A case of recurrent giant cell tumor of bone with malignant transformation and benign pulmonary metastases
© Miller et al; licensee BioMed Central Ltd. 2010
Received: 11 August 2010
Accepted: 22 September 2010
Published: 22 September 2010
Giant cell tumor (GCT) of bone is a locally destructive tumor that occurs predominantly in long bones of post-pubertal adolescents and young adults, where it occurs in the epiphysis. The majority are treated by aggressive curettage or resection. Vascular invasion outside the boundary of the tumor can be seen. Metastasis, with identical morphology to the primary tumor, occurs in a few percent of cases, usually to the lung. On occasion GCTs of bone undergo frank malignant transformation to undifferentiated sarcomas. Here we report a case of GCT of bone that at the time of recurrence was found to have undergone malignant transformation. Concurrent metastases were found in the lung, but these were non-transformed GCT.
Giant cell tumor of bone is a locally destructive tumor that occurs predominantly in long bones of post pubertal adolescents and young adults, where it occurs in the epiphysis. The majority are treated by aggressive curettage or resection. Histologically, giant cell tumor of bone classically shows many large multinucleated giant cells with interspersed haphazardly arranged mononuclear cells, and the nuclear features of both elements are described as similar. Some tumors also have areas with a fascicular or storiform pattern devoid of giant cells resembling a benign fibrous histiocytoma. Vascular invasion outside the boundary of the tumor can be seen. The rate of local recurrence varies among centers and is influenced by the completeness of surgical treatment, with high speed burring, adjuvants, and bone cement adding to the effectiveness of curettage treatment. Unresectable tumors such as large sacral masses can be treated with radiation. New therapies targeting the Receptor Activator of NF-κB (RANK) signaling pathway, such as with the anti-RANK ligand antibody denosumomab are in early stages of investigation. Metastasis, with identical morphology to the primary tumor, occurs in a few percent of cases, usually to the lung. These cases are treated with wedge resection with good long term outlook. On occasion giant cell tumors of bone undergo frank malignant transformation to undifferentiated sarcomas. Here we report a case of giant cell tumor of bone that at the time of recurrence was found to have undergone malignant transformation. Concurrent metastases were found in the lung, but these were non-transformed giant cell tumor. Contemporaneous histologically benign pulmonary metastases and locally recurrent giant cell tumor of bone with transformation to sarcoma has not to our knowledge been previously reported.
Materials and methods
This study was performed with the approval of the Rush University IRB, ORA#: 09092501-CA01. The study included detailed clinical information, imaging and pathology. Tissue was fixed in 10% buffered formalin at room temperature and dehydrated and paraffin embedded in overnight processing. Immunohistochemical stains were performed as follows: The following antibodies were used on Ventana Benchmark and the manufacturer's solution CC1 for antigen retrieval.: CD4 (Biocare Medical, Concord, CA) 1:10 dilution, CD43 (Cell Marque, Rocklin, CA) prediluted, P63 (Fisher Scientific, Pittsburgh, PA) 1:500. Ki-67 immunostaining was performed on the Dako autostainer PLUS with FLEX Envision chemistry using clone MIB-1 (Dako, Carpentaria, CA), at 1:400 dilution after citrate buffer antigen retrieval under pressure in a microwave oven. Images were captured on an Olympus BX41 microscope with a Spot Insight color camera with Spot Advanced software.
Report of a case
A 29 year-old male was diagnosed with a giant cell tumor of the left proximal tibia at an outside institution in January 2005. He underwent intralesional curettage followed by heat cauterization and methacrylation. Eight months later, in September 2005, the patient had a local recurrence of the tumor which was treated with cement removal and repeat curettage followed by argon beam ablation and repeat cementing.
Comment and discussion
Giant cell tumors of bone are neoplasms of stromal cells that recruit a mononuclear population of hematopoietic origin . These monocytes and/or multinucleated giant cells may in turn produce factors that support growth of the stromal cells, but this has not been explored. The onocytederived component is highlighted in immunohistochemical stains for the lysosomal marker CD68 and for monocyte lineage specific markers. The lineage of the stromal cells is still poorly characterized, but a subset variably expresses alkaline phosphatase, similar to osteoblasts . Factors such as monocyte colony stimulating factor (m-CSF) and RANK ligand, which are important for osteoclastogenesis and for fusion of monocytes to form multinucleated giant cells, are expressed in giant cell tumors of bone. Presumably the stromal cells are the source of m-CSF, akin to the situation in localized and diffuse giant cell tumors of tendon sheath/synovium where m-CSF is overexpressed by the neoplastic cells, sometimes secondary to a recurrent translocation[10, 11]. Accordingly, cultured giant cell tumor stromal cells are chemoattractant to peripheral blood monocytes.
In karyotypic analysis of giant cell tumors of bone, end-to-end fusions of various chromosomes, termed telomeric associations, are seen in most tumors in a subset of cells, and these have been localized by FISH studies to the CD68 negative spindled stromal component. At lower frequency than telomeric associations, clonal chromosome gains, deletions and translocations can also be found in GCT of bone. Translocations occur more frequently in tumors that have more telomeric associations, and they probably result from ensuing problems in separation of dicentric chromosomes during telophase. However, cells with chromosomal abnormalities do not have enough of a growth advantage to dominate the tumor population, and analyses of many metaphases is required to recognize that there are clonal subpopulations in the tumor. In Goronova's study there was no association between karyotype and prognosis. Also, no dominant recurrent cytogenetic abnormality was seen that might give clues to pathogenesis. Thus, this peculiar low level chromosome instability reflects an underlying defect in chromosome maintenance, though probably not due to a generalized defect in telomerase activity. The minor genomic instability seen in vitro is reflected by a low but definite probability of transformation clinically, as seen here. However, because of the current lack of a defined molecular or cytogenetic marker of GCT of bone, formal proof that the rare cases of malignant transformation are due to evolution of the spindle cells of GCT of bone is lacking. An alternative hypothesis would be that that GCT of bone predisposes to malignancy in an unrelated cell--akin to secondary malignancy in the setting of osteonecrosis or Paget's disease of bone. Notably, cases are considered secondary malignant giant cell tumors even if, on recurrence, only the malignant component is seen.
Reported incidence of malignancy associated with giant cell tumor of bone in large published series
We report here the case of a giant cell tumor of the proximal tibia of a 29 year old man treated with aggressive curettage that recurred 4 years later with malignant transformation and "benign" metastases to the lung. Recurrence, malignant transformation, and metastasis with "benign" morphology all occur in giant cell tumor of bone. This is the first report of all three occurring in a single patient. The influence of local recurrence on malignant transformation and pulmonary metastases is largely unknown. Malignant transformation has been reported most frequently with radiation even in nonrecurrent tumors. Similarly, benign pulmonary metastases have been reported to occur in recurrent and nonrecurrent tumors. The current report adds little to the discussion of the fate of locally recurrent giant cell tumor of bone. The molecular pathways leading to giant cell tumors of bone are still largely uncharacterized.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this Journal.
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