of recurrence of the tumor in the orbit (Fig 4).
PDB is a sporadic, polyostotic or, rarely monostotic, disease which usually affects patients over 55 years of age. The most common sites are the lumbosacral spine, the pelvis, and the skull. Giant cell tumors (osteoclastomas) in PBD can occur sporadically or in cases related by family or geography in pagetic bones. Extraskeletal osteoclastomas have also been described in 2 pagetic patients.5,6 A variant of PBD with increased tendency to form solitary or multicentric osteoclastomas with an extensive soft-tissue component exhibits familial and geographic clustering to
PATHOLOGY Gross examination showed a 5 ⫻ 3 ⫻ 2 cm soft, friable, fleshy and red-brown tissue. Microscopically, an even mixture of mononuclear and osteoclast-like giant cells was observed in a moderately vascularized stroma (Fig 5). The mononuclear cells were round, and had round or oval nuclei with bland chromatin distribution and narrow eosinophilic cytoplasm. The giant cells contained up to 50 vesicular bland nuclei and were often provided with eosinophilic intranuclear bodies. The cytoplasm was eosinophilic centrally, amphophilic peripherally, and occasionally contained vacuoles (Fig 5, insert). Mononuclear and giant cells showed no atypism or evident mitotic activity. A fragment of periorbita and a few spicules of
FIGURE 2. Computed tomographic scan shows a large tumor dilating the roof of the right orbit. The eyeball is compressed and displaced downward.
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FIGURE 3. (A) Sagittal MRI of the orbital lesion, showing involvement of the inner portion of the upper eyelid and the deep posterior extension. In addition to the mass, a marked enlargement of the diploic space, accompanied by the typical “cotton-wool” densities, is shown in these sagittal (B), and coronal (C) images. (C) The orbital tumor is shown after injection of gadolinium diethylene-triamine-pentaacetic acid.
Avellino, Italy.7,8 The patient herein described originated, indeed, from Avellino and reported that her father had died with skeletal deformities. So far, other osteoclastomas have not been detected in the present case, perhaps due to the relatively short follow-up period (3 years). Osteoclastoma of PBD typically occurs with polyostotic involvement and commonly presents itself as a nontender mass in the skull and facial bones, less commonly in the remaining axial skeleton, and rarely in the extremities. Symptoms are caused by encroachment of the tumor on neighboring structures, and the appearance of the giant cell tumor does not induce a sudden elevation of the serum alkaline phosphatase. The great majority of osteoclastomas show a benign course and do not recur locally or metastatize after simple curettage. Osteoclastoma complicating PBD should be differentiated microscopically from giant-cell reparative granuloma and other reactive giant cell– containing lesions, such as nonossifying fibroma, chondroblastoma, chondromyxoid fibroma, the solid areas of aneurysmal bone cysts, malignant fibrous histiocytoma, and giant cell–rich osteosarcoma. One
of the main microscopic differences between true giant cell tumor and giant cell variants resides in the regular and even distribution of the giant and the stromal cells in the former lesion, while the giant cells themselves do not differ significantly in the 2 groups. Primary extraskeletal osteoclastoma-like tumors are composed of mononuclear and giant cells with mesenchymal/ histiocytic differentiation; however, they can be differentiated from true giant cell tumors based on the presence of epithelial elements in the neoplastic tissue.9 Giant cell carcinomas, on the other hand, are characterised by immunoreactivity to cytokeratins and negativity to markers of hystiocytic differentiation in the giant cell component. Conventional giant cell tumor and the brown tumor of hyperparathyroidism are microscopically identical to osteoclastoma of PBD but occur in non-pagetic patients. The former very rarely arises in the craniofacial skeleton. The few cases that fulfill the criteria of de novo giant cell tumor of craniofacial bones are most frequently located in the sphenoid bone10 from where they extend into the orbit, superior
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FIGURE 4. MRI imaging performed 15 months postoperatively, showing the absence of an orbital tumor.
