Osteogenic Sarcoma (Osteosarcoma)

by Mej Amm M. Batoon Medical Intern/Clerk

Osteosarcoma is the followed by chondrosarcoma and Ewing sarcoma. This disease is thought to arise from primitive mesenchymal bone-forming cells, and its histologic hallmark is the production of malignant osteoid. is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of the bone tissue. ,

 Osteosarcoma is a deadly form of musculoskeletal cancer that most commonly causes patients to die from pulmonary metastatic disease disease. Most osteosarcomas arise as solitary lesions within the fastest growing areas of the long bones of children. However, multiple sites may become apparent within a period of about 6 months ( ), or multiple sites may be noted over a period longer than 6 months ( ). Such multifocal osteosarcoma is decidedly rare, but when it occurs, it tends to be in patients younger than 10 years.

OSTEOGENIC SARCOMA

Most common primary bone malignancy. Accounts for almost 45% of all bone sarcomas 60-75% occur in children and adolescents Very rare in young children aged <5yo Incidence increases steadily with age Increases dramatically in adolescents corresponding with the growth spurt

 Has a

first peak during adolescence (10-14year-old age group, coinciding with the pubertal growth spurt) second peak in older adulthood (adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Paget's disease, bone infarcts and prior irradiation)

 Slightly higher in males than in females (1.5-2 times in males than in females) incidence is slightly higher in blacks than in whites

 Commonly occurs in long bones of extremities near metaphyseal growth plates Most common sites:

(42%,with 75% in the distal femur) (19%, with 80% in the proximal tibia) (10%, with 90% in the proxumal humerus) Other likely conditions are the skull or jaw (8%) and the pelvis (8%) Any bone may be involved

 Exact cause is unknown Usually associated with:

Rapid bone growth Radiation exposure Genetic predisposition:

Retinoblastoma germ-line mutations in the RB gene (up to 1000x risk) Li-Fraumeni syndrome germ-line p53 mutation Paget disease and other bone dysplasias Rothmund-Thomson syndrome autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism and cataracts

 Classic category (75%)

Osteoblastic Chondoblastic Fibroblastic

 Remaining 25% variants:

Clinical characteristics
Osteosarcoma of the jaw Postradiation osteosarcoma Paget s Osteosarcoma Telangiectatic osteosarcoma Small cell osteosarcoma Epithelioid osteosarcoma Parosteal osteosarcoma Periosteal osteosarcoma

Morphologic characteristics

Location

 Most common presenting symptom is pain and swelling of the affected site Pathologic fractures common in telangiectactic type of osteosarcoma Usually metastasize to lungs, which rarely presents with respiratory symptoms

 Mass: may be present or absent Decreased range of motion of affected site Lymphadenopathy: involvement of local or regional lymph nodes is unusual Respiratory findings: auscultation is usually uninformative unless the disease is extensive

Plain Films
Primary lesion Chest
posteroanterior (PA) lateral chest views

Osteosarcoma lesions can be purely osteolytic (approximately 30% of cases), purely osteoblastic (approximately 45% of cases), or a mixture of both. Elevation of the periosteum may appear as the characteristic . Extension of the tumor through the periosteum may result in a so-called (approximately 60% of cases). Obtain an image of the entire bone and adjacent joint to assess for skip lesions or joint involvement. Telangiectatic osteosarcomas are often very cystic and can be mistaken for an aneurysmal bone cyst.

 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].

 Osteogenic sarcoma fibula. Destruction of bone with sunburst appearance

CT Scan
CT scanning of the
To delineate the location and extent of the tumor Critical for surgical planning.

CT scanning of the
More sensitive than plain film radiography for assessing pulmonary metastases Ideally done before performing a biopsy to avoid ambiguity that can arise from postanesthesia atelectasis.

