Osteosarcoma Workup

Most of the laboratory studies that are obtained relate to the use of chemotherapy. It is important to assess organ function before administering chemotherapy and to monitor function after chemotherapy. Important laboratory studies include the following:

• Lactic dehydrogenase (LDH)
• Alkaline phosphatase (ALP)
• Complete blood count (CBC), including differential
• Platelet count
• Liver function tests - Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and albumin
• Electrolyte levels - Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus
• Renal function tests - Blood urea nitrogen (BUN), creatinine
• Urinalysis

The only blood tests with prognostic significance are LDH and ALP. Patients with an elevated ALP at diagnosis are more likely to have pulmonary metastases. In patients without metastases, those with an elevated LDH are less likely to do well than are those with a normal LDH.

Plain radiography

Plain radiography in primary, posteroanterior (PA), and lateral chest views is helpful (see the image below). Plain films of the suspected lesions should be obtained in two views. No single feature on a radiograph is diagnostic. Osteosarcoma lesions can be purely osteolytic (~30% of cases), purely osteoblastic (~45% of cases), or a mixture of both.

Radiographic appearance (plain radiograph) of a proximal humeral osteosarcoma (same patient as previous image). Note the radiodense matrix of the intramedullary portion of the lesion, as well as the soft-tissue extension and aggressive periosteal reaction.

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Elevation of the periosteum may appear as the characteristic Codman triangle. Codman described this entity in 1909, stating, "In many cases near the junction of the healthy bone with the tumor, there is a reactive new bone formation beneath the periosteum. At the edge of the tumor, this layer of new bone ends abruptly and gives a characteristic appearance in the skiagraph [radiograph]." ^[22]

Extension of the tumor through the periosteum may result in a so-called sunburst appearance (~60% of cases). An image of the entire bone and the adjacent joint should be obtained to assess for skip lesions or joint involvement. Telangiectatic osteosarcomas are often very cystic and can be mistaken for an aneurysmal bone cyst.

Bone scanning

Radionuclide bone scanning with technetium-99 (^99mTc)-methylene diphosphonate (MDP/MDI) is important in evaluating for the presence of metastatic or multifocal disease (see the images below). After the bone scan, an image of abnormal areas should be obtained with computed tomography (CT) or magnetic resonance imaging (MRI).

Intense radionuclide uptake of the proximal humerus is noted on a bone scan (same patient as previous 2 images).

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A comparison bone scan of the involved shoulder (right image) with the uninvolved shoulder (left image) (same patient as previous 3 images).

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Computed tomography

A CT scan of the primary lesion and a CT scan of the chest (high resolution) should be obtained. CT of the primary lesion helps delineate the location and extent of the tumor and is critical for surgical planning.

CT of the chest is more sensitive than plain film radiography is for assessing pulmonary metastases. Ideally, the chest CT scan of the chest should be obtained before a biopsy is performed so as to avoid the ambiguity that can arise from postanesthesia atelectasis.

Magnetic resonance imaging

MRI of the primary lesion is the best method of assessing the extent of intramedullary disease, as well as associated soft-tissue masses and skip lesions (see the image below). This imaging modality is perhaps the single most important study for accurate surgical staging of the lesion with use of the Enneking staging system. The MRI should be of the entire bone (compartment).

Magnetic resonance image appearance (T1-weighted image) of osteosarcoma of the proximal humerus (same patient as previous 4 images). Note the dramatic tumor extension into the adjacent soft-tissue regions.

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In a meta-analysis of six studies including a total of 66 patients, Kupo et al found that percent slope analysis of dynamic MRI was useful for preoperative evaluation of the response of osteosarcoma patients to neoadjuvant chemotherapy. ^[23]

Other modalities

Echocardiography or multiple gated acquisition (MUGA) scanning may be useful. Cardiac function should be assessed before and at various intervals after treatment with doxorubicin hydrochloride.

Audiography may be considered. Hearing loss is an adverse effect of cisplatin. It typically occurs during treatment; once treatment is completed, obtaining audiograms is not typically a part of long-term follow-up care.

Two elements are important to the histologic examination of the tumor. The first, tumor type, can be assessed on the biopsy. The second, response to treatment, can be assessed on the definitive resection following chemotherapy.