nasal cavity, and/or anterior cranial fossa. More common primary bone lesions such as fibrous dysplasia, brown tumor of hyperparathyroidism, and giant-cell reparative granuloma have often been inappropriately classified as conventional giant-cell tumors in ophthalmic pathology.11,12 Giant cell tumor of the tendon sheaths (extraarticular localized pigmented villonodular tenosynovitis) has been occasionally associated with PBD13,14 and, in view of the present tumor’s attachment to an extraocular muscle, has to be considered in the differential diagnosis. Giant cell tumor of tendon sheaths typically involves the acral soft tissue, though rare cases are reported in the temporomandibular joint. The lesion has never been described in the orbit. The case described by Levine and Enrile13 arose from the patellar tendon of a woman suffering from PBD and was unusual in respect of location and large size. The published histological pictures show a giant cell lesion almost
identical to an osteoclastoma. Therefore, we suspect that the giant cell tumor described by Levine and Enrile13 might well have been an extraskeletal osteoclastoma and was not classified as such because the entity was not recognized in 1971. Abdalla and Hosni11 also reported a giant cell tumor affecting a 5-year-old boy which compressed an extraocular muscle and appeared to be unrelated to the orbital bones. However, the patient was apparently not suffering from PBD; furthermore, the presence of old blood pigment, cystic cavities, and trabeculae of newly formed reactive bone in the tumor tissue is more reminiscent of a giant cell reparative granuloma. More similar to our case is the patient with PBD, described by Man ˜ o´s-Pujol et al,15 who developed an orbital osteoclastoma with firm adhesion to the periorbital tissue but no apparent bone erosion. Every effort must be made to categorize these tumors with giant cells that complicate PBD, because the treatment and prognosis vary greatly with the type of tumor. Particularly, skeletal and extraskeletal osteoclastomas of PBD have been reported to respond dramatically to systemic dexamethasone therapy.6,8 Also, histology of the steroid-treated tumors has evidenced replacement of small mononuclear cells and multinucleated giant cells with foamy histiocytes in sheet-like arrangement.16 Because we suspected our patient harboured a malignancy of the lacrimal gland, steroid therapy was not administered. Positivity of occasional mononucleated stromal cells to smooth-muscle actin was observed in this case. Ultrastructural myofibroblastic differentiation has already been described by Desai and Steiner17 in the mononuclear and giant cells of the brown tumor of hyperparathyroidism and giant cell reparative granuloma. However, in our case we failed to obtain any positive result to smooth-muscle actin antibody in the giant cells of our case. To the best of our knowledge, the myofibroblastic nature of part of the stromal cells in osteoclastoma of PBD has never been described before. Negative results to the proliferative antigen MIB-1 and to the wild-type p53 are an additional confirmation of the benign nature of osteoclastomas of PBD. Besides the rarity of osteoclastoma of PBD, our case is unusual in that the tumor arose in an orbit where PBD was not seen radiographically. Other reported cases have been characterized by the absence of alterations of the bone adjacent to the osteoclastoma of PBD,18,19 although in 1 case,19 lytic lesions appeared 2 months later, suggesting that the tumor had arisen in a bone with early changes of PBD, and in
FIGURE 5. Microscopically, the orbital tumor is composed of plump mononuclear cells uniformly interspersed with multinucleated giant cells. The latter predominate over the stromal cells and display a large number of nuclei (insert), some of which contain prominent intranuclear inclusions (arrow). Foamy vacuoles are present in the cytoplasm (asterisks). (Hematoxylin & eosin, original magnification ⫻250 and ⫻400.)
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FIGURE 6. The tumor is adjacent to a fibrous tissue consistent with periorbita but does not invade it. Tiny spicules of essentially normal bone (arrow) can also be observed. (Hematoxylin & eosin, original magnification ⫻100.)
