Osteosarcoma

Osteosarcoma
Classification and external resources
Intermediate magnification micrograph of an osteosarcoma (center and right of image) adjacent to non-malignant bone (left-bottom of image). The top-right of the image has poorly-differentiated tumor. Osteoid with a high density of malignant cells is seen between the non-malignant bone and poorly-differentiated tumor. H&E stain.
ICD-10	C40-C41
ICD-9	170
ICD-O:	M9180/3
OMIM	259500
DiseasesDB	9392
MedlinePlus	001650
eMedicine	ped/1684 orthoped/531 radio/504 radio/505
MeSH	D012516

Osteosarcoma is an aggressive malignant neoplasm arising from primitive transformed cells of mesenchymal origin (and thus a sarcoma) that exhibit osteoblastic differentiation and produce malignant osteoid. It is the most common histological form of primary bone cancer.^[1]

Incidence

Osteosarcoma is the eighth most common form of childhood cancer, comprising 2.4% of all malignancies in pediatric patients, and approximately 20% of all primary bone cancers.^[1]

Incidence rates for osteosarcoma in U.S. patients under 20 years of age are estimated at 5.0 per million per year in the general population, with a slight variation between individuals of black, Hispanic, and white ethnicities (6.8, 6.5, and 4.6 per million per year, respectively). It is slightly more common in males (5.4 per million per year) than in females (4.0 per million per year).^[1]

It originates more frequently in the metaphyseal region of tubular long bones, with 42% occurring in the femur, 19% in the tibia, and 10% in the humerus. About 8% of all cases occur in the skull and jaw, and another 8% in the pelvis.^[1]

Prevalence

Osteogenic sarcoma is the sixth leading cancer in children under age 15.^{[citation needed]} Osteogenic sarcoma affects 400 children under age 20 and 500 adults (most between the ages of 15-30) every year in the USA.^{[citation needed]} Approximately 300 of the 900 will die each year. A second peak in incidence occurs in the elderly, usually associated with an underlying bone pathology such as Paget's disease of bone

Genetic predisposition

• Familial cases where the deletion of chromosome '13q14' inactivates the retinoblastoma gene is associated with a high risk of osteosarcoma development.
• Bone dysplasias, including Paget's disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses, increase the risk of osteosarcoma.
• Li–Fraumeni syndrome (germline TP53 mutation) is a predisposing factor for osteosarcoma development.
• Rothmund–Thomson syndrome (i.e. autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and cataracts) is associated with increased risk of this disease.

Variants

• Conventional: osteoblastic, chondroblastic, fibroblastic OS
• Telangiectatic OS
• Small cell OS
• Low-grade central OS
• Periosteal OS
• Paraosteal OS
• Secondary OS
• High-grade surface OS
• Extraskeletal OS

^[2]

Mortality and survival

Deaths due to malignant neoplasms of the bones and joints account for an unknown number of childhood cancer deaths. Mortality rates due to osteosarcoma have been declining at approximately 1.3% per year. Long-term survival probabilities for osteosarcoma have improved dramatically during the late 20th century and approximated 68% in 2009.^[1]

Pathology

Predilections of osteosarcoma

The tumor may be localized at the end of the long bone. Most often it affects the proximal end of tibia or humerus, or distal end of femur. Osteosarcoma tends to affect regions around the knee in 60% of cases, 15% around the hip, 10% at the shoulder, and 8% in the jaw. The tumor is solid, hard, irregular ("fir-tree," "moth-eaten" or "sun-burst" appearance on X-ray examination) due to the tumor spicules of calcified bone radiating in right angles. These right angles form what is known as Codman's triangle. Surrounding tissues are infiltrated.

