Definition
Osteosarcoma of the skeleton is defined as a primary mesenchymal malignancy of bone in which the neoplastic cells synthesize and secrete the organic components of bone matrix, which may or may not be mineralized. There is no minimal amount of bone matrix required to classify the tumor as osteosarcoma, therefore, the presence of any neoplastic bone, even if only microscopic in amounts, justifies categorizing the tumor as osteosarcoma.

Classification (Table1) The classification of osteosarcoma is based on a variety of characteristics including its histologic features, biologic potential (grade), relationship to bone of origin (surface or intramedullary), multiplicity (solitary and multifocal) and the pre-existing state of underlying bone (primary or secondary) [1, 2, 3, 4, 5] . The vast majority of osteosarcomas can be categorized into three important groups: 1) conventional osteosarcoma and its histologic subtypes, 2) intramedullary well-differentiated osteosarcoma, and 3) surface osteosarcomas. Conventional osteosarcoma, namely garden-variety osteosarcoma, is solitary, arises in the medullary cavity of an otherwise normal bone, is high-grade and produces neoplastic bone with or without cartilaginous or fibroblastic components. Approximately 75%-80% of osteosarcomas are the conventional type, 5-10% are juxtacortical in origin, 10% are secondary and arise in a diseased bone, and 1% are intramedullary and well-differentiated.

Table 1: Classification of Osteosarcoma

Histologic features osteoblastic chondroblastic fibroblastic telangiectatic small cell giant cell rich epithelioid Biologic potential low grade intermediate grade high grade Relationship to bone of origin intramedullary juxtacortical or surface parosteal, periosteal, high grade surface intracortical Multiplicity solitary multifocal synchronous metachronous State of underlying bone primary (bone normal) secondary (bone abnormal) radiation, Paget's disease, infarction, osteomyelitis, prosthesis, pre-existing benign neoplasm

Grading
Grading osteosarcoma is subjective and reflects the pathologists' assessment of the biologic potential of the tumor [3]. It is founded on the relationship between clinical behavior and morphology, the latter, which rests on the evaluation of histologic features, such as degree of cellularity, cytologic atypia, mitotic atypia, and necrosis.

Unfortunately, there is no standardized, uniform, grading system that incorporates qualitative and quantitative features, which has been analyzed in a peer review fashion, as exists for soft tissue sarcomas. Presently, grading schemes use two, three, and four tiered systems that separate tumors into biologically indolent and aggressive neoplasms. The two-tiered format divides the tumors into those that are low- and high-grade. The three-tiered system categorizes the tumors into low-grade (grade1/3), intermediate-grade (grade2/3) and high-grade (grade 3/3). The four-tiered system was structured according to Broders's scheme of grading malignancies and groups the tumors into low-grade (grades 1/4 and 2/4], intermediate-grade (grade 3/4) and high-grade (grade 4/4) [3]. Generally, the intermediate and high-grade tumors are viewed as biologically aggressive and associated with a high risk of local recurrence and metastasis and are treated in an identical fashion.

Epidemiology
Osteosarcoma has been recognized for almost two centuries and is the most common primary non-hematopoietic malignancy of the skeletal system. It accounts for approximately 20% of all primary malignant bone tumors and its incidence rate in the United States is 4-5 per million individuals with 1,000-1,500 new cases diagnosed annually [1]. Osteosarcoma has a bimodal age distribution and a propensity to develop in adolescents and young adults with 60% of tumors occurring in patients younger than 25 years and only 13-30% in persons older than 40 years [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48] . Males are affected more frequently than females at a ratio of 1.3-1.6:1 and the tumor is equally distributed amongst the races. Osteosarcoma can arise in any bone of the body, but the vast majority originates in the long bones of the appendicular skeleton, especially the distal femur, followed by the proximal tibia and proximal humerus – sites containing the most proliferative growth plates. In the long bones the tumor is most frequently centered in the metaphysis (90%), infrequently in the diaphysis (9%), and rarely in the epiphysis (WHO).

