Approximately 0.2 % of bone tumors are primary, which is less frequent than metastasis to the bone and less common than soft tissue counterparts (1:10). There are 19 main subtypes of benign bone tumors and 22 subtypes of bone sarcomas. Table 13.2 summarizes the most common and recent cytogenetic and molecular abnormality of bone neoplasms.

Bone tumors are primarily of mesenchymal origin. Tumors of the bone as classified by the World Health Organization may be cartilaginous, osteogenic, fibrogenic, fibrohistiocytic, vascular, myogenic, lipogenic, neural, or notochordal [1]. However, there are instances when bone is involved by tumors of neuroectodermal origin, such as Ewing Sarcoma, or by tumors of undefined histogenesis, such as aneurysmal bone cyst.

Cartilagenous tumors produce a chondroid matrix and may either be benign or malignant in nature. Osteochondroma, a cartilage capped bony projection arising on the external surface of bone containing a marrow cavity continuous with that of the underlying bone, may form as a solitary lesion or multiple lesions as in hereditary multiple osteochondromas (HMO) [1]. Cytogenetic aberrations have been identified in the EXT1 gene located at 8p22-24.1 in sporadic and hereditary osteochondromas. Specifically, germline mutations in the tumor suppressor genes EXT1 located at 8q24 and EXT2 located at 11p11-p12 have been found in HMO [59–61]. Enchondroma is a benign hyaline cartilage tumor of medullary bone commonly involving the hands and feet [1]. By conventional cytogenetic analysis, aberrations involving chromosome 12 have been detected [62, 63]. Chondromyxoid fibroma frequently occurs in the long bones, particularly the tibia. It is a benign tumor composed of lobules of spindle-shaped cells with abundant myxoid or chondroid intercellular material [1]. Structural rearrangements of chromosome 6 have been found to be non-random, specifically involving the long arm (q13 and q25) and short arm (p25) [64–68]. Chondrosarcoma is a malignant tumor of hyaline cartilage differentiation that may contain myxoid changes, calcifications, or areas of ossification [1]. There are several subtypes of chondrosarcoma, including conventional, periosteal, dedifferentiated, mesenchymal, and clear cell. Genetic alterations involving chondrosarcoma are heterogeneous. Comparative genomic hybridization studies have revealed extensive genetic alterations, including gains of whole chromosomes or chromosome arms at 20q, 20p, and 14q23 or partial losses [69]. Loss of genetic material from 13q was found to be an independent predictor of metastasis development, regardless of tumor grade or size [68, 70, 71]. Dedifferentiated chondrosarcoma, a subtype of chondrosarcoma composed of a well-differentiated cartilage tumor juxtaposed to a high-grade non-cartilaginous sarcoma; reportedly possesses frequent structural and numerical alterations of chromosome 1 and 9 [1, 66, 72–75]. Identical somatic deletion in exon 7 of p53 have been identified in the cartilaginous, as well as within the dedifferentiated part [1, 66]. Mesenchymal chondrosarcoma is a rare subtype characterized by a biphasic pattern composed of undifferentiated small round cells and islands of well-differentiated hyaline cartilage [1]. In two cases of mesenchymal chondrosarcoma a Robertsonian (13;21) translocation was observed [76].

Osteogenic tumors produce a bony matrix or what is referred to as ‘osteoid’ and, depending on their behavior, are considered either benign or malignant. However, rarely benign osteogenic tumors undergo malignant transformation [1]. Osteoid osteoma is a benign cortically based bone-forming tumor defined by its small size, limited growth potential (seldom exceeds 1.0 cm), and disproportionate pain. Reportedly, there have been two of three cases of osteoid osteoma in which a loss of the distal part of chromosome arm 17q was detected [77]. Osteosarcoma, a highly malignant bone tumor, commonly arises within the long bones of children; however, about 15 % arise in adults secondary to a pre-existing condition, such as Paget disease [1]. The classical or conventional osteosarcoma may histologically show a variable of features and be subtyped as either osteoblastic, chondroblastic, or fibroblastic. There are other more rare subtypes, including telangiectatic osteosarcoma, small cell osteosarcoma, parosteal osteosarcoma, periosteal osteosarcoma, high-grade surface osteosarcoma, and more. Most osteosarcomas possess complex chromosomal alterations. However, there appear to be certain chromosomal regions that display recurrent amplifications. Amplification at 1q21-23 and 17p, together with co-amplification of 12q13-15, are frequently reported [78–84]. The MDM2 gene is amplified in 14–27 % of osteosarcomas [82, 85, 86]. Amplification of CDK4 gene is found in aggressive lesions [87–89]. Lastly, the MYC gene has been shown to be amplified in 44 % of osteosarcomas (8q24) [90]. Understandably, low-grade variants of osteosarcoma have not been found to harbor complex aberrations. For example, low-grade central osteosarcoma show recurrent gains in minimal common regions at 12q13-14, 12p, and 6p21 [91]. Parosteal osteosarcoma, another low-grade osteosarcoma that arises on the surface of bone, reportedly shows ring chromosomes with co-amplification of SAS, CDK4, and MDM2 genes with a minimal common region at 12q13-15 [92–94]. As stated previously, osteosarcomas may arise secondary to a pre-existing condition (Paget disease) or after radiation therapy. In tumors forming after radiation therapy, chromosomal losses are more often observed than gains [95]; 1p is lost in 57 % of post-radiation osteosarcomas, in contrast to conventional osteosarcomas that demonstrate only a 3 % loss [95, 96]. Osteosarcomas arising secondary to Paget disease of the bone show a frequent loss of heterozygosity at 18q [97]. A unique and rare tumorous lesion with aggressive growth known as bizarre parosteal osteochondromatous proliferation (Nora’s lesion) is an exception to the rule, in that this neoplasm possesses a unique recurrent aberration t(1;17)(q32;q21) not found in most bone-forming tumors [98].