the other case,18 typical changes of PBD were shown by microscopic examination in the bone adjacent to the giant cell tumor. Although, in the present case, bone biopsy was not performed, the patient has been followed for 3 years. The last MRI examination failed to detect any abnormalities in the orbital bones yet confirmed the disease in the skull. In fact, the tumor itself was not attached to the bones of the orbit but only involved the orbital soft tissues. An extensive soft-tissue component, reported to be rare in pagetic osteoclastoma, was noted in 4 patients with ancestral roots in Avellino by Potter et al.20 Because osteoclasts are not normally present in this location, we speculate that a systemic stimulus may have induced circulating monocyte-macrophage precursors to undergo osteoclastic differentiation in extraskeletal tissues, causing the tumor to grow in the orbit. This hypothesis could also explain the frequent multicentricity of osteoclastomas in patients with familial and geographic clustering in Avellino. Of interest are the recent observations that bone marrow of pagetic patients from apparently uninvolved sites yields numerous giant cells in culture reminiscent of multinucleated pagetic osteoclasts.21 The discovery of virus-like inclusions within the osteoclasts in 100% of cases of Paget’s disease, pagetic osteoclastomas, and sarcomas has supported the concept that cellular fusion and osteoclastic activation could be promoted by a viral agent, possibly of the paramixovirus type. The recent detection of measles virus (paramixovirus) nucleocapsid transcripts in Paget’s patients’ marrow samples containing point mutations22 confirms that the viral theory, coupled with the genetical predisposition of individuals, remains the most promising one. Acknowledgment. The authors wish to thank Prof. Ermanno Bonucci for his critical review of the manuscript and Ms Antonella Piroli for her technical support.
REFERENCES 1. Singer FR, Mills BG: Giant cell tumor arising in Paget’s disease of bone. Clin Orthop 293:293-301, 1993 2. Wilson MW, Grossniklaus HE: Orbital lesions in the North America. Oftalmologia Clinica Nord America 9:13-22, 1997
3. Mirra JM, Brien EW, Tehranzadeh J: Paget’s disease of bone: Review with emphasis on radiologic features, part II. Skeletal Radiol 24:173-184, 1995 4. Haibach H, Farrell C, Dittrich FJ: Neoplasms arising in Paget’s disease of bone: A study of 82 cases. Am J Clin Pathol 83:594-600, 1985 5. Kim GS, Kim JK, Park JY, et al: Paget bone disease involving young adults in 3 generations of a Corean family. Medicine 76:157-169, 1997 6. Ziambaras K, Totty Wa, Teitelbaum SL, et al: Extraskeletal osteoclastomas responsive to dexamethasone treatment in Paget bone disease. J Clin Endocrinol Metab 82:3826-34, 1997 7. Hutter RVP, Foote FW, Frazell EL, et al: Giant cell tumors complicating Paget’s disease of bone. Cancer 16:1044-1056, 1963 8. Jacobs TP, Michelsen J, Polay JS, et al: Giant cell tumor in Paget’s disease of bone. Familial and geographic clustering. Cancer 44:742-47, 1979 9. Orosz Z, Toth E, Viski A: Osteoclastoma-like giant cell tumor of the lung. Pathology Oncol Res 2:84-88, 1996 10. Dahlin DC, Cupps RE, Johnson EW: Giant-cell tumor: A study of 195 cases. Cancer 25:1061-1070, 1970 11. Abdalla MI, Hosni F: Osteoclastoma of the orbit. Case report. Br J Ophthalmol 50:95-98, 1966 12. Dorfman HD, Czerniak B: Giant-cell lesions, in Dorfman HD, Czerniak B (eds): Bone Tumors. St Louis, MO, Mosby Inc, 1998, pp 559-606 13. Levine HA, Enrile F: Giant-cell tumor of patellar tendon coincident with Paget’s disease. J Bone Joint Surg 53A:335-340, 1971 14. Mirra JM, Finerman G, Lindholm S: Diffuse pigmented villonodular synovitis in association with PBD. Clin Orthop, 149:305, 1980 15. Man ˜ o´s-Pujol M, Ca´novas Robles