conventional osteosarcoma

Definition: Conventional osteosarcoma is a primary intramedullary high grade malignant tumour in which the neoplastic cells produce osteoid, even if only in small amounts.

Images

 Male 17 y/o Osteosarcoma

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ICD-O codes

 Osteosarcoma, not otherwise specified 9180/3
 Chondroblastic osteosarcoma 9181/3
 Fibroblastic osteosarcoma, osteofibrosarcoma 9182/3
 Central osteosarcoma, conventional central osteosarcoma, medullary osteosarcoma 9180/3
 Intracortical osteosarcoma 9195/3

Sites of involvement

Conventional osteosarcoma shows a profound propensity for involvement of the long bones of the appendicular
skeleton; in particular, the distal femur, proximal tibia, and proximal humerus.

It tends to be a disease of the metaphysis (91%) or diaphysis (@<@9%). Primary involvement of the epiphyses is extraordinarily
rare.

Although the long bones remain the most frequent sites of primary conventional osteosarcoma, the relative incidence in non-long bone (i.e., jaws, pelvis, spine, and skull) involvement tends to increase with age.

Osteosarcoma arising in bones distal to the wrists and ankles is extremely unusual.

Because of unusual clinical factors, imaging features, histological
findings and/or unique treatment problems, tumours arising in certain sites (e.g., jaws, skull, spine, pelvis, intra-cortical, multicentric, and skip metastases).

Macroscopy

Osteosarcoma is often a large (over 5 cm), metaphyseally centered, fleshy or hard tumour which may contain cartilage.

It frequently transgresses the cortex and is associated with a soft tissue mass.

Some osteoblastic osteosarcomas may appear grey-tan and randomly granular (pumice-like), while others become denser, sclerotic and more yellow-white.

Chondroblastic osteosarcomas tend to be white to tan, and variably calcified with a fish-flesh or rope-like cut surface.

Microscopy

As a sarcoma, conventional osteosarcoma is frequently referred to as a "spindlecell" tumour; a reference which over-simplifies its cytological appearance.

It tends to be a highly anaplastic, pleomorphic tumour in which the tumour cells may be:
 epithelioid,
 plasmacytoid,
 fusiform,
 ovoid,
 small round cells,
 clear cells,
 mono- or multinucleated giant cells,
 spindle cells.

Most cases are complex mixtures of two or more of these
cell types.

The diagnosis of osteosarcoma is predicated on the accurate identification of osteoid. Histologically, osteoid is a dense, pink, amorphous intercellular material, which may appear somewhat refractile.

It must be distinguished from other eosinophilic extra-cellular materials
such as fibrin and amyloid. Unequivocal discrimination between osteoid and nonosseous collagen may be difficult, and at times somewhat arbitrary.

Non-osseous collagen tends to be linear, fibrillar, and
compresses between neoplastic cells. In contrast, osteoid is curvilinear with small nubs, arborisation, and, what appears to be abortive, lacunae formation.

The thickness of the osteoid is highly variable with the thinnest referred to as "filigree" osteoid.

Osseous matrix also has a predisposition for appositional deposition
upon previously existing normal bone trabeculae (i.e., "scaffolding").

When neoplastic cells are confined within large amounts of bone matrix, they frequently appear as small, pyknotic, minimally atypical cells, a feature referred to as "normalisaton."

An under-appreciated architectural feature is the tendency for
conventional osteosarcoma to grow in an angiocentric fashion which imparts an overall "basket-weave" or "cording" pattern
to the tumour.

Conventional osteosarcoma can also produce varying amounts of cartilage and/or fibrous tissue. Many investigators further subdivide conventional osteosarcoma in terms of the predominant matrix.

The algorithm is identify the presence or absence of matrix and, if significant matrix is present, determine the matrix form.

This system divides conventional osteosarcoma into three major subtypes:
 osteoblastic osteosarcoma (50%),
 chondroblastic osteosarcoma (25%),
 fibroblastic osteosarcoma (25%).

Classification is a function of the primary tumour. There is a tendency for metastases to mimic the primary, but exceptions are frequent and there is a higher-than-expected incidence of fibroblastic differentiation in metastases.

