Osteosarcoma

Tumor biology and incidence

Osteosarcoma, also referred to as osteogenic sarcoma is a malignant osteoid producing tumor that involves the skeletal system.  The abnormal cell is the malignant osteoblast.  The cells are spindle shaped cells with variable amounts of pleomorphism, cytologic atypia and mitotic activity.

Osteosarcoma has a strong genetic association with defects in the retinoblastoma (RB) gene.  The majority of tumors will show evidence of a loss of function mutation in this gene.  Patients with RB gene defects are at very high risk of developing osteosarcoma.  P53, another tumor suppressor gene, like the RB is also frequently found to have loss of function in osteosarcoma cells.

Osteosarcoma is the most common primary bone malignancy comprising 22% of all malignant primary bone tumors (Mirra, 1989).  There are approximately 900 new cases of osteosarcoma reported each year in the united states (American Cancer Society (ACS), 2007).  This is in comparison to 180,000 new cases of breast cancer each year in the United States (ACS, 2007).

Osteosarcoma Variants

Conventional high-grade intramedullary osteosarcoma accounts for 90% of all osteosarcomas. Numerous variants account for the remaining 10%, including:

• Parosteal osteosarcoma
• Periosteal osteosarcoma
• Low-grade intramedullary osteosarcoma
• Telangiectatic osteosarcoma
• Small cell osteosarcoma
• Multifocal osteosarcoma
• High-grade surface osteosarcoma
• Intracortical osteosarcoma
• Secondary osteosarcoma (e.g. post-radiation, Paget's)

Age

Osteosarcoma has a bimodal distribution with the larger spike occurring in the 2nd and 3rd decades of life.  The second spike occurs later is people over the age of 60 and usually represents secondary osteosarcoma arising from another benign or low grade bone lesion, like Paget's disease.  This later age presentation comprises about 10% of osteosarcoma cases.

Gender

Males are 1.5 times more likely to be diagnosed with osteosarcoma compared to females.

Presentation

Patients with osteosarcoma frequently present with a period of worsening pain in the involved site that may initially only be present with activity, but progresses to pain at rest and pain that wakes them at night.  Some patients will report a recent history of an injury to the involved area that may have incited the pain onset.  This is usually coincidental.  Patients will often have a limp.  They may also experience swelling or a lump at the site of involvement.  The limb is frequently warmer than the uninvolved side.  Approximately 10% of patients will present with a fracture at the site of involvement.

Physical findings

On physical examination, patients will frequently have a limp.  There will be pain, tenderness and warmth at the site.  There is often a palpable mass.  Atrophy of the surrounding muscle is also a frequent finding.  It is rare to find vascular compromise in the involved limb, but a careful vascular exam should be performed in all patients.  If the tumor compresses on a nerve, than the patient may have numbness and weakness in the extremity distal to the site of involvement.

A careful examination of the lungs and heart with a stethoscope should be performed on all patients being considered for the diagnosis of osteosarcoma.  The most common site of metastasis is the lungs.  Ronchi or wheezing on exam may be a clue to early diagnosis of metastatic disease.

Plain films

Fig 1. Osteosarcoma	Fig 2. Osteosarcoma

Plain films frequently show a bone forming tumor with mixed lytic and blastic components.  Bone destruction is a common feature.  In the case of conventional osteosarcoma, the tumor is within the medullary canal, but may extend outside the canal into the soft tissue.  This will appear as soft tissue calcification on plain films.  Periosteal elevation and onion skinning may also be seen on plain films, as the tumor stimulates a reactive process within the periosteum.  When this occurs in the proximal humerus, this is referred to as Codman's triangle, named after the person who first described this phenomenon.

The most common site within the bone for osteosarcoma to appear is in the metaphyseal region of long bones. There may be extension into the epiphysis and diaphysis as well.  Other types of osteosarcoma may have different patterns on plain film.  Telangectatic variants are usually completely lytic on plain film and may look like an aneurysmal bone cyst.  Juxtacortical osteosarcomas will be predominantly on the surface of the bone, rather than in the intramedullary canal.