Surface osteosarcomas account for only approximately 5-10% (parosteal 3-5%, periosteal 2-4% and high grade surface 1%) of all osteosarcomas [26, 27, 28, 29, 30, 31, 32, 33] . Juxtacortical well-differentiated osteosarcoma (parosteal osteosarcoma) usually arises during the 3^rd decade of life, whereas, juxtacortical intermediate-grade chondroblastic osteosarcoma (periosteal osteosarcoma) and high-grade osteoblastic osteosarcoma (high grade surface osteosarcoma) commonly develop in the second decade. Parosteal and periosteal osteosarcomas have a predilection for females, whereas, high-grade surface osteosarcoma more frequently affect males. Parosteal osteosarcoma typically is based on the posterior femoral cortex in the metaphyseal-diaphyseal area of the popliteal region followed by the metaphyseal-diaphyseal zone of the proximal tibia; periosteal osteosarcoma originates from the cortex of the diaphysis or metaphysis of the tibia, followed in frequency by the femur and high-grade surface osteosarcoma arises on the metaphyseal surface of long bones in a distribution similar to conventional osteosarcoma and especially involves the distal femur and proximal humerus.

Intramedullary well-differentiated osteosarcoma is very uncommon and represents only 1% of all osteosarcomas. Most develop during the 2^nd-5^th decades of life and almost 50% of affected individuals are in their twenties at the time of diagnosis [34, 35, 36, 37] .

Etiology
The etiology of osteosarcoma is unknown, however, a variety of agents and disease states are associated with its development

The best-known etiologic association with osteosarcoma is radiation and its causal relationship was first documented in the radium dial painters. The painters, who were mostly woman, put the tips of their bushes in their mouths to facilitate placing a fine point of radium on the watch dials [9]. Since that time, numerous studies have evaluated the minimum dosage, the accumulated dosage, and the rate of delivery of the dosage of radiation necessary to induce an osteosarcoma [8, 10] . Radiation induced osteosarcoma following therapeutic irradiation is an uncommon complication and usually develops after a lag period of approximately 15 (range 3-55) years following an average dosage of radiation of 6100 cGY [11, 12] .

Osteosarcoma is associated with genetic syndromes including the Rothmund-Thomson syndrome (mutation of chromosome 8q24.3 encoding a DNA helicase), Bloom syndrome (mutation of chromosome 15q26.1 encoding a DNA helicase), Werner syndrome (mutation of chromosome 8p11 encoding a DNA helicase), Li-Fraumani syndrome (mutation of chromosome 17p13 encoding p53, a tumor suppressor), and bilateral retinoblastoma gene (mutation of chromosome 13q14 encoding a transcription regulator). Information derived from these relationships has provided insight into the molecular pathogenesis of sporadic osteosarcoma, which appears to result from a complex accrual of a variety of genetic alterations usually involving the inactivation of tumor suppressor genes and the over-expression of oncogenes (see Table 2) [8].

Table 2: Molecular genetic alterations implicated in the development of sporadic osteosarcoma.

Tumor suppressor genes	Oncogenes
RB1 Tp53 p16 CDk4 cyclin D1 MDM2 p14	c-MYC FOS ERBB2 MET/HGF

Cytogenetic abnormalities are found in approximately 70% of osteosarcomas and are frequently complex [8]. Unfortunately, they have proven to be of little importance in diagnosing, predicting prognosis, and understanding their molecular pathogenesis [7]. Aneuploidy is common in osteosarcoma with DNA content ranging from near haploid to near hexaploid. Some of the more frequent numeric chromosomal abnormalities involve gain of chromosome 1, and loss of chromosome 6,9,10,13,and 17 and some of the more recurring structural rearrangements are found in regions of chromosome 1p11-13, 1q11-12, 1q21-22, 11p14-15, 14p11-13, 15p1-13, 17p and 19q13 [7, 15, 16] . Comparative genomic hybridization studies have shown DNA sequence copy number changes involving 1q21, 3q26, 6p, 8q, 12q12-q13, 14q24-qter, 17p11.2-p12, and 19q12-q13 [6, 7] . Amplification of genes in the form of ring chromosomes, double minutes and homogeneously staining regions are commonplace in osteosarcoma. However, tumors with chromosomal abnormalities limited mainly to ring chromosomes are almost always parosteal osteosarcomas (low grade surface osteosarcomas] and the ring chromosomes are composed of amplified regions of 12q13-15 [17]. Similar ring chromosomes, as well as, abnormalities in chromosome 6p are present in low-grade intramedullary osteosarcomas [15].

