Case 9 -

Giant Cell Tumor Scott Kilpatrick

Clinical History: The patient is a 27-year-old male with a painful lytic lesion of the proximal tibia. Diagnosis: Giant Cell Tumor. Many people define a "giant cell tumor" by the presence of numerous giant cells, specifically osteoclast-type giant cells. Morphologically, such giant cells are typically large cells containing multiple, uniform-appearing, round to ovoid nuclei that are randomly distributed throughout their cytoplasm. Although individual osteoclast-type giant cells may vary in size and number of nuclei present, there should be little to no cytologic and nuclear variability from one giant cell to the next. The latter helps distinguish these benign-appearing giant cells from "malignant" giant cells. When examining lesions rich in osteoclast-type giant cells, it is absolutely necessary to pay particular attention to the background stromal cells, as their morphologic appearance (not the osteoclast-type giant cells), coupled with clinical and radiological correlation, establishes the diagnosis in question. Giant cell tumor (GCT), also known as osteoclastoma, is a benign but locally aggressive neoplasm generally arising in young to middle aged adults, between the ages of 20 and 40 years. [1] There may be a slight female predominance. Patients complain initially of pain and swelling, rarely associated with fracture. The most common anatomic locations include the distal femur, proximal tibia, distal radius, and sacrum. GCT may also involve the pelvic bones and vertebral bodies (but not the dorsal elements); however, the small digit bones are rarely affected. [2] Radiologically, GCT form geographic, lytic lesions that, in the long bones, are almost always epiphyseal-centered. A sclerotic rim is usually absent. GCT frequently destroy the cortex and extend into soft tissues, but a periosteal reaction is rarely seen. When giant cell tumors extend into or locally recur in soft tissues, a peripheral shell of ossification is often present. Rarely, GCT may occur solely within extraskeletal superficial and deep soft tissues. Unlike GCT of bone, soft tissue GCT most commonly arises from the upper extremity, usually the arm or hand. [3] The vast majority of GCT of soft tissue occur above the superficial fascia, localized to the dermis or in the subcutaneous adipose tissue. In most cases, the most striking histologic feature of GCT is the presence of innumerable osteoclast-type giant cells. These giant cells may be quite large with variable numbers of nuclei, ranging up to 100 per cell. The background stromal cells are slightly spindled to ovoid, containing nuclei closely resembling those observed in the osteoclast-type giant cells. Significant nuclear atypia is not observed in either the giant cells or the background stromal cells. Mitotic figures within the stromal cells may be numerous. Necrosis is a common finding in GCT, often leaving behind residual "tombstones" or "ghost" giant cells. Other areas may lack the typical osteoclast-type giant cells and include abundant fibrous tissue and spindled cells arranged in short fascicles and storiform patterns, resembling metaphyseal fibrous defect. Abundant foamy histiocytes may also be present. Reactive-appearing bone formation is common and is often seen at the periphery of the lesion, especially in GCT of bone that have extended into soft tissues. Similar findings are also observed in the soft tissue variant of GCT. Hyaline cartilage and chondroid matrix are never present in GCT. Secondary aneurysmal bone cyst-like changes may be seen in both bone and soft tissue GCT. To date, a specific and reproducible translocation in GCT has not been found. The most frequent chromosomal aberrations are telomeric alterations, most commonly affecting chromosomes 11p, 13p, 14p, 15p, 19q, 20q, and 21p. [4] GCT associated with aneurysmal bone cysts may have rearrangements of 16q22 or 17p13. [5] GCT of bone and soft tissue should be considered at least locally aggressive lesions with the potential, albeit rare, of metastasis. There are no histologic features predictive of prognosis. Minimal curettage and bone grafting lead to local recurrence in up to 40-50% of cases. Between 1-3% of patients with giant cell tumor will develop pulmonary metastasis. However, this usually ominous sign leads to death in only a minority of patients. Most pulmonary lesions from a "benign metastasizing giant cell tumor" grow slowly and may remain stationary. [6] Spontaneous resolution has been documented. [7] Some advocate surgical resection for these lesions. Malignancy in GCT represents a dedifferentiation of a conventional GCT. Consequently, the diagnosis may be established in two clinical settings—sarcoma arising (or co-existing) with a GCT or a sarcoma arising at the site of a previously histologically-documented GCT. Malignant transformation of GCT occurs in <1% of cases, most following radiation therapy. The distal femur and proximal tibia are the most common sites. [8] Radiologic features are not significantly different than those observed in other high grade sarcomas (e.g. osteosarcoma), but the lesions are generally lytic without mineralization. Morphologically, the sarcomatous component is high grade and may manifest as fibrosarcoma, osteosarcoma, or malignant fibrous histiocytoma. The pre-existing GCT is often no longer recognizable. The differential diagnosis of GCT includes virtually any lesion containing the characteristic giant cells. The lesions most likely to be confused with giant cell tumor of bone include giant cell reparative granuloma, aneurysmal bone cyst, and metaphyseal fibrous defect. Giant cell reparative granuloma (GCRG) refers to a group of histologically similar lesions arising in a variety of distinct clinical settings. Brown tumor of hyperparathyroidism is indistinguishable from GCRG arising in the digits or in the jawbones. Patients with Paget's disease of bone may also develop similar-appearing giant cell lesions, usually in the skull. GCRG usually arises as a lytic lesion within the jaws or digits of female patients between 5 and 20 years of age. [9] In the jaw, GCRG most commonly localizes to the anterior portion of the mandible (central giant cell lesion), although involvement of the maxilla and inter-osseous sinuses occasionally occur. Most