E, Lorenzo JC, et al: Lesiones sinusales por ce´lulas gigantes: Granuloma de ce´lulas gigantes y tumor de ce´lulas gigantes coincidente con enfermedad de Paget de cra´neo. Anales ORL Iber-Amer 2:111-126, 1984 16. Ueda T, Healey JH, Huvos AG, et al: Scapular pain and swelling in a 60-year-old man with Paget’s disease. Clin Orthop 326:284-286, 1996 17. Desai P, Steiner GC: Ultrastructure of brown tumor of hyperparathyroidism. Ultrastruct Pathol 14:505-511, 1990 18. Mirra JM, Bauer FCH, Grant TT: Giant cell tumor with viral-like intranuclear inclusions associated with Paget’s disease. Clin Orthop 158:243251, 1981 19. Pazzaglia UE, Barbieri D, Ceciliani L: An epiphyseal giant cell tumor associated with early Paget’s disease. A case report. Clin Orthop 234:217-220, 1988 20. Potter HG, Schneider R, Ghelman B, et al: Multiple giant cell tumors and Paget disease of bone: Radiographic and clinical correlations. Radiology 180:261-264, 1991 21. Demulder A, Takahashi S, Singer FR, et al: Abnormalities in osteoclast precursors and the marrow accessory cells in Paget’s disease. Endocrinology 133:1978-82, 1990 22. Reddy SV, Singer FR, Roodman GD: Bone marrow mononuclear cells from patients with Paget’s disease contain measles virus nucleocapsid messenger ribonucleic acid that has mutations in a specific region of the sequence. J Clin Endocrinol Metab 80:2108-2111, 1995
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ORBITAL OSTEOCLASTOMA OF APPARENT EXTRASKELETAL ORIGIN IN A PAGETIC PATIENT: A CASE REPORT IRENE PECORELLA, MD, ANTONIO CIARDI, MD, GIORGIO AMADEO, MD, ANDREA BAIOCCHINI, MD, ANGELA MARASCO, MD, AND UGO DI TONDO A large mass in the right orbit, causing proptosis, ptosis of the right upper eyelid, and limitation to eye movements, was surgically removed from a 51-year-old woman suffering from Paget’s bone disease (PBD). Histologically, a giant cell tumor of the bone (osteoclastoma) was diagnosed. No bony involvement was apparent either operatively, microscopically, or on preoperative computed tomographic scans. The neoplasm has not recurred in a 3-year follow-up.
In addition to the fact that osteoclastoma complicating PBD is rare, the extraskeletal origin of the tumor is a matter of interest and can be tentatively explained by an unusually powerful systemic stimulus acting on circulating osteoclast precursors. HUM PATHOL 31: 1527-1531. Copyright © 2000 by W.B. Saunders Company Key words: osteoclastoma, orbit, soft tissue, Paget’s disease. Abbreviations: PBD, Paget’s disease of bone; TRAP, tartrateresistant acid phosphatase.
Osteoclastoma (giant cell tumor) is a rare complication of Paget’s disease of bone (PBD) and, in contrast to the conventional type of giant cell tumor, most commonly affects the skull and facial bones or other anatomic sites involved in PBD; the orbit, however, appears to be affected very seldomly, because there are only few reports of osteoclastoma of PBD arising from the orbital bones in the literature.1 The rarity of such an involvement is, furthermore, highlighted by the results of a large combined series of 4,563 orbital lesions diagnosed in the United States,2 which includes 8 cases (0.17%) of PBD, but none of osteoclastoma. The tumor is found very rarely elsewhere in the body, with Paget’s sarcoma being from 10 to 30 times more frequent, and conventional giant cell tumor of epiphysis about 50 to 100 times more common than osteoclastoma of PBD.3 In a combined series of 340 neoplasms arising in PBD, osteoclastoma accounted for only 3.5% of the cases.4
Here we describe a woman with polyostotic PBD who developed an orbital osteoclastoma with neither apparent changes of PBD in the orbital bones, nor evidence of bone origin. The possibility that this tumor may have arisen from the orbital soft tissues is discussed.