High magnification micrograph showing osteoid formation in an osteosarcoma, H&E stain

Microscopically: The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumor. Tumor cells are very pleomorphic (anaplastic), some are giant, numerous atypical mitoses. These cells produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central calcification (hematoxylinophilic/blue, granular) - tumor bone. Tumor cells are included in the osteoid matrix. Depending on the features of the tumor cells present (whether they resemble bone cells, cartilage cells or fibroblast cells), the tumor can be subclassified. Osteosarcomas may exhibit multinucleated osteoclast-like giant cells.^[3]

Causes

The causes of osteosarcoma are not known. Several research groups are investigating cancer stem cells and their potential to cause tumors.^[4] Radiotherapy for unrelated conditions may be a rare cause.^[5]

Symptoms

Many patients first complain of pain that may be worse at night, and may have been occurring for some time. If the tumor is large, it can appear as a swelling. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture). According to The Bone Cancer Research Trust (BCRT) the pain may come and go and vary in intensity. The swelling will not be visible if it is not near the surface of the body such as on the pelvis.

Diagnosis

Family physicians and orthopedists rarely see a malignant bone tumor (most bone tumors are benign). Thus, many patients are initially misdiagnosed with cysts or muscle problems^{[citation needed]}, and some are sent straight to physical therapy without an x-ray^{[citation needed]}.

The route to osteosarcoma diagnosis usually begins with an x-ray, continues with a combination of scans (CT scan, PET scan, bone scan, MRI) and ends with a surgical biopsy. A characteristic often seen in an X-ray is the 'Codman's Triangle' which is basically a subperiosteal lesion formed when the periosteum is raised due to the tumor. Films are suggestive, but bone biopsy is the only definitive method to determine whether a tumor is malignant or benign.

The biopsy of suspected osteosarcoma should be performed by a qualified orthopedic oncologist. The American Cancer Society states: "Probably in no other cancer is it as important to perform this procedure properly. An improperly performed biopsy may make it difficult to save the affected limb from amputation." It may also metastasise to the lungs mainly appearing on the CXR as solitary or multiple round nodules most common at the lower regions.

Treatment

Complete radical surgical en bloc resection is the treatment of choice in osteosarcoma.^[1]

Although about 90% of patients are able to have limb-salvage surgery, complications - particularly infection, prosthetic loosening and non-union - or local tumor recurrence may cause the need for further surgery or amputation. Mifamurtide is used after a patient has had surgery to remove the tumor and together with chemotherapy to kill remaining cancer cells to reduce the risk of cancer recurrence.

Patients with osteosarcoma are best managed by a medical oncologist and an orthopedic oncologist experienced in managing sarcomas. Current standard treatment is to use neoadjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection. The percentage of tumor cell necrosis (cell death) seen in the tumor after surgery gives an idea of the prognosis and also lets the oncologist know if the chemotherapy regimen should be altered after surgery.

Standard therapy is a combination of limb-salvage orthopedic surgery when possible (or amputation in some cases) and a combination of high dose methotrexate with leucovorin rescue, intra-arterial cisplatin, adriamycin, ifosfamide with mesna, BCD (bleomycin, cyclophosphamide, dactinomycin), etoposide, muramyl tri-peptite (MTP). Rotationplasty is also another surgical technique that may be used. Ifosfamide can be used as an adjuvant treatment if the necrosis rate is low.

Despite the success of chemotherapy for osteosarcoma, it has one of the lowest survival rates for pediatric cancer. The best reported 10-year survival rate is 92%; the protocol used is an aggressive intra-arterial regimen that individualizes therapy based on arteriographic response.^[6] Three-year event-free survival ranges from 50% to 75%, and five-year survival ranges from 60% to 85+% in some studies. Overall, 65-70% patients treated five years ago will be alive today.^[7] These survival rates are overall averages and vary greatly depending on the individual necrosis rate.

Fluids are given for hydration, while antiemetic drugs (such as the 5-HT₃ receptor antagonists e.g. granisetron and ondansetron) help with nausea and vomiting. Filgrastim or pegfilgrastim help with white blood cell counts and neutrophil counts. Blood transfusions and epoetin alfa help with anemia.

