Osteosarcoma

The eighth edition of the Union for International Cancer Control (UICC) TNM classification of malignant tumors stages osteosarcoma of the appendicular skeleton, trunk, skull, and facial bones on the basis of the greatest tumor dimension (≤ 8 cm: T1; > 8 cm: T2) and discontinuous involvement of the primary bone site (T3). Staging of spinal and pelvic tumors is based on anatomical intraosseous and extraosseous extension and size. The eighth edition of the American Joint Committee on Cancer (AJCC) AJCC cancer staging manual stages osteosarcoma arising in the appendicular, truncal, and craniofacial bones on the basis of the presence or absence of distant metastasis, histological grade, and greatest tumor dimension (≤ 8 cm or > 8 cm). However, dichotomization of tumor size fails to contribute prognostically significant information in this staging system. Tumors of the pelvic or spinal skeleton are now substaged on the basis of the anatomical extent of intraosseous invasion or the presence of extraosseous invasion.

The pathogenesis and cell of origin of COS are unknown. Many potential driver genes in osteosarcoma have been identified; the largest sequencing study to date found 67 different driver genes in a series of 112 COSs. Although these mutations certainly occur early in the course of the disease, it seems likely that chromothripsis/chromoplexy caused by an unknown trigger initiates chromosomal instability and subsequent tumor development.

COS usually presents as a large (> 5–10 cm) intramedullary mass centered in the metaphyseal region with variable extension into the adjacent diaphysis and epiphysis. The cut surface is heterogeneous, depending on the type and degree of mineralization of the predominant matrix. Heavily mineralized tumors are tan-white/yellow and densely solid (resembling cortical bone), whereas non-mineralized cartilaginous components are either grey and rubbery (if hyaline in nature) or mucoid (if the matrix has undergone myxoid degeneration). Areas of hemorrhage, tumor necrosis, and cystic change are common. Intramedullary involvement is often considerable. When extraosseous infiltration occurs, the tumor usually forms an eccentric or circumferential soft tissue mass that displaces the periosteum peripherally. TAEOS shows a hemorrhagic multicystic lesion filled with blood clots, classically described as a bag of blood. Solid fleshy or sclerotic areas are usually not seen. Extensive cortical erosion or destruction associated with nearby soft tissue involvement may be seen. The gross features of SCOS are indistinguishable from those of COS.

COS has a broad histomorphological spectrum. Essential to the diagnosis is the identification of neoplastic bone formation. The tumor grows with a permeative pattern; replacing the marrow space and encasing and eroding pre-existing trabeculae, it fills and expands haversian systems within cortical bone. The neoplastic cells typically demonstrate severe anaplasia and pleomorphism, and they may be fusiform, plasmacytoid, or epithelioid. Neoplastic cells often become small and normalized in appearance (mimicking benign osteocytes) when surrounded by bone matrix. Mitotic activity is usually brisk, and abundant atypical mitotic figures are often present, which are useful in the differential diagnosis of benign mimics of osteosarcoma. No minimum quantity of bone formation is required; any amount is sufficient to render the diagnosis. Characteristically, the bone is intimately associated with the tumor cells; varies in quantity; is woven in architecture; and is deposited as primitive, disorganized trabeculae that may produce fine (filigree) or coarse lace-like patterns, or as broad, large sheets of compact bone formed by coalescing trabeculae.

Bone matrix is eosinophilic on H&E-stained sections if unmineralized and basophilic/purple if mineralized, and it may have a pagetoid appearance imparted by haphazardly deposited cement lines. Distinguishing unmineralized matrix (osteoid) from other eosinophilic extracellular materials such as collagen or compacted fibrin matrices may be difficult and subjective. Collagen tends to be less glassy and more fibrillar, and it is frequently deposited in broad aggregates or elongated fibrils compressed between lesional cells.