From the Dipartimento di Medicina Sperimentale e Patologia, Universita` degli Studi “La Sapienza,” Presidio Ospedaliero “Villa Betania,” Via Nicolo` Piccolomini, and Istituto di Anatomia Patologica, Ospedale S. Spirito, Lungotevere in Sassia, Roma, Italy. Address correspondence and reprint requests to Irene Pecorella, MD, Dipartimento di Medicina Sperimentale e Patologia, Universita` degli Studi “La Sapienza,” Viale Regina Elena, 324-00161 Roma, Italy. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3112-0013$10.00/0 doi:10.1053/hupa.2000.20411
CASE REPORT A 51-year-old woman, who was born in Avellino, Italy, and had been suffering from Paget’s disease of the pelvis, hips, and proximal femur (Fig 1) for 10 years, presented with a unilateral right proptosis, ptosis of the right upper eyelid and limitations to eye movements in all directions. The symptoms had been present for 3 months and had gradually worsened. The left orbit and eye were normal. Routine laboratory work-up showed high levels of serum alkaline phosphatase (1513 U/L; normal level, 50-136), increased erithrocyte sedimentation rate (57 mm/h, normal level, 10), and mild anemia. White cell blood count and serum calcium, phosphorous, and parathormone levels were within normal range. Computed tomographic (CT) scans of the right orbit showed a large, homogeneous, solid mass in the upper quadrant, which appeared to be adherent inferiorly to the superior rectus and oblique muscles (Fig 2). The tumor extended anteriorly into the inner part of the upper eyelid and posteriorly up to the orbital apex. The lacrimal gland appeared to be infiltrated, and the eyeball was compressed and displaced to the down-and-out position. The mass was isodense to the orbital muscles and showed homogeneous intravenous con-
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normal bone were observed separate from the tumor (Fig 6), but the tumor itself displayed no osteoid or new bone formation. Extensive recent or old hemorrhages and xanthomatous foci were also absent, as well as any muscle tissue, which was most probably not sampled. Abundant tartrate-resistant acid phosphatase (TRAP) activity was shown in the multinucleated giant cells, which is consistent with the osteoclastic origin of the cells. Immunohistochemical stains showed positivity to CD68 (Dako, Glostrup, Denmark) and negativity to MIB-1 and p53 (Dako) antibodies in the giant cells; focal positivity to CD68 and to smooth-muscle actin (Dako) was observed in the mononuclear stromal cells. The histopathological, histochemical, and immunohistochemical findings were consistent with a giant cell tumor of bone. DISCUSSION
FIGURE 1. Plain radiographs of the patient’s pelvis, hips, and proximal femur, showing diffuse abnormalities of the bone structure, with a “cotton-wool” appearance.
trast enhancement. The frontal bone was compressed and markedly thinned nasally but not disrupted. No bony defect was seen in the remainder of the orbit. The skull showed marked enlargement of the calvarium with thickening of the diploic space and changes of a “cotton-wool” appearance. These findings are typical of PDB. Magnetic resonance imaging (MRI) in the axial, sagittal, and coronal planes confirmed the presence of an extraconal solid mass located in between the superior rectus muscle and the orbit roof, which did not show contrast enhancement after injection of gadolinium (Figs 3A,B,C). The optic nerve was essentially normal, whereas in the paranasal, fronto-ethmoidal, and maxillary cavities a polipoid, inflammatory thickening of the mucosal layer was seen. The general clinical examination disclosed no other tumors. A malignant neoplasm of the lacrimal gland was diagnosed, and the patient underwent a lateral orbitotomy. During surgery, the mass appeared to be adherent to the periorbital tissue of the supero-temporal quadrant, the lacrimal gland, and the superior rectus. Isolation from the former 2 structures was possible, whereas a partial resection of the superior rectus muscle was deemed necessary to free it from the tumor. No bony attachment was present. The surgical excision appeared complete. The postoperative course was uneventful, with resolution of the ocular signs. Repeated MRI studies, performed 15 months later, did not uncover any evidence of recurrence of the tumor in the orbit (Fig 4).
PDB is a sporadic, polyostotic or, rarely monostotic, disease which usually affects patients over 55 years of age. The most common sites are the lumbosacral spine, the pelvis, and the skull. Giant cell tumors (osteoclastomas) in PBD can occur sporadically or in cases related by family or geography in pagetic bones. Extraskeletal osteoclastomas have also been described in 2 pagetic patients.5,6 A variant of PBD with increased tendency to form solitary or multicentric osteoclastomas with an extensive soft-tissue component exhibits familial and geographic clustering to
PATHOLOGY Gross examination showed a 5 ⫻ 3 ⫻ 2 cm soft, friable, fleshy and red-brown tissue. Microscopically, an even mixture of mononuclear and osteoclast-like giant cells was observed in a moderately vascularized stroma (Fig 5). The mononuclear cells were round, and had round or oval nuclei with bland chromatin distribution and narrow eosinophilic cytoplasm. The giant cells contained up to 50 vesicular bland nuclei and were often provided with eosinophilic intranuclear bodies. The cytoplasm was eosinophilic centrally, amphophilic peripherally, and occasionally contained vacuoles (Fig 5, insert). Mononuclear and giant cells showed no atypism or evident mitotic activity. A fragment of periorbita and a few spicules of
FIGURE 2. Computed tomographic scan shows a large tumor dilating the roof of the right orbit. The eyeball is compressed and displaced downward.
