A 26-year-old female was referred to our hospital in June 2014 with a complaint of dull pain in the right knee for six months. Physical examination showed tenderness in the proximal right tibia. Radiography and computed tomography (CT) revealed eccentric, well-defined osteolytic destruction in the proximal metaphysis of the right tibia, suggesting the imaging diagnosis of GCTB (Campanacci grade II) (Figure 1A-D). Chest CT scan (Figure 2A) and single-photon emission CT (Figure 1E) did not reveal any metastatic lesions.An open biopsy from a lateral incision was performed thereafter, and pathological results showed multinucleated osteoclast giant cells with a large number of nuclei scattered among mononuclear tumor cells, which confirmed the diagnosis of a benign GCTB (Figure 3A). Subsequently, the patient underwent intralesional curettage following the biopsy tract. Utilizing high-speed drilling and ethyl alcohol, 1 cm of spongy bone and 1 mm of cortical bone were removed. The remaining cavity was then packed with cement (Figure 4A and B). After the procedures, immobilization was recommended to prevent pathological fracture. However, nine months later, a palpable mass was detected in the right popliteal fossa. Radiography, CT, and magnetic resonance imaging revealed local cortical bone destruction with soft tissue extension (Figure 4C-F) which indicated Campanacci grade III. Chest CT showed no evidence of metastases. Because of the extensive recurrence and stage III rating, the patient underwent wide resection of the lesion with prosthetic reconstruction. Postoperative pathologic features and presence of multinucleated giant cells were detected by immunohistochemical (IHC) staining with a monoclonal antibody against CD68 (PG-M1) and were similar to that of the pre-surgical specimens, revealing the recurrence of GCTB without malignant transformation (Figure 3B and C). The IHC staining also identified tumor cells positive for VEGFR-2 (Figure 3D). The patient was regularly followed-up every three months in our orthopedic clinic.
Two years after the latest surgery, the patient presented to our clinic with a complaint of hemoptysis. The lung CT scans were evaluated by experienced musculoskeletal surgeons and radiologists who verified more than 100 pulmonary nodules in both lungs (Figure 2B). Although biopsy of the lung mass was not performed owing to the refusal of the patient, the imaging diagnosis of metastatic GCTB was considered based on the presence of multiple lesions. Meanwhile, lung cancer was excluded because the level of serum cytokeratin fragment antigen 21-1, a sensitive tumor marker of lung cancer, was negative.
Since both biopsy and resection are traumatic operations with risks and complications, and the multiple metastases could not be completely removed by surgery or benefit from it. On the other hand, our patient could not tolerate chemotherapy because of an Eastern Cooperative Oncology Group performance status score of 3. Therefore, the patient chose subcutaneous denosumab administration, which was initiated at a dose of 120 mg every 28 days, with additional doses on days 8 and 15 of the first month. The patient was also supplemented with calcium and vitamin D. However, after four months of denosumab therapy, the symptoms of hemoptysis became more severe. The lung CT scan showed the metastatic nodules had increased in size and number, indicating progression of disease (Figure 2C). After multiple interdisciplinary team discussions, and in view of the high-level VEGFR-2 expression and rapidly progression, the patient was tentatively administered the TKI apatinib in combination with denosumab treatment. Denosumab was injected every month with a dose of 120 mg and apatinib was administered with an oral dosage of 500 mg daily. After three months of denosumab and apatinib treatment, the patient showed noticeable improvement of hemoptysis and visibly reduced tumor size (Figure 2D).
At a follow-up of 42 months, chest CT images showed a significant size reduction in the lung nodules. The largest one had greatly decreased in size from 12.2x8.5 cm to 3.5x1.5 cm (Figure 2E and F), and the tumor volume shrinkage rate was 95%. Moreover, the number of metastatic nodules decreased to less than 30. After initiation of apatinib therapy, a few drug-related toxicity reactions were noted, including hand-foot skin syndrome, gastrointestinal discomfort, and hypopigmentation of the hair. All adverse reactions were mild (grade 1 or 2) according to the Common Terminology Criteria for Adverse Events and were easily controlled by symptomatic treatments. The efficacy was evaluated as a significant partial response (PR) to denosumab and apatinib treatment by the Response Evaluation Criteria for Solid Tumors 1.1. The patient is under stable condition at the time of this writing.
CT of the chest. (B) Multiple pulmonary metastases were found and denosumab initiated.