The value of recognizing suspect diagnoses in the triple diagnosis of giant cell tumor of bone

Giant cell tumor (GCT) of bone is the most frequently over-diagnosed neoplasm in orthopedic pathology because giant cells are a common component of many neoplastic and nonneoplastic conditions of bone. Triple diagnosis, requiring substantial individual and collective inputs by orthopedic surgeons, radiologists and pathologists, is the preferred method for the workup of patients with suspected bone neoplasms. At each stage in triple diagnosis, deviations from the typical must be regarded as clues to alternate diagnoses: the greater the deviation, the more a diagnosis of GCT must be considered suspect. A suspect diagnosis must trigger renewed analysis of the available data and a diligent search to exclude alternate diagnoses. This review lists suspect diagnoses of GCT with a brief overview of each.

O rthopedic pathologists were among the earliest to setting, the histopathological picture of diffusely dispersed emphasize the importance of a combined approach osteoclast-like giant cells in the characteristic stroma is to tumor diagnosis. Essentially, this means that diagnostic of giant cell tumor. the diagnoses based on a) clinical data, b) radiological and other imaging analysis and c) pathologic evaluation The morphology of the background population of must, individually and collectively, contribute substantially mononuclear cells is crucial to the diagnosis. Essentially towards establishing the correct diagnosis.
these are round, oval or polygonal in shape with nuclei closely resembling those in the giant cells [ Figure 1]. A brief listing of the clinical and radiographic features Sometimes the mononuclear cells are spindled with of the case at hand, the location of the lesion: whether varying amounts of eosinophilic cytoplasm; these are less epiphyseal, metaphyseal or diaphyseal and the clinical and diagnostic and efforts to examine more tissue to look for the radiological diagnosis or a list of differential diagnoses, must diagnostic cells must be made. Mitoses may be abundant therefore be a minimum requirement for submitting tissue in the mononuclear cells, but do not predict behavior of for histopathological analysis. Armed with this information the tumor. the pathologist is expected to make an intelligent assessment of the histopathology to come to a diagnosis.
The giant cells in GCT often contain a large number of nuclei, sometimes over a hundred, a feature rarely seen in

THE CLASSIC GIANT CELL TUMOR OF BONE
other osseus neoplasms. It is thought that giant cells form by fusion of the mononuclear cells. Supporting this concept The many elaborate descriptions of giant cell tumor of is the fact that mitosis is never seen in the giant cell nuclei. bone in the literature 1-3 scarcely require repetition. Briefly, the classic GCT affects the mature skeleton with closed epiphyseal plates, most commonly in the third decade of life. Serum chemistries are typically normal. Located near the articular ends of the lower end of the femur or upper end of the tibia, the epiphysis is invariably involved by the radiographically lytic lesion. In this clinical and radiological Osteoclast-like giant cells in GCT are thought to derive from a monocyte-macrophage lineage. Besides others, 4 they have been shown to express the macrophage marker HAM-56. 5 The stromal cells are thought to originate from mesenchymal stem cells. 6 Many neoplastic and nonneoplastic lesions of bone may contain varying proportions of giant cells. Probably the best way to minimize the risk of misdiagnosis is to consider any variation from the classical as a clue to an alternate diagnosis. Identifying a suspect diagnosis is thus an important first step towards the correct diagnosis.

DIFFERENTIAL DIAGNOSIS
A brief consideration of the differential diagnosis of each of these situations is presented below [ Table 1].

GCT in an immature skeleton with open epiphyseal plates
Most GCTs occur in patients older than 20 years of age i.e., Kotru M, et al.: Diagnosis of giant cell tumor pathology, must enter the differential diagnosis in patients with immature skeleton.