Microscopical subtypes

 osteoblastic osteosarcoma, conventional
 osteoblastic osteosarcoma, slerosing type
 chondroblastic osteosarcoma ICD-O:9181/3
 fibrobastic osteosarcoma (osteofibrosarcoma) ICD-O:9182/3
 osteosarcoma NOS (not otherwise specified) ICD-O:9180/3
 osteosarcoma resembling osteoblastoma
 chonromyxoid fibroma-like osteosarcoma
 chondroblastoma-like osteosarcoma
 clear-cell osteosarcoma
 malignant fibrous histiocytoma-like osteosarcoma
 giant cell-rich osteosarcoma
 epithelioid osteosarcoma

Other types of osteosarcoma

 central osteosarcoma (conventional central osteosarcoma, medullary osteosarcoma) ICD-O:9180/3
 intracortical osteosarcoma ICD-O:9195/3

Immunochemistry

The absence of reproducible evidence of specific findings minimises the use of both immunohistochemistry and electron microscopy in osteosarcoma.

In both cases their primary utility lies in their ability to exclude other diagnostic possibilities such as metastatic sarcomatoid carcinoma, and synovial sarcoma.

Certain potential pitfalls exist. Osteosarcoma may be immunoreactive for cytokeratin and is frequently immunoreactive with antibodies to smooth muscle actin.

Osteosarcoma usually has diffuse moderate to strong intra-cytoplasmic staining for CD99.

Osteocalcin and osteonectin have sometimes been used to highlight osteoid.

 +/- CD99

Cytogenetics

Most, if not all, osteosarcomas contain clonal chromosomal aberrations. The aberrations are complex, comprising an abundance of numerical and structural alterations. The modal chromosome number is highly variable. Multiple clones are common and may be related or unrelated.

Diploid ploidy pattern by DNA cytofluorometry has been reported to be a poor prognostic sign.

Although no specific translocation or any other diagnostically consequential structural alteration has been assigned to conventional osteosarcoma, involvement of certain chromosomal regions is recurrent.

Chromosomal regions 1p11-13, 1q11-12, 1q21-22, 11p14-15,
14p11-13, 15p11-13, 17p and 19q13 are most frequently affected by structural changes, and the most common imbalances are +1, -6q, -9, -10, -13, and -17.

Homogenously staining regions (hsr) and double minutes (dmin), cytogenetic manifestations of gene amplification, are frequently seen in conventional osteosarcomas.

DNA copy numbers

Comparative genomic hybridization analysis reveals that chromosomal
regions 3q26, 4q12-13, 5p13-14, 7q31- 32, 8q21-23, 12q12-13, 12q14-15, and 17p11-12 are most frequently gained.

Gain of 8q23 is seen in 50% of tumours and seems to be a sign of poor prognosis.

Increased copy number of the MYC gene localized to 8q24 was detected by fluorescence in situ hybridization (FISH) in 44% of cases.

The 17p amplicon is intriguing as it is rarely seen in other tumour types. The most frequent losses are seen at 2q, 6q, 8p, and 10p.

Loss of heterozygosity (LOH)

Chromosome arms 3q, 13q, 17p, and 18q are most frequently involved in LOH.

As the incidence of LOH is high at 3q26.6-26.3, this area has been suggested to harbour a putative suppressor gene.

Molecular genetics

Target genes of recurrent amplifications

Amplifications at 1q21-23 and at 17p are frequent findings in conventional osteo-sarcoma.

Several genes have been reported to be involved in the 1q21-23 amplicon. Similarly, a variety of genes in the 12q13-15 region are co-amplified.

MDM2 and PRIM1 amplifications have been detected in 14-27% and 41% of osteosarcoma cases, respectively.

In aggressive osteosarcomas CDK4 is most consistently amplified, alone or together with MDM2.

The amplification and overexpression patterns of CDK4, SAS, and MDM2 appear to differ from those in parosteal osteosarcoma.

Recently, it was shown by FISH analysis that sequences, including CCND2, ETV6, and KRAS2, at 12p and MDM2 at 12q were differently amplified in low grade osteosarcomas (parosteal osteosarcoma) and high grade osteosarcomas.