MRI
MRI of the primary lesion
Best method to assess the extent of intramedullary disease as well as associated soft-tissue masses and skip lesions

single most important study for accurate surgical staging of the lesion with use of the

Bone Scan
Radionuclide bone scanning with technetium-99 (99m Tc)-methylene diphosphonate (MDP/MDI) Important to evaluate for the presence of metastatic or multifocal disease

Others
Echocardiography or multiple gated acquisition scanning: Assess cardiac function before, and at various intervals following, treatment with Adriamycin.

Chest radiograph of patient with osteosarcoma who died from pulmonary metastatic disease. Note the presence of a pneumothorax as well as radiodense (bone-forming) metastatic lesions.

Clinical appearance of a teenager who presented with osteosarcoma of the proximal humerus. Note the impressive swelling throughout the deltoid region, as well as the disuse atrophy of the pectoral musculature.

Radiographic appearance (plain radiograph) of a proximal humeral osteosarcoma. Note the radiodense matrix of the intramedullary portion of the lesion, as well as the softtissue extension and aggressive periosteal reaction.

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

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

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.

Enneking Staging system

Features of the tumor that may impact prognosis

Stage
I II III low-grade lesions high-grade lesions Metastases

Substage

A Intracompartmental lesion (intramedullary lesion for bone tumors) B Extracompartmental lesion (extramedullary spread for bone tumors) Distal extremity Best Distal femur Intermediate Axial skeleton Worst

Site of primary tumors

 Size of initial tumor

In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who underwent surgery and chemotherapy were reviewed. The authors found that 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 still under debate) to preoperative chemotherapy appear to have a better prognosis, although this is still under investigation

Histologic response

Medical Therapy
Before the use of chemotherapy (which began in the 1970s), osteosarcoma was treated (usually primarily with amputation).Despite such good local control, more than 80% of patients subsequently developed recurrent disease that typically presented as . The high recurrence rate indicates that most patients disease at the time of have diagnosis. Therefore, the use of is critical for the treatment of patients with osteosarcoma.

 So-called neoadjuvant (preoperative) chemotherapy has been found not only to facilitate subsequent surgical removal by causing tumor shrinkage but also to provide oncologists with an important risk parameter. Patients in whom there has been a good histopathologic response to neoadjuvant chemotherapy (>95% tumor cell kill or necrosis) have a better prognosis than those whose tumors do not respond as favorably. Thus, future chemotherapy trials will incorporate adjuvant tumor cell kill to provide risk-adapted treatment regimens.

Surgical Indications
The 2 main procedures performed by orthopedic surgeons: - biopsy - wide resection

Neither of these procedures should be undertaken unless complete tumor staging has been completed preoperatively.

Biopsy
Biopsy procedures include:
open biopsy (preferred to avoid sampling error and to provide adequate tissue for biologic studies), trephine biopsy or core needle biopsy (preferred for vertebral bodies and many pelvic lesions), or fine needle aspiration (not recommended).

Carefully plan the incision for an open biopsy to avoid tumor contamination of the neurovascular structures and to facilitate removal of the biopsy tract en bloc during definitive surgery.

Core needle biopsy instruments commonly used for bony specimens. Craig needle set.

Close-up view of Craig needle biopsy instruments. Cutting cannula with T-handle attached (top) and sheath through which the cutting cannula passes (bottom).

Resected specimen of a proximal tibia osteosarcoma. The primary lesion was such that the knee joint was resected with the primary lesion. Note that the previous longitudinal biopsy tract was completely excised with the specimen.

Surgical Therapy
The orthopedic surgeon is of paramount importance in the care of patients with osteosarcoma. Often, patients thought to have osteosarcoma are referred to the orthopedic surgeon first to make the diagnosis. In addition, because osteosarcomas are not particularly responsive to radiotherapy, (local control).In addition, an oncologic type of total joint prosthesis or complex bone reconstruction may be required following surgical resection. Therefore, close involvement of the orthopedic surgeon with the medical oncologist at the time of diagnosis, as well as during and after chemotherapy, is critical.