Fibrogenic tumors do not produce a mineralized matrix, but form collagen. Desmoplastic fibroma of the bone is a rare, benign neoplasm composed of spindle cells with minimal atypia and abundant collagen [1]. The histomorphology is identical to fibromatosis of the soft tissue. Like its soft tissue counterpart, a subset of desmoplastic fibromas of the bone show trisomies of 8 and 20 [99].

Ewing’s sarcoma, as previously mentioned above, demonstrates the same aberrations as seen in its soft tissue counterpart.

Giant cell tumor of the bone is a locally aggressive neoplasm. Histology reveals sheets of neoplastic ovoid mononuclear cells interspersed with uniformly distributed large osteoclast-like giant cells [1]. A frequent chromosomal aberration detected in giant cell tumor of the bone is a reduction in the length of telomeres. Most commonly affected telomeres are 11p, 13p, 14p, 15p, 19q, 20q, and 21p [100–105].

Chordoma is a neoplasm that arises from notochordal remnants. It usually occurs in the sacrum or clivus. Typically, chordomas display a lobular growth pattern and contain neoplastic cells with bubbly cytoplasm known as “physaliphorous cells” [1]. In 9 of 16 cases of chordomas, hypodiploidy was identified. Chromosomes 3, 4, 10, and 13 were frequently lost [68, 106]. A tumor suppressor gene is believed to exist on distal 1p due to loss of heterozygosity at band 1p36 [107].

Admantinoma, a malignant biphasic tumor characterized by an epithelial and osteofibrous component, may derive from their osteofibrous dysplasia-like counterparts. Osteofibrous dysplasia and adamantinoma show similar cytogenetic alterations such as trisomies of chromosomes 7, 8, 12, 19, and 21 [108–111].

As described in soft tissue tumors, there are also tumors of undefined histogenesis that occur in the bone. Primary aneurysmal bone cyst, a cystic lesion of bone composed of blood-filled spaces separated by connective tissue septa with fibroblasts, giant cells, and reactive woven bone, has been shown to harbor a recurrent translocation t(16:17) in several cases [1, 112]. However, rearrangements are absent in secondary aneurysmal bone cysts [113]. Over the years, additional translocations have been identified, all of which result in oncogenic activation of the USP6 gene on chromosome 17p13 [114–116]. Fibrous dysplasia, a benign medullary fibro-osseous lesion, may involve one (monostotic) or more bones (polyostotic) [1]. It is characterized by activating mutations in the GNAS1 gene located on chromosome 20q12–q13.3, encoding the alpha subunit of the stimulatory G protein [117].

Benign tumors are generally treated with surgical excision. Malignant tumors (sarcomas) can be treated with combination therapy, including surgery, chemotherapy, targeted therapy, radiation therapy, hormonal therapy, and immunotherapy. Surgery achieves local control and removes tumor burden. Radiation therapy is applicable when the surgical margin is positive or used neoadjuvant to facilitate subsequent resection. Cytotoxic chemotherapy is used for metastatic disease, unresectable tumors, or sensitive histological types. Sensitivity to chemotherapy is variable among sarcomas, and, at this time, histology appears to be the best predictor of response. Chemotherapy-sensitive tumors include Ewing’s sarcoma, rhabdomyosarcoma, myxoid/round cell liposarcoma, synovial sarcoma, uterine leiomyosarcoma, desmoid tumor (fibromatosis), desmoplastic small-round-cell tumor, and angiosarcoma. Resistant histologic types include ASPS, clear cell sarcoma, and extraskeletal myxoid chondrosarcoma. Dedifferentiated liposarcomas, epithelioid sarcomas, and perivascular epithelioid cell tumors are minimally sensitive to cytotoxic chemotherapy, whereas fibrosarcoma, high-grade undifferentiated sarcoma, malignant peripheral nerve sheath tumor, solitary fibrous tumor/hemangiopericytoma, and hemangioendothelioma exhibit intermediate sensitivity to chemotherapy. Although histology may be the best predictor of response, histologic grade is the greatest predictor of recurrence [118]. Unfortunately, there are many more high-grade sarcoma subtypes resistant to anthracycline-based therapies compared to chemotherapy-sensitive subtypes. Furthermore, most clinical trials from the 1970s to present often “lump” multiple histologic subtypes together to increase the total sample size at the expense of diluting the overall effect of the chemotherapeutic agent. Thus, endpoints such as response rate or survival are often modest in benefit, resulting in controversy among many sarcoma specialists. Clearly, there is a need to improve our understanding of the molecular pathology so that the survival of patients afflicted with these rare diseases can be improved.

