The current report describes an unusual case of aggressive GCT of the uterus and its response to chemotherapy with pegylated-liposomal doxorubicin, ifosfamide, and bevacizumab. The role of chemotherapy in GCT is not well defined. Pegylated-liposomal doxorubicin and ifosfamide are active in soft tissue and bone sarcomas [8
]. Angiogenic growth factor expression, including VEGF, has been previously reported in a variety of sarcomas and in GCT of bone [16
], providing a rationale for the potential role of therapy directed against the VEGF signaling pathway, such as bevacizumab, in sarcomas, including GCT. In addition, VEGF is capable of inducing osteoclastogenesis in osteopetrotic mice (op/op) [24
]. The current case responded well to therapy with pegylated-liposomal doxorubicin, ifosfamide, and bevacizumab. It is of interest that in the first two specimens obtained before treatment (endometrial curetting and lung aspirate) there were large numbers of giant cells and these were evenly distributed. In contrast, the hysterectomy specimen after chemotherapy, showed only rare osteoclast-type giant cells, and there was extensive replacement of tumor cells by necrosis and reactive histiocytes.
Usually GCT is a primary osteolytic bone neoplasm in which monocytic macrophage/osteoclast precursor cells and multinucleated osteoclast-like giant cells infiltrate the tumor [1
]. These multinucleated giant cells have biochemical and functional characteristics of osteoclasts (reviewed in [18
]). While usually benign, GCT is locally aggressive and most commonly occurs in the epiphysis of long bones. GCT of soft parts are very rare, but have been described [25
], as have GCT of the thyroid [27
] and pancreas [28
Pulmonary metastases of GCT of bone usually grow slowly, and are often treated by surgery, though in some cases chemotherapy with various agents or radiation therapy have been used [30
]. Two cases of rapidly progressive metastatic GCT of bone have been reported that were treated with chemotherapy with a transient response [40
]. Several reports have suggested the potential utility of interferon alpha in GCT of bone [30
Walker observed that osteoclasts are derived from monocytic progenitors found in the blood [4
], providing the first demonstration of the existence of stem cells in blood for non-hematopoietic tissue. The etiology of GCT is unknown, however the tumor cells of GCT have been reported to produce chemoattractants that can recruit osteoclasts and osteoclast precursors [3
Many reactive conditions and benign and malignant tumors contain osteoclast-type giant cells. An important difference between many of these entities and the "true" giant cell tumor is that the spatial relationship between the giant cells and the tumor cells is different. In giant cell tumor, the osteoclast-type giant cells are distributed regularly and uniformly throughout the tumor; in other entities, the giant cells tend to be clustered, frequently in areas of hemorrhage, that alternate with areas completely devoid of giant cells. This difference in distribution probably reflects differences in pathogenesis. It has been suggested that in the various entities with unevenly distributed giant cells, the latter are probably the result of cytokines produced that attract osteoclast precursors. In giant cell tumor, the even distribution may reflect interaction/co-dependence as in a paracrine loop between the tumor stromal cells and the reactive, osteoclast type giant cells.
We found reports of 9 other cases of GCT of the uterus [45
]. Three patients in whom follow up was available died of their tumors. Four of the cases were thought to also have smooth muscle differentiation. Absence of desmin and myosin and only focal and weak reactivity for actin argue against true smooth muscle differentiation in our case.
The tumor cells of GCT of bone have been reported to produce chemoattractants, including both TGF beta1 and monocyte chemoattractant protein 1 (MCP-1), that can attract osteoclasts and TRAP-positive monocytic osteoclast precursors. Other growth factors indicative of an osteoclastogenic environment of potential importance in GCT, including RANKL, have been identified in GCT [6
]. RANKL (OPGL) binds specific hematopoietic progenitor cells and induces osteoclast differentiation. RANKL also activates osteoclasts, and administration of RANKL to mice results in hypercalcemia [55
]. RANKL is necessary and sufficient for osteoclastogenesis [52
]. RANKL mRNA expression was recently reported to be over-expressed in the stromal-like tumor cells of GCT, while its receptor, RANK, was expressed only in the macrophage-like mononuclear cells and multinucleated giant cells [6
]. The potential role for tumor cell-osteoclast interaction/co-dependence, as in a paracrine loop between the stromal tumor cells and the osteoclast-like cells, in GCT is unknown. In this regard, it is of interest that the marked decrease in the population of viable tumor cells in the hysterectomy specimen after chemotherapy was associated with a marked reduction in the number of osteoclast-type giant cells and with loss of their spatial relationship. Thus, it is intriguing to speculate that new agents that inhibit osteoclastogenesis via the RANK/RANKL pathway, such as denosumab, could be useful in the treatment of GCT. Recent studies also suggest that bisphosphonates may induce apoptosis in both osteoclast-like giant cells and stromal tumor cells in vivo and in vitro in GCT [56
], possibly by interfering with an autocrine and/or paracrine loop in the tumor between stromal tumor cells and osteoclast-like giant cells.
Aggressive metastasizing GCT may arise in the uterus, and may respond to combination chemotherapy. The addition of bevacizumab is logical, though its contribution to the effect observed in this case is unclear.