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FIGURE 3. (A) Sagittal MRI of the orbital lesion, showing involvement of the inner portion of the upper eyelid and the deep posterior extension. In addition to the mass, a marked enlargement of the diploic space, accompanied by the typical “cotton-wool” densities, is shown in these sagittal (B), and coronal (C) images. (C) The orbital tumor is shown after injection of gadolinium diethylene-triamine-pentaacetic acid.
Avellino, Italy.7,8 The patient herein described originated, indeed, from Avellino and reported that her father had died with skeletal deformities. So far, other osteoclastomas have not been detected in the present case, perhaps due to the relatively short follow-up period (3 years). Osteoclastoma of PBD typically occurs with polyostotic involvement and commonly presents itself as a nontender mass in the skull and facial bones, less commonly in the remaining axial skeleton, and rarely in the extremities. Symptoms are caused by encroachment of the tumor on neighboring structures, and the appearance of the giant cell tumor does not induce a sudden elevation of the serum alkaline phosphatase. The great majority of osteoclastomas show a benign course and do not recur locally or metastatize after simple curettage. Osteoclastoma complicating PBD should be differentiated microscopically from giant-cell reparative granuloma and other reactive giant cell– containing lesions, such as nonossifying fibroma, chondroblastoma, chondromyxoid fibroma, the solid areas of aneurysmal bone cysts, malignant fibrous histiocytoma, and giant cell–rich osteosarcoma. One
of the main microscopic differences between true giant cell tumor and giant cell variants resides in the regular and even distribution of the giant and the stromal cells in the former lesion, while the giant cells themselves do not differ significantly in the 2 groups. Primary extraskeletal osteoclastoma-like tumors are composed of mononuclear and giant cells with mesenchymal/ histiocytic differentiation; however, they can be differentiated from true giant cell tumors based on the presence of epithelial elements in the neoplastic tissue.9 Giant cell carcinomas, on the other hand, are characterised by immunoreactivity to cytokeratins and negativity to markers of hystiocytic differentiation in the giant cell component. Conventional giant cell tumor and the brown tumor of hyperparathyroidism are microscopically identical to osteoclastoma of PBD but occur in non-pagetic patients. The former very rarely arises in the craniofacial skeleton. The few cases that fulfill the criteria of de novo giant cell tumor of craniofacial bones are most frequently located in the sphenoid bone10 from where they extend into the orbit, superior
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FIGURE 4. MRI imaging performed 15 months postoperatively, showing the absence of an orbital tumor.