represent asymptomatic incidental findings or come to clinical attention due to painless swelling of the affected bone. When GCRG involves the hands or feet, the phalanges, metacarpals, or metatarsal bones may be involved. Most patients present with pain and, occasionally, soft tissue swelling. [11] Radiographically, GCRG, regardless of origin, are characteristically lytic and expansile but usually well circumscribed without cortical erosion. Less commonly, GCRG appear more aggressive, especially in the tubular bones, with destruction of the cortex and extension into soft tissues. In the jawbones, resorption of teeth may also occur. Morphologically, GCRG of all clinical types are associated with numerous, randomly distributed, osteoclast-type giant cells admixed with a uniform population of ovoid to spindled stromal cells. Unlike conventional GCT, the background stroma tends to be more fibrotic and hypervascular. Pigmented histiocytes are often present. Foci of osteoid and reactive bone are usually observed. The histologic features closely resemble those seen in aneurysmal bone cyst, including occasional blood-filled cysts, and are essentially identical to brown tumor of hyperparathyroidism. Clinical and radiologic correlation is essential to establishing the diagnosis of GCRG. ABC occurs predominantly in the first two decades of life but may be observed at virtually any age. Up to 50% of cases may be intimately associated with other entities, primarily giant cell tumor, chondroblastoma, and fibrous dysplasia. Complaints of pain and soft tissue swelling are frequently present. The metaphyseal regions of the long bones, especially the distal femur and proximal tibia, and vertebral column (posterior arches) represent the most common anatomic sites. Radiologically, ABC produces an expansile and lytic, metaphyseal-centered lesion, generally well-circumscribed with a sclerotic rim and often associated with periosteal new bone formation. Cardinal morphologic features include the presence of numerous but variably-sized cavernous spaces filled with blood but lacking a definite endothelial lining. The cyst walls contain randomly-distributed fibroblasts, osteoclast-type giant cells, and variable amounts of osteoid and new bone formation. Chondroid and even hyaline cartilage rarely are observed. [10] Within the fibroblastic areas, numerous mitotic figures may be present but atypical forms are never seen. Regardless of anatomic location, all biopsy or curettage material from a suspected ABC should be meticulously sampled to exclude other pathologic entities. Additionally, cytologic atypia is not observed in ABC and, if present, should raise the possibility of telangiectatic osteosarcoma. Recent evidence suggests "chromosome bands 16q22 and/or 17p11-13 are nonrandomly rearranged in aneurysmal bone cyst, irrespective of subtype (classic, solid, primary, secondary) and location (osseous or extraosseous)." [5] Metaphyseal fibrous defects (MFD), also known as nonossifying fibroma, fibroma, and fibrous cortical defect, typically involve the metaphysis of a long bone and most likely do not represent true "neoplastic" change. In general, MFD are incidental findings, usually presenting between 10 and 20 years of age, younger than typically seen with GCT. Occasionally, patients present with pathologic fracture. The most common anatomic locations in decreasing order of frequency include the distal femur, distal tibia, proximal tibia and proximal fibula. Radiologically, MFD are eccentrically positioned, generally along the long axis of the metaphysis of a long bone. Size is variable, ranging from small intracortical lesions to those involving virtually the entire diameter of the bone. When MFD are observed in adults, the lesions may be diaphyseal-centered and show mineralization (healing). MFD may be expansile but are almost always sharply marginated with a sclerotic rim. Microscopically, MFD are hypercellular lesions consisting of a uniform population of spindle cells characteristically arranged in fascicles and storiform patterns. The nuclei of the spindle cells often contain prominent nucleoli but remain regular and monotonous. Numerous mitotic figures may be present. Randomly distributed throughout the lesion are numerous osteoclast-type giant cells, foamy histiocytes, and occasional hemosiderin-laden macrophages. Reactive new bone formation may be present, especially in the presence of pathologic fracture. Older lesions often show increased mature trabecular bone. For these reasons, the term nonossifying fibroma should probably be avoided. In those cases in which the integrity of the bone is not compromised, simple observation is adequate treatment. McDonald DJ, Sim FH, McLeod RA, Dahlin DC. Giant cell tumor of bone. J Bone Joint Surg [Am] 1986;68:235-242. Biscaglia R, Bacchini P, Bertoni F. Giant cell tumor of the bones of the hand and foot. Cancer 2000;88:2022-2032. Folpe AL, Morris RJ, Weiss SW. Soft tissue giant cell tumor of low malignant potential: a proposal for the reclassification of malignant giant cell tumor of soft parts. Mod Pathol 1999;12:894-902. Bridge JA, Neff JR, Mouron BJ. Giant cell tumor of bone: chromosomal analysis of 48 specimens and review of the literature. Cancer Genet Cytogenet 1992;58:2-13. Sciot R, Dorfman H, Brys P, et al. Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone, and combined lesions. A report from the CHAMP study group. Mod Pathol 2000;13:1206-1210. Tubbs WS, Brown LR, Beabout JW, et al. Benign giant-cell tumor of bone with pulmonary metastasis: clinical findings and radiologic appearance of metastases in 13 cases. AJR 1992;158:331-334. Kay RM, Eckhardt JJ, Seeger LL, et al. Pulmonary metastasis of benign giant cell tumor of bone: six histologically confirmed cases, including one of spontaneous resolution. Clin Orthop 1994;302:219-230. Rock MG, Sim FH, Unni KK, et al. Secondary malignant giant-cell tumor of bone: clinicopathological assessment of nineteen patients. J Bone Joint Surg [Am] 1986;68:1073-1079. Yamaguchi T, Dorfman HD. Giant cell reparative granuloma: a comparative clinicopathologic study of lesions in gnathic and extragnathic sites. Int J Surg Pathol 2001;9:189-200. Vergel De Dios A, Bond JR, Shives TC. Aneurysmal bone cyst: a clinicopathologic study of 238 cases. Cancer 1992;69:2921-2931.