In some populations, Paget's disease of the skeleton occurs in approximately 3-5% of adults older than 40 years. Estimates reveal that 1% of these affected individuals eventually develop osteosarcoma in an involved bone, which reflects a several thousand-fold increase in the risk of developing osteosarcoma in comparison to the general population [18]. Genetic predisposition to the development of Paget's disease, including its familiar form, is linked to a region on chromosome 18q [19]. Loss of heterozygosity in this locus is present in both sporadic and pagetic high-grade osteosarcomas suggesting that this chromosomal region harbors a tumor suppressor gene important in the genesis of both diseases.

Osteosarcoma may also arise in areas of previous bone infarction, chronic osteomyelitis, pre-existing primary benign bone tumors (osteochondroma, enchondroma, fibrous dysplasia, giant cell tumor, osteoblastoma, aneurysmal bone cyst and unicameral bone cyst), foci of chronic osteomyelitis, and adjacent to metallic implants. As a group, these secondary osteosarcomas account for only a very small percentage of osteosarcomas and their pathogenesis is likely related to the associated underlying disease states.

Clinical Presentation
Conventional osteosarcoma typically manifests as a progressively enlarging, painful mass. The pain is deep seated and boring in nature and is frequently noted months prior to diagnosis, gradually increasing in intensity and eventually producing unremitting discomfort. The overlying skin may be warm, erythematous, edematous, and cartographed by prominent engorged veins. Large tumors may restrict range of motion, decrease musculoskeletal function, produce joint effusions and in far advanced cases; result in weight loss and cachexia. In 5-10% of cases the heralding event is a sudden, devastating, pathologic fracture through the destructive mass.

The surface osteosarcomas may or may not be associated with pain, but usually present as an enlarging, fixed mass. The low-grade variants are slow growing, may be painless and are frequently of long duration.

Well-differentiated intramedullary osteosarcomas frequently cause pain that persists for months to years prior to diagnosis. In some instances, the tumor may be first detected as an enlarging palpable mass and we have seen cases in which the neoplasm is discovered incidentally.

Laboratory studies are usually not helpful in assessing osteosarcoma; however, in many cases the serum alkaline phosphatase level is elevated. Higher levels are associated with the presence of metastatic disease [20].

Radiographic Manifestations
The radiographic appearance of osteosarcoma is extremely variable; conventional tumors typically present as a large, destructive, poorly defined, mixed lytic and blastic mass that transgresses the cortex and forms a large soft tissue mass. In some cases the tumor is entirely lytic, while in others it is diffusely mineralized producing a densely sclerotic mass. The periphery of the lesion is usually the least mineralized and soft tissue components may have a fine "cloud-like" pattern of radiodensity. Osteosarcoma is frequently situated eccentrically within the medullary cavity and its largest dimension parallels the long axis of the underlying bone. As the enlarging mass destroys and permeates the cortex it mechanically elevates the periosteum, which produces reactive bone in the form of Codman's triangle at the proximal and distal extent of the tumor and sunburst or onion skin-like patterns along the bulk of its length. Conventional osteosarcoma is heterogeneous on CT and MRI and these modalities provide valuable information regarding the overall dimensions of the tumor, its extent within the medullary cavity and soft tissue, and its relationship to important neighboring anatomic structures. This information is vital to planning successful limb salvage surgical resection.

