Osteoclast-rich lesions of bone: a clinical and molecular overview

Definition

Giant cell tumor of bone is classified as a primary tumor of bone and defined as a locally aggressive and rarely metastasizing neoplasm (intermediate category of behavior) [ ]. Overall 96% of cases harbor a driver mutation in histone 3.3 variants exclusively in H3-3A , the vast majority of which occur in G34W [ ].

Epidemiology

Giant cell tumors occur in all ethnic groups, accounting for 4%–5% of all primary bone tumors and approximately 18% of nonsarcomatous bone tumors in the Western world, whereas they represent approximately 20% of primary bone tumors in the Chinese population [ , ]. In contrast to most bone tumors, giant cell tumors occur slightly more commonly in females [ ].

Sites of involvement and imaging

The histopathological features of giant cell tumors overlap with other osteoclast-rich lesions. However, detection of the characteristic H3-3A mutation in an osteoclast-rich tumor provides a definitive diagnosis of a GCT. When hyperparathyroidism has been excluded, this tumor presents in the vast majority of cases in skeletally mature individuals and involves the subarticular/epiphyseal region [ , ]. Detection of the mutation demonstrates that occasionally a GCT presents in an immature skeleton although in most of these cases fusion of the growth plate has occurred in at least some skeletal sites [ , ].

Giant cell tumors are radiologically expansile, osteolytic, radiolucent lesions without a sclerotic margin and usually without a periosteal reaction ( Fig. 44.1 ) [ ]. The tumors are typically large at presentation, with diameters generally in the range of 5–7 cm. Eighty-five percent of giant cell tumors occur in long bones, with 50% being sited in the distal femur or proximal tibia, and approximately 5% in the bones of the hand and feet. Approximately 5% also involve flat bones, particularly those of the pelvis, with most occurring in the sacrum [ ]. Occasionally, the entire sacrum is involved with the tumor extending across the sacroiliac joint to involve the ilium, and across the L5–S1 disc to involve the posterior elements of the L5 vertebra. The location of giant cell tumors within vertebrae varies but most commonly occur in the body, followed by the vertebral arch and as a result there is a risk of extension into the spinal canal, with cord compression and consequent neurological symptoms [ ].

Molecular genetics

96% of giant cell tumors of bone harbor histone 3.3 variants exclusively in H3-3A , leading to p.Gly34Trp (G34W) in the vast majority of cases and occasionally to p.Gly34Leu (G34L) alterations. The mutations are restricted to the stromal cell population and not detected in osteoclasts or their precursors [ ]. H3-3A and H3-3B are found on chromosomes 1 and 17, respectively, and represent two genes encoding histone 3.3: they have different exonic and intronic DNA sequences, but both encode histone 3.3 proteins of identical amino acid sequence [ , ]. A total of 95% of chondroblastomas, another osteoclast-rich tumor, have been found to harbor p.Lys36Met (K36M) mutations predominantly encoded in H3-3B [ , ]. The H3-3A and H3-3B mutations represent the sole genetic drivers in giant cell tumor of bone and chondroblastoma [ , ].

H3-3A K27M and G34 R/V mutations have previously been reported in childhood brain tumors [ ] but the remarkable tumor-type specificity of histone 3-F3 mutations indicates distinct functions of histone residues, mutations, and genes. Telomeric fusions/association, noncovalent interactions at chromosomal ends (telomeric region), mostly affecting chromosomes 11p, 13p, 14p, 15p, 19q, 20q, and 21p [ , ] have also been reported in giant cell tumor of bone. However, these generally represent polyclonal lesions although clonal alterations may be more prevalent in recurrent giant cell tumors, which possibly indicate that tumor recurrence represents subclonal evolution [ ].

Morphology

The typical giant cell tumor of bone, as with other osteoclast-rich lesions, is dominated by two cell types which include the mononuclear stromal cell that represents an osteogenic progenitor, and the osteoclast-like giant cell containing between five and several hundred nuclei ( Fig. 44.2 ). It was the presence of osteoclast-like cells that led Jaffe and colleagues to describe this tumor as an “osteoclastoma” and considered it to be a neoplasm of osteoclast lineage [ ]. However, it is now accepted that giant cell tumor of bone is a neoplasm of osteoblastic lineage [ , ]. The combination of the osteoprogenitor and the osteoclast suggests a disrupted normal coupling of bone formation and resorption [ ].

The mononuclear cell component varies in number and distribution in giant cell tumors: some areas of tumors are composed of solid sheets of osteoclast-like cells with the mononuclear cell population being difficult to identify, whereas others contain fibroblast-rich areas which can be mitotically active, often arranged in a storiform growth pattern, in which only small numbers of osteoclasts are present ( Fig. 44.3 ). Giant cell tumors containing conspicuous areas of fibroblastic overgrowth are not infrequently related to areas of infarction, and are associated with numerous foamy macrophages, and cyst formation, referred to as secondary aneurysmal bone cyst ( vide infra ). Cyst formation can be so striking that distinguishing giant cell tumor from a primary aneurysmal bone cyst can be troublesome. However, this is now largely resolved by the mutually exclusive presence of the H3-3A in giant cell tumors of bone and the structural alteration involving the fusion of the oncogene USP6 with a number of different partners in approximately 70% of cases of primary aneurysmal bone cyst (discussed in greater detail below) [ , ].

Benign fibrous histiocytoma is also an osteoclast-rich tumor and occurs in the subarticular area. However, it is a diagnosis rarely used today probably because these tumors are diagnosed, a giant cell tumor of bone because of the detection of H3-3A mutation or a nonossifying fibroma because of the detection of a somatic FGFR1 or KRAS or germline NF1 alterations [ ].