Definitive resection
The primary aim of definitive resection is patient survival. As such, margins on all sides of the tumor must contain normal tissue ( ). The thickness of the margin is important only for the marrow, where an adequate margin is thought to be depicted on MRI or bone scan. , defined as removal of the entire involved compartment (bone, joint to joint; muscle, origin to insertion), are usually not required for cure. A less-than-wide margin (marginal or intralesional margin) may be functionally helpful as a debulking therapy, but intrinsically, it will not be locally curative. may be the treatment of choice in some circumstances.

 If possible, a number of options exist for limb-salvage reconstruction, which must be chosen based on individual considerations, as follows:
Autologous bone graft Allograft Prosthesis Rotationplasty

 Resection of pulmonary nodules:

wedge resection Lobar resection or pneumonectomy (should be performed at the time of the primary tumor resection) bilateral thoracotomies are recommended for bilateral disease (each side separated by a few weeks)

For an osteosarcoma that recurs as one or more lung lesions only more than 1 year after the patient is off therapy, surgical resection alone can be curative, as the likelihood of metastases to other sites is low. Chemotherapy is warranted if recurrence occurs earlier, as the risk of other micrometastatic disease is high.

Contraindications!
Because osteosarcoma is a deadly form of cancer, no absolute contraindications to treatment exist.

Relative contraindications would include situations in which the patient is so frail that the risks of general anesthesia outweigh any potential benefits of surgery. Another relative contraindication would be a situation in which the patient has extensive, overwhelming metastatic disease, and the benefits of comfort and/or hospice care outweigh the potential benefits of surgical intervention.

Follow up: Inpatient care

: generally require inpatient admission for administration and monitoring. Active drugs include:
Methotrexate Cisplatin Doxorubicin Ifosfamide

Patients treated with high-dose alkylating agents are at higher risk for myelodysplasia and leukemia. Therefore, a CBC count should be performed periodically.

: Admission is required for intravenous (IV) antibiotics and monitoring. : Admission is required perioperatively for local control (surgical resection, amputation), usually around week 10 of therapy. Resection of metastatic disease (eg, lung nodules) is also performed at this time. Other: Patients may require admission for a multitude of other medical problems during their chemotherapy treatment phase, including, but not limited to, varicella infection (for IV acyclovir and monitoring), mucositis (for narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

Outpatient
: done twice each week for patients on granulocyte colony-stimulating factor (G-CSF), so that G-CSF can be discontinued when the absolute neutrophil count has reached a predetermined level (usually 1000 or 5000/ L). : and liver function test for patients on parenteral nutrition or who have a history of toxicity (especially if nephrotoxic or hepatotoxic antibiotics or other drugs are continued). : blood work and radiographic scans done:
every 3 months for the first year every 6 months for the second and, perhaps, third year yearly thereafter.

: When patients have been without therapy for 5 or more years, they are considered long-term survivors. These individuals should be seen annually in a late-effects clinic and monitored with appropriate studies depending on their therapy and side effects. Visits may include hormonal, psychosocial, cardiology, and neurologic evaluations.

Complications
Hearing loss is an adverse effect of cisplatin. Fever and neutropenia may occur, and if they do, patient admission is required for IV antibiotics and monitoring. Patients may require admission for a multitude of other medical problems during their chemotherapy treatment phase, including, but not limited to, varicella infection (for IV acyclovir and monitoring), mucositis (for narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

Outcome and Prognosis

The overall 5-year survival rate for patients diagnosed between 1974 and 1994 was 63% (59% for males, 70% for females). 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.

References:
Harrison s Principles of Internal Medicine, 17th edition Robbins and Cotran s Pathologic Basis of Disease, 7th edition Ottaviani G and Jaffe N. 2009. The epidemiology of Osteosarcoma. Cancer Treat Res. 2009: 152:3-13. EMEDICINE