COS may have different histological patterns. Currently, however, there is no relationship between histological patterns, treatment, and prognosis. COS commonly contains varying amounts of neoplastic cartilage and/or fibroblastic components; on the basis of the predominant matrix, they are subdivided into osteoblastic (76–80%), chondroblastic (10–13%), and fibroblastic (10%) types. In osteoblastic osteosarcoma, neoplastic bone is the principal matrix and varies from thin, lace-like trabeculae to compact bone. When the latter is pronounced, the tumor is designated as a sclerosing type.
In chondroblastic osteosarcoma, the predominant component is hyaline cartilage with severe cytological atypia, but the chondroid matrix may also appear myxoid with single cells or delicate cords of cells displaying more subtle atypia, particularly in tumors arising in gnathic bones. Neoplastic cartilage usually merges with areas containing neoplastic bone, often with condensation and spindling of tumor cells at the periphery of the chondroid nodules. In the appropriate context, a biopsy containing only high-grade malignant cartilage should strongly raise the suspicion of chondroblastic osteosarcoma, especially in younger patients (in whom chondrosarcoma is much less common) and in the jaws, where chondrosarcoma practically does not occur. In fibroblastic osteosarcoma, the malignant cells are usually spindled and less frequently epithelioid; they often, but not always, demonstrate severe cytological atypia. The tumor cells are associated with extracellular collagen, which can be extensive, and they are often arranged in a storiform pattern. Non-neoplastic, osteoclast-type giant cells scattered throughout the tumor are the hallmark of the giant cell–rich subtype. Some bone sarcomas without associated giant cell tumor of bone histology harbor an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation; these are usually sited in the epiphysis in young people, suggesting a relationship with a giant cell tumor of bone. Therefore, there is a move to expand the definition of primary malignant giant cell tumor of bone on the basis of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation. Large polyhedral tumor cells characterize the epithelioid osteosarcoma subtype. In the osteoblastoma-like subtype, the tumor cells usually show less-pronounced atypia and rim the neoplastic bony trabeculae as typically observed in osteoblastoma. However, the tumor infiltrates and encases pre-existing bone trabeculae as a sign of osteodestructive growth.

In TAEOS, the tumor is composed of blood-filled or empty cystic spaces closely simulating aneurysmal bone cyst. The septa show variable thickness and are populated by pleomorphic cells showing substantial nuclear hyperchromasia. Some malignant cells can be seen floating in the hemorrhagic areas. Atypical mitoses are easily identified. Osteoid formation is usually focal and confluent but may be absent in a biopsy. The septa also contain osteoclast-type giant cells. At the edges of the lesion, tumor permeation into pre-existing bone trabeculae is often observed.

SCOS is composed of small cells with scant cytoplasm, associated with osteoid production. Nuclei are round to oval and the chromatin may be fine to coarse; mitoses can easily be found. In the less frequent spindle cell type, nuclei are short and oval to spindle, with granular chromatin and inconspicuous nucleoli. A focal hemangiopericytoma-like pattern may be seen. Lace-like osteoid production is always present. Particular care must be taken to distinguish osteoid from fibrin deposits that may be seen among Ewing sarcoma cells.

Aggressive local growth and rapid hematogenous systemic dissemination characterize the clinical course of COS. Pulmonary metastases, followed by skeletal deposits (sometimes presenting as skip metastases), are the most frequent sites of systemic disease. High-grade osteosarcoma is therefore usually treated with preoperative and postoperative chemotherapy; local control is achieved via surgical resection with wide margins, often using limb-salvage techniques. Radiation can be used for unresectable tumors. The use of multiagent chemotherapy for COS has had a dramatic impact on outcome. In the pre-chemotherapy era, > 80% of patients treated with surgery alone died of disease, whereas 70% of patients with localized osteosarcoma of the extremities are currently long-term survivors. Unfortunately, patients presenting with metastatic or recurrent disease have a survival rate of < 30%. The histological response to neoadjuvant chemotherapy remains one of the most important prognosticators of overall and disease-free survival. A good response is usually defined as ≥ 90% necrosis. The prognosis of osteosarcoma is also influenced by tumor stage, anatomical location, and adequacy of surgical resection margins. Localized distal disease, > 90% chemotherapy-induced tumor necrosis, and complete resection are positive prognostic factors associated with a 5-year survival rate of > 80%. Predictors of poor outcome include proximal extremity or axial skeleton involvement, large tumor size/volume, detectable metastases at diagnosis, and poor response to preoperative chemotherapy (< 90% tumor necrosis). TAEOS is exquisitely sensitive to chemotherapy, and the overall survival for these patients is similar to that seen with COS. SCOS has a slightly worse prognosis than COS, but no particular histological, imaging, or genetic findings related to prognosis have been identified to date.

No specific diagnostic molecular pathology tests are available for osteosarcoma. However, chromosomal alterations such as chromothripsis and chromoplexy are characteristic of the disease. Inactivation of TP53 is the most common mutation in osteosarcoma, occurring in over 90% of cases. Other recurrent mutations include RB1, ATRX, and NF2. MDM2 amplification is present in about 10% of cases, suggesting a pre-existing central low-grade osteosarcoma that underwent dedifferentiation in at least a subset of cases.

Essential: bone tumor with compatible imaging; bone production by tumor cells; permeative and destructive growth pattern. For telangiectatic osteosarcoma (TAEOS): blood-filled or empty cystic spaces separated by fibrous septa. For small cell osteosarcoma (SCOS): small blue round cell morphology with focal neoplastic bone formation.

Desirable: tumor cells with high-grade atypia; atypical mitotic figures frequently present.