In general, the characteristic feature of osteosarcoma is the presence of osteoid in the lesion, even at sites distant from bone (eg, lung). Although osteoid formation is usually obvious, electron microscopy occasionally may be required to reveal this process. Stromal cells may be spindle-shaped and atypical, with irregularly shaped nuclei.

A number of different histologic types of osteosarcoma exist, as follows:

• The conventional type is the most common in childhood and adolescence and has been subdivided according to the predominant features of the cells (osteoblastic, chondroblastic, or fibroblastic), though the subtypes are clinically indistinguishable
• The telangiectatic type contains large, blood-filled spaces and is commonly seen in adolescence and early adulthood
• The parosteal type usually arises from the bone cortex, is commonly a low grade tumor, and can be seen in childhood or adulthood; it most commonly arises on the distal posterior aspect of the femur
• The periosteal type is a low- to intermediate-grade tumor that typically arises immediately below the periosteum in children; it most frequently involves the tibia and is more common in adults.

The purpose of staging tumors is to stratify risk groups. The conventional staging used for other solid tumors is not appropriate for skeletal tumors, because these tumors rarely involve lymph nodes or regional spread.

Instead, the staging system introduced by Enneking in 1980 is based on histologic grade (low vs high), anatomic location (intracompartmental vs extracompartmental), and presence or absence of metastases. ^{[24, 25]} This system (also referred to as the staging system of the Musculoskeletal Tumor Society [MSTS]) applies to all musculoskeletal tumors (both bone and soft tissue). It has been credited with bringing order to the surgical treatment of a group of tumors for which treatment was previously approached rather haphazardly.

The Enneking staging system is typically outlined as follows:

• Low-grade tumor, intracompartmental – IA
• Low-grade tumor, extracompartmental – IB
• High-grade tumor, intracompartmental – IIA
• High-grade tumor, extracompartmental – IIB
• Any tumor (low- or high-grade, intra- or extracompartmental) with evidence of metastasis – III

The definition of a compartment is a central and crucial concept in this staging system. In general, a compartment may be defined as any individual bone (ie, each bone is a compartment unto itself), intra-articular space (ie, a purely intra-articular lesion is intracompartmental), or clearly identified fascially enclosed space (eg, the anterior compartment of the lower leg). Many of these compartments are the same ones that a surgeon would release in the setting of compartment syndrome; these relate much more to soft-tissue tumors than to bone tumors.

The Enneking staging system considers some areas of the body to be extracompartmental by definition, including the antecubital fossa, the inguinal region, the popliteal space, and intrapelvic and paraspinal lesions. Because of the unique challenges of spinal tumors, Weinstein, Boriani, and Biagin proposed an entirely separate staging system for these areas, commonly referred to as the WBB staging system.

First introduced in 1996, the WBB system focuses on the general anatomic location about the spine (conceptualizing a spinal segment as if it were the face of a clock), as well as the specific anatomic location about the spine (eg, extraosseous soft-tissue extension into muscular areas vs intradural extraosseous extension). ^{[26, 27]} Just as spinal anatomy is complex, the WBB staging system is complex, but its use is slowly increasing.

In osteosarcoma, the foremost initial question for staging is whether the tumor has metastasized. Other tumor features, though not technically used in staging, may impact the prognosis. These include the following:

• LDH and ALP measurements
• Site of primary tumor (mostly related to ease of complete resection)
• Histologic response to chemotherapy
• Cause of the disease (patients with osteosarcomas arising from Paget disease have a particularly poor prognosis)

Patients with isolated jaw lesions tend to do better and have a lower incidence of metastases.

Different primary tumor sites are associated with differing prognoses, as follows:

• Distal extremity – Best
• Distal femur – Intermediate
• Axial skeleton – Worst

In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who underwent surgery and chemotherapy were reviewed. ^[28] The authors found that the initial tumor size appears to be associated with histologic response and is an important prognostic factor in osteosarcoma.

Patients with tumors that have a good histologic response (the definition of which is still under debate) to preoperative chemotherapy appear to have a better prognosis, though this still is under investigation.

The National Comprehensive Cancer Network (NCCN) ^[29]  follows both the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) and the Surgical Staging System from the Musculoskeletal Tumor Society (MTS) for staging. The European Society for Medical Oncology (ESMO), the European Reference Network for Paediatric Cancers (PaedCan), and the European Network for Rare Adult Solid Cancer (EURACAN) ^[30]  do not provide a specific recommendation for which system should be followed.