Common Diagnostic Dilemmas in Bone and Soft Tissue Surgical Pathology
Case 9 -
Giant Cell Tumor
The patient is a 27-year-old male with a
painful lytic lesion of the proximal tibia.
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.  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.  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. 
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.  GCT associated with aneurysmal bone cysts may have rearrangements of
16q22 or 17p13.  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.  Spontaneous
resolution has been documented.  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.  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
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.  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.  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.  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)."
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.
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