Giant cell tumors of bone (GCTBs) are rare tumors that often occur in the epiphysis of long bones and are less commonly encountered in the metaphysis or diaphysis.1 Conventional GCTB is locally destructive with the rare potential for pulmonary metastatic lesions.2 The histology and imaging of GCTB are typically diagnostic, but mimickers can include giant cell–rich osteosarcoma, aneurysmal bone cyst, brown tumor of hyperparathyroidism, and benign fibrous histiocytoma.3,4 Local recurrence is common, with most published recurrence rates between 5% and 15%,1–3 but some rates are as high as 50%.5 Cases of malignant transformation of GCTB are well documented; however, these typically occur after multiple recurrences or after radiation.6,7 Even rarer are cases of primary malignant GCTB that are histologically similar to, but behave more aggressively than, their benign counterpart.1,4 The term malignant GCTB is vague and has been used to describe a spectrum from primary bone tumors predominated by giant cells to secondary transformations of previously histologically benign GCTB as well as dedifferentiated GCTB, which is described as GCTB alongside a sarcoma. For the purpose of this article, we utilize Enneking's4 classic description of giant cell sarcoma as frankly sarcomatous giant cell tumors with aggressive features and behavior. We present the following case to illustrate a primary giant cell sarcoma and the difficulties encountered in making the diagnosis.
The patient is an otherwise healthy 24-year-old man active duty service member who initially presented with 6 weeks of progressive thigh pain after minimal trauma. Presenting radiographs demonstrated a geographic bone lesion about the mid to distal femur with mixed sclerosis and lytic portions of the lesion (Fig. 1). Periosteal bowing and an associated soft tissue mass were also present (Fig. 2). He underwent an ultrasound-guided biopsy, which demonstrated a giant cell–rich neoplasm believed to be consistent with GCTB. He subsequently underwent curettage with local adjuvant and bone grafting. Intraoperative pathology was consistent with a giant cell lesion, and permanent sections from the case confirmed a benign-appearing giant cell neoplasm (Fig. 3).
The patient had routine clinical follow-up until he began to have increasing pain about the right knee and thigh 12 weeks postoperatively. New imaging was obtained, demonstrating a recurrence of the mass associated with bony destruction and a large soft tissue mass (Figs. 4, 5). Repeat ultrasound-guided biopsy revealed a recurrent giant cell–rich tumor, which was again favored to be benign by two independent pathologists. Single-agent denosumab was initiated, but interval imaging demonstrated an enlarging soft tissue mass as well as new, rapidly enlarging pulmonary nodules. The patient underwent an incisional biopsy of the right thigh mass as well as a right lower lobe wedge resection (Figs. 6A and B and 7, respectively). The radiological images and pathology slides were reviewed by a bone and soft tissue pathologist and were thought to be consistent with recurrent GCTB with benign pulmonary metastatic lesions. The clinical history, radiological images, and slides were then sent to a regional sarcoma center for further testing. Initial review demonstrated histologic characteristics consistent with GCTB, but with an abnormally high mitotic rate and negative testing for a GCTB-specific marker (H3G34W5). Given the atypical aggressive behavior, radiological features, histologic findings, and the lack of response to denosumab, the diagnosis was more consistent with a primary sarcoma of bone.
The patient was started on 10 weeks of a conventional osteosarcoma-based chemotherapy of adriamycin, cisplatin, and high-dose methotrexate. Of note, genomic analysis revealed a KRAS mutation. The patient subsequently underwent an above-knee amputation with negative margins. Final pathology from the amputation was consistent with primary giant cell sarcoma of bone with greater than 90% tumor necrosis (Fig. 8). The patient remained disease-free until 13 months postoperatively from his above-knee amputation when a surveillance positron emission tomography scan discovered recurrent pulmonary disease. Repeat biopsy was consistent with previous histology, and patient was planned to undergo 8 cycles of salvage chemotherapy.
Our patient's initial presentation was that of an atypically located diaphyseal GCTB, and a giant cell–rich sarcoma was considered in the differential diagnosis. During the course of his treatment, the lesion's imaging took on a far more destructive appearance, but well within the confines of an aggressive giant cell tumor, especially with multiple reassuring samples from the lesion. Giant cell–rich osteosarcoma was considered at multiple points, but no osteoid was evident throughout multiple samples, as well as negative vimentin staining and low-grade appearance (lack of nuclear pleomorphism and atypical mitotic figures) made this a less likely diagnosis.8,9 Initial high-grade pathology may have been missed due to small sample size, but with full resection the sampling error was minimized.
Review of his most recent biopsy by a regional sarcoma center resulted in testing for a histone mutation (H3G34W) that has been previously reported to have a high correlation with GCTB and rarely, if ever, present in giant cell–rich sarcomas.10 The lack of H3G34W was ultimately the deciding factor in diagnosing and treating the lesion as a primary giant cell sarcoma in the setting of imaging and biopsies that could not clearly delineate a sarcomatous nature. The potential exists that H3G34W testing on the original biopsy would have also suggested a sarcoma, but there was a noted increase in the mitotic activity of the final tissue samples not present earlier. It is also possible that this tumor represents an early secondary conversion to a malignant GCTB; however, this has typically been reported 3 to 15 years after resection rather than 3 months and after multiple surgical resections or radiation.3,6,7 Without histone mutation testing of the original samples, we suggest a diagnosis of an early giant cell sarcoma arising after resection of a GCTB given the marked change in histology and radiographic aggressiveness.
The differential diagnosis for giant cell–rich tumors is broad, and it is often difficult to distinguish benign GCTB from more malignant tumors based on histology alone. Moreover, the available literature regarding treatment and outcomes of the malignant variety is scarce. The importance of a multidisciplinary approach involving pathology, medical oncology, radiology, and orthopedic surgery is paramount in difficult and rare cases in order to establish the proper diagnosis and treatment plan.
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