nasal cavity, and/or anterior cranial fossa. More common primary bone lesions such as fibrous dysplasia, brown tumor of hyperparathyroidism, and giant-cell reparative granuloma have often been inappropriately classified as conventional giant-cell tumors in ophthalmic pathology.11,12 Giant cell tumor of the tendon sheaths (extraarticular localized pigmented villonodular tenosynovitis) has been occasionally associated with PBD13,14 and, in view of the present tumor’s attachment to an extraocular muscle, has to be considered in the differential diagnosis. Giant cell tumor of tendon sheaths typically involves the acral soft tissue, though rare cases are reported in the temporomandibular joint. The lesion has never been described in the orbit. The case described by Levine and Enrile13 arose from the patellar tendon of a woman suffering from PBD and was unusual in respect of location and large size. The published histological pictures show a giant cell lesion almost
identical to an osteoclastoma. Therefore, we suspect that the giant cell tumor described by Levine and Enrile13 might well have been an extraskeletal osteoclastoma and was not classified as such because the entity was not recognized in 1971. Abdalla and Hosni11 also reported a giant cell tumor affecting a 5-year-old boy which compressed an extraocular muscle and appeared to be unrelated to the orbital bones. However, the patient was apparently not suffering from PBD; furthermore, the presence of old blood pigment, cystic cavities, and trabeculae of newly formed reactive bone in the tumor tissue is more reminiscent of a giant cell reparative granuloma. More similar to our case is the patient with PBD, described by Man ˜ o´s-Pujol et al,15 who developed an orbital osteoclastoma with firm adhesion to the periorbital tissue but no apparent bone erosion. Every effort must be made to categorize these tumors with giant cells that complicate PBD, because the treatment and prognosis vary greatly with the type of tumor. Particularly, skeletal and extraskeletal osteoclastomas of PBD have been reported to respond dramatically to systemic dexamethasone therapy.6,8 Also, histology of the steroid-treated tumors has evidenced replacement of small mononuclear cells and multinucleated giant cells with foamy histiocytes in sheet-like arrangement.16 Because we suspected our patient harboured a malignancy of the lacrimal gland, steroid therapy was not administered. Positivity of occasional mononucleated stromal cells to smooth-muscle actin was observed in this case. Ultrastructural myofibroblastic differentiation has already been described by Desai and Steiner17 in the mononuclear and giant cells of the brown tumor of hyperparathyroidism and giant cell reparative granuloma. However, in our case we failed to obtain any positive result to smooth-muscle actin antibody in the giant cells of our case. To the best of our knowledge, the myofibroblastic nature of part of the stromal cells in osteoclastoma of PBD has never been described before. Negative results to the proliferative antigen MIB-1 and to the wild-type p53 are an additional confirmation of the benign nature of osteoclastomas of PBD. Besides the rarity of osteoclastoma of PBD, our case is unusual in that the tumor arose in an orbit where PBD was not seen radiographically. Other reported cases have been characterized by the absence of alterations of the bone adjacent to the osteoclastoma of PBD,18,19 although in 1 case,19 lytic lesions appeared 2 months later, suggesting that the tumor had arisen in a bone with early changes of PBD, and in
FIGURE 5. Microscopically, the orbital tumor is composed of plump mononuclear cells uniformly interspersed with multinucleated giant cells. The latter predominate over the stromal cells and display a large number of nuclei (insert), some of which contain prominent intranuclear inclusions (arrow). Foamy vacuoles are present in the cytoplasm (asterisks). (Hematoxylin & eosin, original magnification ⫻250 and ⫻400.)
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FIGURE 6. The tumor is adjacent to a fibrous tissue consistent with periorbita but does not invade it. Tiny spicules of essentially normal bone (arrow) can also be observed. (Hematoxylin & eosin, original magnification ⫻100.)
the other case,18 typical changes of PBD were shown by microscopic examination in the bone adjacent to the giant cell tumor. Although, in the present case, bone biopsy was not performed, the patient has been followed for 3 years. The last MRI examination failed to detect any abnormalities in the orbital bones yet confirmed the disease in the skull. In fact, the tumor itself was not attached to the bones of the orbit but only involved the orbital soft tissues. An extensive soft-tissue component, reported to be rare in pagetic osteoclastoma, was noted in 4 patients with ancestral roots in Avellino by Potter et al.20 Because osteoclasts are not normally present in this location, we speculate that a systemic stimulus may have induced circulating monocyte-macrophage precursors to undergo osteoclastic differentiation in extraskeletal tissues, causing the tumor to grow in the orbit. This hypothesis could also explain the frequent multicentricity of osteoclastomas in patients with familial and geographic clustering in Avellino. Of interest are the recent observations that bone marrow of pagetic patients from apparently uninvolved sites yields numerous giant cells in culture reminiscent of multinucleated pagetic osteoclasts.21 The discovery of virus-like inclusions within the osteoclasts in 100% of cases of Paget’s disease, pagetic osteoclastomas, and sarcomas has supported the concept that cellular fusion and osteoclastic activation could be promoted by a viral agent, possibly of the paramixovirus type. The recent detection of measles virus (paramixovirus) nucleocapsid transcripts in Paget’s patients’ marrow samples containing point mutations22 confirms that the viral theory, coupled with the genetical predisposition of individuals, remains the most promising one. Acknowledgment. The authors wish to thank Prof. Ermanno Bonucci for his critical review of the manuscript and Ms Antonella Piroli for her technical support.