GCT occurring de novo in a patient older than 55 years
De novo tumors in older patients are more likely to be malignant tumors other than GCT. Occasionally, a primary malignant GCT, which may have sarcomatous areas, can be encountered. Spontaneous malignant transformation of GCT in older patients has also been described. 8 There after the closure of epiphyses. The peak incidence is in the third decade. Very rarely, GCT occurs in younger patients. 7 In such cases it is seen in late teenage involving the bones of hands and feet. Osteosarcoma with prominent giant cells, one of the most serious diagnostic pitfalls in orthopedic appears to be no reliable way of knowing which of these tumors will undergo malignant change. 9

GCT in a patient with elevated serum calcium
Elevated serum calcium must suggest brown tumor of hyperparathyroidism 10 and giant cell reparative granuloma, which regardless of its location, is histologically indistinguishable from it. Serum calcium, phosphate and alkaline phosphatase levels should be determined. Serum parathyroid hormone levels should be determined when calcium levels are at the upper limits of normal to exclude normocalcemic hyperparathyroidism.
GCT near articular ends of long tubular bones (other than around the knee joint): (i) distal radius, (ii) proximal femur, (iii) proximal humerus and (iv) distal tibia.
More than 50% GCTs occur in the region of the knee. 3 If all other parameters are in agreement, the diagnosis is most likely to be correct at this site than at any other. Giant cell tumor has been reported in the distal radius, proximal femur, proximal humerus and distal tibia in reducing order of frequency compared to around the knee joint. Therefore, at these sites the diagnosis of GCT must be considered • GCT with perilesional sclerosis • GCT with diffusely permeative growth older than 55 years pattern GCT in a patient with elevated serum • GCT with periosteal calcifications (sunburst, • GCT with reactive sclerosis onionskin, Codman triangle)

GCT involving the flat bones other than the sacrum and the pelvis
When GCT does occur in the flat bones, the sacrum and the pelvis are favored sites, albeit with the caveat that these are relatively rare sites. 11 GCT of the craniofacial (particularly the jaw) bones, except in a patient with Paget's disease Kotru M, et

GCT with diffusely permeative growth pattern
Diffusely permeative radiographic and histopathological growth patterns are indicative of malignant tumors, notably osteosarcoma, 18 which often infiltrate considerably into surrounding tissue. Exceptions occur when the metaphyseal region of a GCT is sampled: a permeative growth pattern, corresponding to the ill-defined margin seen radiographically, may be seen on microscopic

GCT with periosteal calcifications (sunburst, GCT with cartilage in unfractured tumors onionskin, Codman triangle)
Cartilage may be seen in fractured GCT as a manifestation Most Paget sarcomas are osteosarcomas. GCT very rarely examination. Identification of the region of the tumor that arises in patients with Paget's disease, when it may involve has been sampled -essential for correct interpretation -can the craniofacial bones. 12 The distribution of GCT tends to be a problem with curetted material. When dealing with parallel the distribution of uncomplicated Paget's disease.
resection specimens, specimen radiography as an aid to It pays to remember that most giant cell lesions of the jaw tissue sampling is beneficial. are giant cell reparative granulomas 13,14 in which the giant cells tend to have fewer nuclei and be aggregated around

GCT with perilesional sclerosis
The interpretation of radiographic features is outside the scope of most pathologists' work, emphasizing the reliance that must be placed on the radiologists' input.

GCT in the presence of uninvolved or open epiphysis
Involvement of the epiphysis can be ascertained by the pathologist only in resection or amputation specimens. The pathologist must be informed of radiographic evidence of epiphyseal involvement when curettings are submitted for of healing fracture. 3 Healing fracture is a diagnostic pitfall for many osseus and cartilaginous neoplasms of bone.
Careful evaluation for histopathological signs of organization and zonation in healing fracture must be made. Unless fracture can be supported by radiographic evidence, a diagnosis of GCT must not be made in the presence of cartilage.

GCT with giant cells in clusters
In general, uniform distribution of large giant cells in the appropriate stromal background is characteristic of GCT. Smaller giant cells, with fewer nuclei, aggregate around areas of hemorrhage in reparative granuloma 21 and brown tumor of hyperparathyroidism. In other situations giant cells present focally should be a clue to an alternate diagnosis such as aneurysmal bone cyst.

Behavior
GCT is an aggressive lesion with high degree of local recurrence and malignant potential. Despite the advocacy of several grading systems, 22 previously treated with irradiation.