Surface osteosarcomas have a broad base of attachment to the underlying cortex. Parosteal tumors may be circumferential; mushroom shaped, are usually densely mineralized, but, may have radiolucent areas and have a lobulated contour with little or no periosteal reaction. A radiolucent line separating the base of the tumor from the adjacent cortex is sometimes present [26, 27, 28] . Periosteal osteosarcomas are fusiform, predominately lucent and are frequently associated with a periosteal reaction in the form of Codman's triangle and perpendicular linear striae that radiate from the underlying bone [26, 29, 30, 31] . High-grade surface osteosarcoma is similar in appearance to periosteal osteosarcoma, but, in addition, tends to have fine cloud-like areas of radiopaucity [32, 33] . CT is helpful in assessing invasion of the cortex and medullary canal and MRI facilitates the identification of cartilage, which in parosteal osteosarcoma may be in the form a peripheral cap and in periosteal and high-grade surface tumors is scattered throughout the mass.

Intramedullary well-differentiated osteosarcomas have heterogeneous radiographic findings, which usually include lytic and densely mineralized regions. The tumors have poorly demarcated margins, may cause expansion of the underlying bone with little periosteal reaction and if present, a soft tissue mass that is relatively small compared to the extent of intramedullary involvement [34, 35, 36, 37] .

Pathological Findings

Gross Morphology
Conventional osteosarcoma presents grossly as a large, metaphyseal, intramedullary, tan-gray-white, gritty mass. Tumor containing abundant mineralized bone is tan-white and hard, whereas, non-mineralized cartilaginous components are glistening, gray and may be mucinous if the matrix is myxoid or more rubbery if hyaline in nature. Areas of hemorrhage and cystic change are commonplace and when extensive produces a friable, bloody, and spongy mass. Intramedullary involvement is often considerable and in the central section tumor usually destroys the overlying cortex and forms an eccentric or circumferential soft tissue component that displaces the periosteum peripherally. The dislodged periosteum becomes a sharp interface between the mass and the bordering skeletal muscle and fat, and proximally and distally, where it is first lifted from the cortex, deposits a layer of reactive bone (Codman's triangle). Growth into the joint space, which in some cases may be associated with tumor coating peripheral portions of the articular cartilage, follows pathways offering least resistance to spread, namely beneath the synovium via extension along the cortical surface or through tendoligamentous and joint capsule insertion sites. Open growth plates often function as effective barriers to advancing tumor, however, penetration of the physis and invasion into the epiphysis to the base of the articular surface occurs in some cases. Skip metastases, solitary or multiple, appear as intramedullary, firm, ovoid, tan-white nodules located adjacent to, or far distances, from the main mass.

Surface osteosarcomas are broad based, rigidly attached to the underlying cortex and are usually well demarcated from the neighboring soft tissues. Well-differentiated juxtacortical tumors (parosteal osteosarcoma) are solid, tan-white, hard and gritty and may have a gray firm glistening hyaline cartilage cap or areas that are softer and fish flesh-like representing fibrosarcomatous elements. High-grade juxtacortical osteosarcomas (periosteal and high-grade surface) grossly may be dominated by cartilaginous tissue or be composed of hard tan-white areas admixed with fish flesh-like regions. Destruction of the underlying cortex and invasion into the medullary canal is absent, more often than not, but, when present, is usually only focal. If extensive, it is difficult, if not impossible, to distinguish an intramedullary tumor with an eccentric soft tissue component from a surface neoplasm with extensive invasion of the medullary canal.

Intramedullary well-differentiated y osteosarcoma is typically centered in the medullary cavity of the metaphysis or metaphyseal-diaphyseal region. The tumor is hard, gritty and tan-white and has poorly defined margins. Cortical destruction and an associated soft tissue mass may be present.