Prognosis

Prognosis is separated into three groups.

• Stage I osteosarcoma is rare and includes parosteal osteosarcoma or low-grade central osteosarcoma. It has an excellent prognosis (>90%) with wide resection.
• Stage II prognosis depends on the site of the tumor (proximal tibia, femur, pelvis, etc.), size of the tumor mass (in cm.), and the degree of necrosis from neoadjuvant chemotherapy (chemotherapy prior to surgery). Other pathological factors such as the degree of p-glycoprotein, whether the tumor is cxcr4-positive,^[8] or Her2-positive are also important, as these are associated with distant metastases to the lung. The prognosis for patients with metastatic osteosarcoma improves with longer times to metastases, (more than 12 months-24 months), a smaller number of metastases, and their resectability. It is better to have fewer metastases than longer time to metastases. Those with a longer length of time(>24months) and few nodules (two or fewer) have the best prognosis with a 2-year survival after the metastases of 50%, 5-year of 40% and 10 year of 20%. If metastases are both local and regional, the prognosis is worse.
• Initial presentation of stage III osteosarcoma with lung metastases depends on the resectability of the primary tumor and lung nodules, degree of necrosis of the primary tumor, and maybe the number of metastases. Overall survival prognosis is about 30%.^[9]

Research, information and support

In the UK and Ireland The Bone Cancer Research Trust (BCRT) funds research and provides information on Osteosarcoma and other bone cancers. This includes information for teenagers who have this condition. In the US the Non-Profit Organization Triumph Over Kid Cancer Foundation helps to not only raise awareness about Osteosarcoma, they also help raise funds to try to improve treatment and survivability of Pediatric Bone Cancer. 90% of their proceeds go to research and M.D. Anderson Cancer Hospital MATCHES those funds Dollar for Dollar and use all funds for research in Pediatric Sarcoma. The work will be done under the auspices of the Children's Sarcoma Initiative, and will feature a committee to solicit new research ideas in this area and fund those most likely to lead to progress. Also, because early diagnosis greatly improves prognosis, they work on educational efforts to increase awareness of bone cancer's signs and symptoms in parents and their pediatricians. Finally, since the life of pediatric bone cancer patients is so difficult, TOKC sets aside 10% of our proceeds to help fund the Sunshine Kids Organization which works tirelessly to bring some brief periods of happiness to the lives of these children.

Canine osteosarcoma

X-ray of osteosarcoma of the distal femur in a dog

Risk factors

Osteosarcoma is the most common bone tumor in dogs and typically afflicts middle-age large and giant breed dogs such as Irish Wolfhounds, Greyhounds, German Shepherds, Rottweilers, mountain breeds (great Pyrenees, St. Bernard, Leonberger, Newfoundland), Doberman Pinschers and Great Danes. It has a ten times greater incidence in dogs than humans.^[10] A hereditary base has been shown in St. Bernard dogs.^[11] Spayed/neutered dogs have twice the risk of intact ones to develop osteosarcoma.^[12] Infestation with the parasite Spirocerca lupi can cause osteosarcoma of the esophagus.^[13]

Clinical presentation

The most commonly affected bones are the proximal humerus, the distal radius, the distal femur, and the tibia,^[14] following the basic premise "far from the elbow, close to the knee". Other sites include the ribs, the mandible, the spine, and the pelvis. Rarely, osteosarcoma may arise from soft-tissues (extraskeletal osteosarcoma). Metastasis of tumors involving the limb bones is very common, usually to the lungs. The tumor causes a great deal of pain, and can even lead to fracture of the affected bone. As with human osteosarcoma, bone biopsy is the definitive method to reach a final diagnosis. Osteosarcoma should be differentiated from other bone tumours and a range of other lesions, such as osteomyelitis. Differential diagnosis of the osteosarcoma of the skull in particular includes, among others, chondrosarcoma and the multilobular tumour of bone.^[15][16]

Treatment and prognosis

Amputation is the initial treatment, although this alone will not prevent metastasis. Chemotherapy combined with amputation improves the survival time, but most dogs still die within a year.^[14] There are surgical techniques designed to save the leg (limb-sparing procedures), but they do not improve the prognosis.