Site
Eighty percent of osteosarcomas occur in the appendicular skeleton.  Fifty-percent of all osteogenic sarcomas occur around the knee, with 35% distal femur and 20% proximal tibia.  Another 10% occur in the proximal humerus.  A smaller percentage ovvur in other sites within the body, like the proximal femur, pelvis and rarely spine.

Size

Size of osteosarcoma is very variable depending on the location of the lesion.  Pelvic tumors can grow to a rather large size before detection, while, tumors within the distal extremity tend to be smaller in size.

Bone scan

Bone scan is an important part of the staging for osteosarcoma.  It allows the detection of other bone sites of involvement that may either be metastasis or skip lesion within the same bone.  Bone scan almost uniformly shows intense uptake of radiotracer at the site of involvement.

CT Scan

CT scans allow for a closer look at the osseous matrix of the tumor.  However, now with more advancements in MRI, CT scan is not required for evaluation of the primary tumor.  However, CT scan of the lungs is neccessary for the staging evaluation in patients with osteosarcoma.

MRI

MRI of the entire bone involved is necessary for adequate evaluation of the anatomic nature of the tumor.  MRIs should be performed with and without gadolinium to allow for proper assessment of the tumor extent and involvement of local neurovascular structures.  The tumor will have high signal in T2 images, indication high water content and local edema and low signal on T1 images.

Differential Diagnosis

Osteosarcoma can be mistaken for any number of bone conditions,  but the most common ones are

• Aneurysmal Bone Cyst (ABC), especially in telangectatic osteosarcoma
• Fibrous dysplasia
• Osteoblastoma
• Osteoid osteoma
• Bone cysts
• Osteomyelitis

Natural history

All patients untreated with osteosarcoma will succumb to the disease.  The most likely site of distant metastasis will be the lungs, followed by other bony sites, like the spine.  Prior to the advent of chemotherapy for osteosarcoma in the late 1960's and early 70's, only 20% of patients would survive beyond 5 years with just amputation alone as treatment.  With the use of neoadjuvant chemotherapy and modern surgical techniques, approximatly 65% of patients will be cured of disease.

At the turn of the century, the majority of patients with osteosarcoma were treated with amputation of the involved limb.  However with advances in our understanding of the disease process, surgeons realized that limb sparing surgery could be performed with unchanged long-term survival in patients.

Pathology

Fig 3. Osteosarcoma (H&E 10x)	Fig 4. Osteosarcoma (H&E 40X)

Diagnosis and treatment

Diagnosis starts with adequate x-rays of the involved bone.  The entire bone should be imaged.  Once osteosarcoma is expected as the diagnosis, a biopsy is performed.  Once the patient has biopsy proven osteosarcoma, a chest x-ray and Ct scan of the chest should be performed to r/o metastatic disease to the lungs (the most common site of metastases).  A bone scan should also be performed to r/o bone metastases.  MRI of the entire involved bone should be performed to both characterize the anatomy of the lesion as well as look for skip metastasis with in the bone.  Finally labs, including Lactate dehydrogenase (LDH) and Alkaline phosphotase (AP) showed be obtained prior to the start of chemotherapy.  LDH and AP are measures of burden of disease.
Treatment of osteosarcoma includes pre-resection chemotherapy (neoadjuvant chemotherapy), followed by resection of the tumor (limb salvage or amputation) and than post-operative chemotherapy.  Most institutions give two rounds of chemotherapy prior to surgery.  The specimen, once removed is then analyzed for amount of necrosis, which is a surrogate marker for response of the primary tumor to the chemotherapy.  High necrosis indicates good response and therefore, better prognosis (Huvos, 1981).

Fig 1. Osteosarcoma	Fig 2. Osteosarcoma	Fig 5. Osteosarcoma s/p chemotherapy
Fig 6. Osteosarcoma s/p chemotherapy

Fig 7. Osteosarcoma s/p chemotherapy (H&E 10x)

A H&E stain of a resected specimen showing example of good response to chemo with a >95% tumor cell kill rate. A good response to chemotherapy (>90% tumor cell kill rate) is associated with a 90% cure rate.

Complications

The greatest complication associated with osteogenic sarcoma is death from disease.  Patients most frequently develop metastatic disease to the lungs, which ultimately can be fatal.  Other complications include lose of limb or limb function.

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