Microscopic Morphology
Microscopically, high-grade osteosarcoma grows with a permeative pattern, replacing the marrow space, surrounding and eroding pre-existing bony trabeculae and filling and expanding haversian systems. The conventional type has been subclassified into osteoblastic, chondroblastic, fibroblastic and mixed types, depending on the predominance of the neoplastic component. In osteoblastic foci the malignant cells have an osteoblastic phenotype and are large, pleomorphic and polyhedral or spindle shaped. The nuclei are hyperchromatic, central or eccentric in position, and may contain prominent nucleoli and the cytoplasm is eosinophilic with its volume correlating with cell size. The tumor cells are intimately related to the surface of the neoplastic bone and as they become surrounded and imprisoned by the matrix, the cells are smaller and appear less atypical. The neoplastic bone is woven in architecture, varies in quantity and is deposited as primitive, disorganized trabecula that produces a coarse lace-like pattern, in its delicate form or broad, large sheets fashioned by coalescing trabecula, in its most crude design. Depending on its state of mineralization the bone is eosinophilic or basophilic and may have a pagetoid appearance caused by haphazardly deposited cement lines. Neoplastic cartilage, when present, is usually hyaline, but in a minority of cases, especially in tumors arising in jawbones, it is predominately myxoid. The malignant chondrocytes usually demonstrate severe cytologic atypia and reside in lacunar spaces in hyaline matrix or float singly or in cords in myxoid matrix. Fibroblastic foci manifest as cytologically malignant spindle cells arranged in a herringbone of storiform pattern. The degree of atypia is variable, but is frequently severe. Mitoses are numerous and structurally abnormal forms are common.

High-grade osteosarcoma containing numerous blood-filled cystic spaces that comprise the majority of the tumor fulfills the criteria for the telangiectatic variant [38, 39, 40] . The cyst walls contain, and are lined by, malignant cells that produce variable amounts of neoplastic matrix. In small cell osteosarcoma the neoplastic cells are uniform, small, round, or spindle shaped and contain little cytoplasm [41, 42, 43, 44] . Non-neoplastic osteoclast-type giant cells scattered throughout the tumor are the hallmark of the giant cell rich variant and large polyhedral tumor cells characterize the epithelioid variant [45, 46, 47] . In the osteoblastoma-like variant the tumor cells may be deceptively banal and rim the neoplastic bony trabeculae in a fashion that mimics osteoblastoma. Features that permit their distinction are the permeative growth pattern and solid cellular intertrabecular tissue that are found in osteosarcoma, and not in osteoblastoma [49, 50] .

The hallmark of parosteal osteosarcoma is relatively well-formed trabeculae of woven bone, surrounded by a mildly to moderately cellular spindle cell proliferation that is enmeshed in a collagenous stroma. The spindle cells have elongate nuclei with pointed ends and demonstrate varying degrees of cytologic atypia. In the deceptively banal appearing cases the cell nuclei have finely stippled chromatin, small nucleoli, poorly defined eosinophilic cytoplasm and few mitoses, thereby resembling fibromatosis. In higher-grade tumors, the nuclei have coarsened chromatin and demonstrate a greater degree of mitotic activity. Additionally, it is not uncommon for the tumor cells in higher-grade neoplasms to be arranged in a herringbone pattern. Malignant cartilage is sometimes a component of parosteal osteosarcoma, and when present has a hyaline matrix, contains mildly to moderately atypical chondrocytes, and grows as a cap covering the periphery of the tumor. This latter configuration can cause confusion with osteochondroma. Rarely, parosteal osteosarcoma contains foci of pleomorphic spindle cell sarcoma or even high-grade osteosarcoma; the term dedifferentiated parosteal osteosarcoma represents tumors with this composition [51, 52, 53] .

Periosteal osteosarcoma can be viewed as a grade 2/3 chondroblastic osteosarcoma. Therefore, lobules of neoplastic cartilage that is frequently hyaline predominates and the chondrocytes show moderate to severe cytologic atypia, as well as, mitotic activity. The neoplastic bone, which qualifies the tumor as an osteosarcoma, usually has a coarse lace-like pattern and either merges with, or is surrounded by, the cartilage or arises in the background of significantly atypical proliferating spindle or polyhedral shaped tumor cells.

High-grade surface osteosarcoma is essentially a high-grade osteoblastic osteosarcoma that arises on the external surface of the cortex. The tumors cells show pronounced cytologic atypia, mitotic activity and areas of necrosis are commonplace. As in all high-grade osteosarcomas, neoplastic cartilage and fibroblastic components may be present.