An excellent example of molecular-based therapy involves GISTs. This rare mesenchymal tumor is postulated to arise from the interstitial cell of Cajal and commonly involves the stomach and small intestine of adults (peak age of 60), with less than 10 % of cases in individuals under age 40 years. They may occur in extra-gastrointestinal sites, including the retroperitoneum, mesentery, and omentum. Ninety percent of GISTs harbor a mutation within the KIT gene and/or PDGFRA gene (80 % and 10 %, respectively) [119]. Recently, V600E BRAF mutation was identified in adult patients with GIST lacking KIT and PDGFRA mutations [120, 121]. GIST mutational analysis is important in the evaluation of patients with GIST tumors to analyze prognosis, to make decisions regarding adjuvant treatment, to predict treatment response, and to select appropriate dosage. Different types of mutations involving different exons result in varying clinical prognosis, histologic appearance, and treatment decisions for patients. Internal tandem repeats involving exon 11 are associated with gastric GISTs and an indolent course, whereas deletions within exon 11 are associated with a shorter survival, higher risk of recurrence, and an aggressive course. Exon 9 mutations are associated with small intestinal GISTs and a clinically aggressive course. PDGFRA missense mutations in exon 18, exon 14, or exon 12 occur in GISTs involving the stomach, which have an epithelioid or mixed epithelioid/spindle cell histology [3, 122, 123]. Historically, treatment of advanced GIST is revolved around surgery, with few effective systemic therapeutic options; however, the introduction of imatinib mesylate (ST1571; Gleevec), a selective tryosine kinase inhibitor that targets KIT and PDGFRA, has changed the course of this disease.

Imatinib is an oral FDA-approved drug for use as an adjuvant therapy following complete gross resection of tumor and in the management of unresectable and metastatic disease. GIST tumors with exon 11 mutations are the most responsive to imatinib therapy and GISTs with exon 9 mutations may benefit from an increase dose (800 mg). Patients with wild-type GIST and wild-type PDGFRA rarely show a favorable or sustained response to treatment. In this situation, other less common gene mutations are likely involved, such as in the succinyl dehydrogenase gene, noted in patients with an inherited form of GIST that is often accompanied by the development of paragangliomas, and pulmonary hamartomas [124]. Other forms of wild-type KIT and wild-type PDGFRA GIST include tumors with activation the Ras pathway in NF1 patients or in tumors with insulin-like growth factor 1 receptor (IGF1R) amplification. Unfortunately, there are cases where patients with exon 9 and PDGFRA mutations have primary resistance to imatinib likely due to the structure of the ATP-binding loop, which results in decreased affinity for the drug [125]. Secondary resistance occurs and generally is due to additional mutations involving exon 11. Sunitinib malate (SU11248; Sutent) is a multi-targeted tyrosine kinase inhibitor that also inhibits vascular endothelial growth factor receptors (VEGFRs). It is used to treat patients with primary or secondary resistance to imatinib. Patients with exon 9 mutations or wild-type genotyping demonstrate a good response, although the overall response rate is noted to be less than 10 % [126]. As with imatinib, sunitinib resistance may evolve and thus represents an area of active investigation. Novel therapeutic strategies that target different aspects of the intracellular signaling pathway involving KIT and PDGFRA are being investigated, and potential options include the following: heat-shock protein (HSP)-90 inhibitor, everolimus, nilotinib, sorafenib, dasatinib, regorafenib, masitinib, PI3-kinase/mTOR dual inhibitors, and PI3-kinase inhibitors [127]. In a phase II efficacy study of sorafenib, partial response (13 %) and stable disease (58 %) were reported in 24 patients with resistance to imatinib or sunitinib. A multicenter phase II study of Masitinib revealed preliminary observations of objective partial response (50 %), stable disease (47 %), and primary refractory (3 %) with overall disease rate of 97 %. Phase III studies are underway comparing nilotinib and masitinib as single agents with imatinib in the first-line setting. The HSP-90 inhibitor inhibits HSP-90, a chaperone protein that aids in protein folding to stabilize KIT from degradation, to prevent stabilization of KIT, and to lead to its degradation [127].