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Aneurysmal bone cysts (ABCs) mostly occur in the metaphysis of long bones. Primary paranasal ABCs are extremely rare, and most reported cases reveal typical histopathological features including cystic space with fibrous septa and hemorrhage. Solid-variant ABCs or solid ABCs lacking cyst formation may be histologically indistinguishable from giant cell reparative granulomas, giant cell tumor of bone, and brown tumor. Here we report the case of a 24-year-old woman with a paranasal mass diagnosed as USP6-rearranged solid ABC, mimicking giant cell reparative granuloma, giant cell tumor of bone, and brown tumor. For paranasal sinus bone or soft tissue tumors containing numerous giant cells, molecular analysis including the USP6 gene may serve as a useful diagnostic tool to distinguish solid ABCs from other giant cell-rich lesions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Differentiating osteoclast-rich lesions of bone (giant cell tumor of bone [GCTB], chondroblastoma [CBA], and aneurysmal bone cyst [ABC]) can be challenging, especially in small biopsies or fine-needle aspirations. Mutations affecting codons 34 and 36 of either H3 Histone Family Member 3A (H3F3A) and/or 3B (H3F3B) are characteristically seen in GCTB and CBAs. We devised a simple assay to identify these mutations and evaluated its applicability for routine clinical diagnosis. One hundred twenty-four tissue specimens from 108 patients (43 GCTBs, 38 CBAs and 27 ABCs) were collected from the archives of the Calgary Laboratory Services/University of Calgary and Vanderbilt University Medical Center. Histology was reviewed by an expert orthopedic pathologist. A single base extension assay (SNaPshot) is used to interrogate each nucleotide in codons 34 and 36 of H3F3A and codon 36 of H3F3B. Final diagnoses were generated after re-reviewing cases and incorporating molecular findings. Of 43 GCTBs, 38 (88%) had an H3F3A G34W mutation; 35 of 38 CBAs (92%) had a K36M mutation in either H3F3B (N = 31; 82%) or H3F3A (N = 4; 11%); none of 27 ABCs had a tested mutation. Molecular findings changed the histomorphologic diagnosis in 5 cases (3 GCTB changed to ABC, and 2 ABC changed to GCTB). These findings support the diagnostic utility of mutational analysis for this differential diagnosis in certain challenging cases when clinicoradiologic and histomorphologic features are not definitive, particularly for distinguishing cellular ABC versus GCTB with secondary ABC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.

Giant cell-rich lesions of bone, including giant cell tumor of bone, giant cell reparative granuloma (GCRG), and aneurysmal bone cyst (ABC), may have overlapping clinical, radiologic, and histopathologic features. In fact, GCRG and solid ABC are currently differentiated solely based on skeletal location. Prior cytogenetic studies have reported that telomeric associations are present in the majority of giant cell tumors of bone, whereas translocations involving 16q22 and/or 17p13 are characteristic of ABCs. There is only one previously published karyotype of a GCRG, which revealed a reciprocal translocation, t(X;4)(q22;q31.3). We report 3 cases of giant cell-rich bone lesions with novel karyotypes: one lesion located in the first metacarpal, a typical location for GCRG, was histologically consistent with a giant cell tumor and showed the following karyotype [46,XX,inv(2)(p13q21),t(inv2;11)(q21;q13)]; the second lesion, also a giant cell tumor of bone, in the sacrum showed the following karyotype [46,XX,r(9)(p24q34)[cp7]/46,idem,?r(16)(p13.3q24)[cp10]/46,XX]. The third lesion, a hard palate mass, had the histopathologic features of a GCRG and a karyotype showing a reciprocal translocation, 46,XY,t(2;10)(q23;q24). These findings suggest that at least a subset of GCRGs may be neoplastic and that these lesions differ cytogenetically from classic giant cell tumors of bone or solid ABC, although the latter entity is otherwise indistinguishable from reparative granuloma. Further cytogenetic characterization of giant cell-rich bone lesions may improve the utility of karyotyping as a tool in their differential diagnosis and may shed light on the pathogenetic relationship between these lesions.

Giant cell-rich bone lesions consist of tumor-like lesions and true neoplastic giant cell tumors. In this study it was investigated whether DNA cytometry may contribute to the differential diagnosis between aneurysmal bone cysts and giant cell tumors. Statistically significant differences in the frequency of tetraploid stemlines were detected. Nevertheless, the knowledge of age, localization and radiological signs in addition to morphological findings are essential to distinguish between these lesions.

Aneurysmal bone cyst and giant cell tumor of bone are relatively rare bone tumors that sometimes coexist. We examined the karyotypes of 3 aneurysmal bone cysts, 12 giant cell tumors, and 3 combined lesions. All aneurysmal bone cysts showed involvement of chromosome segments 17p11-13 and/or 16q22. In addition, in 1 of the 3 giant cell tumors with secondary aneurysmal bone cyst, both chromosome bands were rearranged as well, albeit not in a balanced translocation. Seven out of 12 giant cell tumors were characterized by telomeric associations. One giant cell tumor showed a dup(16)(q13q22), suggesting the presence of a (minor) secondary aneurysmal bone cyst component, despite the absence of histological proof. Our results, combined with literature data further substantiate that segments 16q22 and 17p11-13 are nonrandomly involved in at least some aneurysmal bone cysts, irrespective of subtype (primary, secondary, intra/extraosseous, solid or classic). These findings strongly suggest that some aneurysmal bone cysts are true neoplasms. In addition, telomeric associations are the most frequent chromosomal aberrations in giant cell tumor of bone, the significance of which remains elusive. In combined giant cell tumor/aneurysmal bone cyst each component seems to retain its own karyotypic abnormality.

Peripheral giant cell granuloma consists of mononuclear cells and osteoclast-like giant cells. The proliferative ability of peripheral giant cell granuloma is restricted to the mononuclear cell compartment, whereas multinucleated giant cells lack mitotic activity. Although the proliferative compartment of peripheral giant cell granuloma has been investigated in detail, the expression and distribution of proteins regulating apoptosis is unknown. The present study demonstrates strong expression of bak and bax in the majority of giant cells. In contrast, giant cells show only weak positivity for bcl-2 and moderate positivity for bcl-x. Mononuclear cells were negative to weakly positive for bcl-x. Only scattered mononuclear cells were positive for bak, bax and bcl-2. The frequency of apoptotic nuclei detected by TUNEL-staining compared to regular nuclei was 18 times higher in giant cells than in mononuclear cells. In summary, our findings support the presumption that giant cells of bone and soft tissue tumors are reactive cell forms and not of neoplastic origin.