Intramedullary well-differentiated osteosarcoma, like its juxtacortical variant, is composed of mild to moderately cellular cytologically bland spindle cell component that is intimately associated with long trabeculae, or round islands of woven bone, which may have a pagetoid appearance. Unlike fibrous dysplasia, which it may resemble, the tumor grows with an infiltrative pattern, replacing the marrow space and surrounding pre-existing bony trabeculae that may serve as scaffolding for the deposition of tumor bone.

Treatment
The treatment of osteosarcoma is tailored to the age of the patient and the location, size, grade, and stage of the tumor. The goal of therapy is eradication of the primary tumor and the elimination of any metastases [54]. Local therapy is usually limb salvage wide surgical resection for appendicular tumors and surgical excision in combination with radiation for tumors that are not resectable in their entirety with negative margins, which is usually the case for neoplasms involving the axial skeleton. Adjuvant chemotherapy (methotrexate, cisplatin, doxorubicin, ifosfamide) is usually employed in the preoperative setting for all high-grade (grade 2/3, 3/3, 3/4 and 4/4) intramedullary and surface osteosarcomas and continues after the surgical resection has been completed and wound healing has begun [55]. The integration of aggressive polychemotherapy into treatment protocols for high-grade osteosarcomas has had a dramatic impact on an otherwise fatal disease [56]. Intramedullary well-differentiated osteosarcoma and parosteal osteosarcoma are usually treated by surgery alone as they are associated with a low risk of dissemination.

Prognosis
The prognosis of patients with osteosarcoma is dependent upon a number of factors. Variables shown in some studies to have prognostic impact include patient age, gender, tumor size, location, stage and response to chemotherapy, multidrug resistance status, loss of heterozygosity of the RB gene and HER2/erbB-2 expression [56]. Of all patients with osteosarcoma who die of disease, approximately 90% result form unrelenting disease progression and the remainder succumb to treatment related complications (cardiomyopathy and pancytopenia) and the development of secondary malignancies [56]. Important independent prognostic factors portending a poor outcome include proximal location in an extremity or in the axial skeleton, large tumor size, clinically detectable metastases at the time of initial diagnosis, and poor response of the tumor to preoperative chemotherapy [56]. The histologic response of the tumor to preoperative chemotherapy (good response is 90% or greater necrosis, poor response is less than 90% necrosis) is felt to be one of the most important prognostic features for localized high-grade osteosarcoma of the extremities, which accounts for the vast majority of the tumors. The histologic assessment of tumor necrosis requires extensive sampling and evaluation of the treated neoplasm [24, 57, 58] .

Relapse free survival rates for patients with localized conventional high-grade osteosarcoma of the extremity has been reported to vary from 50-80% [56]. Actuarial 10 year survival rates for patients with axial tumors is approximately 30%, for patients presenting with metastatic disease 27%, for patients with large tumors (greater than one-third length of involved bone) 53%, for patients with tumors with a poor response 47%, and for patients with tumors with a good response 73% [56]. Of conventional osteosarcoma subtypes, the chondroblastic variant has been shown to be associated with a poor preoperative chemotherapy response and in some studies has a worse prognosis than other variants [55, 59] . Paget's osteosarcoma has a dismal prognosis with the survival rate being approximately 10% at best and 30-35% for patients with radiation induced tumors [13, 48, 60] .

Parosteal osteosarcoma has an excellent prognosis with survival rates ranging from 91-100% [27, 61] . Periosteal osteosarcoma has a survival rate of approximately 75% although recent a recent study utilizing chemotherapy achieved a 10 year metastasis survival rate of 100% and high-grade surface osteosarcoma has a prognosis similar to conventional intramedullary osteosarcoma [28, 29, 30, 31, 32, 33, 62] .

Intramedullary well-differentiated osteosarcoma is an indolent tumor and is associated with a metastatic rate of approximately 15% [34, 35, 36, 37] . Many of the metastases originate from tumors that have undergone dedifferentiation.

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