Amplifications at 12p were seen in 1/5 low grade osteosarcomas in contrast to 9/19 high grade osteosarcomas.

Gene expression

Overexpression of MET and FOS has been reported in more than 50% of osteosarcoma cases, whereas MYC is overexpressed in less than 15% of cases.

MYC, FOS, and cathepsin L have been shown ,to be overexpressed in a high proportion of relapsed tumours and metastases.

Bone morphogenetic protein-6 and bone morphogenetic protein receptor 2 are expressed in more than 50% of osteosarcomas and the MAGE genes in several cases.

Gene expression profiling

cDNA array analysis of osteosarcoma cell lines and primary tumours showed that HSP90B (heat shock protein 90b) and PABPL1 (binding protein-like 1) were highly overexpressed, whereas FN1 (fibronectin 1) and THBS1 (trombospondin-1) were underexpressed

Genetic susceptibilty

Hereditary retinoblastoma (RB) patients have a high risk of osteosarcoma development. Such tumours are likely to show LOH at 13q and alterations of the RB1 tumour suppressor gene.

According to several studies, the frequency of RB1 alterations in sporadic osteosarcoma has been found to vary between 30-40%.

The prognosis for patients with RB1 alterations seems to be poorer than for patients without RB1 alterations.

Li-Fraumeni syndrome patients with a TP53 germline mutation have an
increased risk to develop a variety of tumours, including osteosarcoma.

In sporadic osteosarcoma LOH at 17p and TP53 mutations are seen in approximately 35% of the tumours.

The eventfree survival rate has been reported to be lower in osteosarcoma patients with TP53 alterations than in those without.

Prognosis

Untreated, conventional osteosarcoma is universally fatal. Aggressive local growth and rapid haematogenous systemic dissemination mark its course.

Although metastases may affect many sites, pulmonary metastases are the most frequent site of clinically significant systemic disease.

Bone is the second most frequent site of metastases, but this is largely a pre-terminal event.

The identification of prognostic factors has been an additive process in which factors have been investigated, identified and incorporated into an overall therapeutic strategy.

Traditionally, age, gender, location, tumour size, stage, and the results of various laboratory tests have been used in
an effort to predict prognosis. However, response to pre-operative therapy is currently the most sensitive indicator of survival.

At the same time, it is recognized that a single system does not apply to all cases.

Unique biological aggressiveness, coupled with an inability to completely resect the tumour at certain sites (e.g., skull, spine) is one example.

There are certain sites (e.g., jaw, pelvis) in which response to therapy does not appear to reflect prognosis despite the capacity for complete surgical tumour removal.

When treated by ablative surgery alone, survival is limited. With the development of effective multi-disciplinary therapy, significant changes have been introduced to the management of osteosarcoma.

The death of 80-90% of osteosarcoma patients with pulmonary metastases, despite the use of immediate ablative surgery and pre-surgical, radiographically normal lungs at the time of diagnosis implies that subclinical pulmonary micro-metastases are present in the vast majority of cases at presentation.

Therefore, osteosarcoma must be viewed as a systemic disease at the time of initial diagnosis.

Contemporary therapy is multi-disciplinary, focusing on both local and systemic manifestations of osteosarcoma through the judicious use of multidisciplinary therapy incorporating surgery and chemotherapy.

The use of such multi-disciplinary therapy has resulted in disease-free
survival of 60-80%, while allowing the use of functional limb-sparing surgery in >80% of patients.

Ultimate survival is directly related to response to pre-operative therapy. In those patients whose tumours have >90% tumour necrosis (i.e., "responders") long-term survival is generally 80-90%. In
those cases, in which tumour necrosis is @<@90% (i.e., "non-responders") and there is no change in post-operative therapy, the survival is extremely poor; usually @<@15%.

It has been demonstrated that, with appropriate changes in post-operative therapy, significant numbers of nonresponders can be salvaged and longterm survival in this group may be greatly improved; in some cases approaching that of responders.

See also

 bone tumors

• osteosarcomas