Some current studies indicate that osteoclast inhibitors such as alendronate and pamidronate may have beneficial effects on the quality of life by reducing osteolysis, thus reducing the degree of pain as well as the risk of pathological fractures.^[17]

Experimental laser procedure

Autologous patient specific tumor antigen response (apSTAR Veterinary Cancer Laser System: The use of a laser combined with a polymer has been shown to enhance tumor immunity and improve the rate of primary and metastatic tumor regression in laboratory models of tumors. apSTAR has also been used for dogs with osteosarcoma and other tumor types.^[18]

Experimental Vaccine

The University of Pennsylvania School of Veterinary Medicine is currently conducting a phase 1 clinical trial on canines with appendicular ostersarcoma that expresses the HER2/neu antigen. The vaccine, developed by Advaxis, Inc., uses a bioengineered, attenuated strain of Listeria monocytogenes as a vector to activate the immune system against tumors expressing the HER2/neu antigen. The study seeks to "determine whether a recombinant L. moncytogenes vaccine can make the dog’s own immune system attack the tumor and prolong survival in dogs with appendicular osteosarcoma." For inclusion canines must have already undergone amputation, a standard regimine of chemotherapy, express the target HER2/neu antigen, and have no evidence of metastases. The study is on-going and open to the public. No results have been released thus far.(Even with standard of care (SOC) treatment (affected limb amputation and follow-up chemotherapy) dogs have a median survival rate of only 1 year. Sasha, a 13 year old American Bulldog and the first dog treated in the study, has survived over 600 days.)^[19]

Osteosarcoma in cats

Osteosarcoma is also the most common bone tumor in the cat, although not as frequently encountered, and most typically affects the rear legs. The cancer is less aggressive in cats than in dogs, and therefore amputation alone can lead to a significant survival time.^[14]

People diagnosed with osteosarcoma

Terry Fox (1958–1981) began a run across Canada to raise money for cancer research. He developed osteogenic sarcoma as a teenager and had a leg amputated.

• Chiara Badano
• Bruce Feiler
• Terry Fox
• Daniel Jacobs (boxer)
• Edward M. Kennedy, Jr.
• Antonietta Meo
• Wayman Tisdale
• Cameron Duncan
• Anna German
• Zach Sobiech
• Kyle Miller (lacrosse)
• Josh Sundquist
• Augustus Waters (fictional character from The Fault In Our Stars)

References

Further reading

• James, H. (1979). Promises in the Dark. New York: Bantam Books. ISBN 0-553-13453-1.  Story of a young girl's osteosarcoma fight and its effect on her relationship with her boyfriend
• Belshaw, Sheila M. (2001). Fly With a Miracle. Denor Press. ISBN 0-9526056-7-8.  The story of a family's journey through teenage osteosarcoma and its aftermath.
• Trottier, Maxine (2005). Terry Fox: A Story of Hope. Markham, Ont: Scholastic Canada. ISBN 0-439-94888-6.  About Terry Fox and his quest to raise $25 million for cancer research by running across Canada on his prosthetic leg. Also The Terry Fox Story, a 1983 movie.
• Jaffe, N. (2010). Pediatric and Adolescent Osteosarcoma. New York: Springer. ISBN 978-1-4419-0283-2.  Osteosarcoma research: past, present and future.

External links

• Osteosarcoma on the Open Directory Project
• EURAMOS - The European and American Osteosarcoma Study Group
• National Cancer Institute - patient information on osteosarcoma
• University of Minnesota - Genetics of Osteosarcoma research study