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3. Mirra JM, Brien EW, Tehranzadeh J: Paget’s disease of bone: Review with emphasis on radiologic features, part II. Skeletal Radiol 24:173-184, 1995 4. Haibach H, Farrell C, Dittrich FJ: Neoplasms arising in Paget’s disease of bone: A study of 82 cases. Am J Clin Pathol 83:594-600, 1985 5. Kim GS, Kim JK, Park JY, et al: Paget bone disease involving young adults in 3 generations of a Corean family. Medicine 76:157-169, 1997 6. Ziambaras K, Totty Wa, Teitelbaum SL, et al: Extraskeletal osteoclastomas responsive to dexamethasone treatment in Paget bone disease. J Clin Endocrinol Metab 82:3826-34, 1997 7. Hutter RVP, Foote FW, Frazell EL, et al: Giant cell tumors complicating Paget’s disease of bone. Cancer 16:1044-1056, 1963 8. Jacobs TP, Michelsen J, Polay JS, et al: Giant cell tumor in Paget’s disease of bone. Familial and geographic clustering. Cancer 44:742-47, 1979 9. Orosz Z, Toth E, Viski A: Osteoclastoma-like giant cell tumor of the lung. Pathology Oncol Res 2:84-88, 1996 10. Dahlin DC, Cupps RE, Johnson EW: Giant-cell tumor: A study of 195 cases. Cancer 25:1061-1070, 1970 11. Abdalla MI, Hosni F: Osteoclastoma of the orbit. Case report. Br J Ophthalmol 50:95-98, 1966 12. Dorfman HD, Czerniak B: Giant-cell lesions, in Dorfman HD, Czerniak B (eds): Bone Tumors. St Louis, MO, Mosby Inc, 1998, pp 559-606 13. Levine HA, Enrile F: Giant-cell tumor of patellar tendon coincident with Paget’s disease. J Bone Joint Surg 53A:335-340, 1971 14. Mirra JM, Finerman G, Lindholm S: Diffuse pigmented villonodular synovitis in association with PBD. Clin Orthop, 149:305, 1980 15. Man ˜ o´s-Pujol M, Ca´novas Robles E, Lorenzo JC, et al: Lesiones sinusales por ce´lulas gigantes: Granuloma de ce´lulas gigantes y tumor de ce´lulas gigantes coincidente con enfermedad de Paget de cra´neo. Anales ORL Iber-Amer 2:111-126, 1984 16. Ueda T, Healey JH, Huvos AG, et al: Scapular pain and swelling in a 60-year-old man with Paget’s disease. Clin Orthop 326:284-286, 1996 17. Desai P, Steiner GC: Ultrastructure of brown tumor of hyperparathyroidism. Ultrastruct Pathol 14:505-511, 1990 18. Mirra JM, Bauer FCH, Grant TT: Giant cell tumor with viral-like intranuclear inclusions associated with Paget’s disease. Clin Orthop 158:243251, 1981 19. Pazzaglia UE, Barbieri D, Ceciliani L: An epiphyseal giant cell tumor associated with early Paget’s disease. A case report. Clin Orthop 234:217-220, 1988 20. Potter HG, Schneider R, Ghelman B, et al: Multiple giant cell tumors and Paget disease of bone: Radiographic and clinical correlations. Radiology 180:261-264, 1991 21. Demulder A, Takahashi S, Singer FR, et al: Abnormalities in osteoclast precursors and the marrow accessory cells in Paget’s disease. Endocrinology 133:1978-82, 1990 22. Reddy SV, Singer FR, Roodman GD: Bone marrow mononuclear cells from patients with Paget’s disease contain measles virus nucleocapsid messenger ribonucleic acid that has mutations in a specific region of the sequence. J Clin Endocrinol Metab 80:2108-2111, 1995
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