Secondary Logo

AAPA Members can view Full text articles for FREE. Not a Member? Join today!

Understanding osteosarcomas

Simpson, Emily, MMSc, PA-C; Brown, Heather L., MS, PA-C, DFAAPA

Journal of the American Academy of PAs: August 2018 - Volume 31 - Issue 8 - p 15–19
doi: 10.1097/01.JAA.0000541477.24116.8d
CME: Oncology
Free
SDC
CME

ABSTRACT This article reviews the cause, clinical presentation, diagnostic methods, and management of osteosarcoma, the most common primary bone tumor and third most common cancer among children and adolescents. In the 1970s, the introduction of adjuvant chemotherapy following tumor resection improved overall 10-year survival from 30% to about 50% of patients. However, since that change in management strategy, the survival rate has since plateaued, with no improvement in overall 10-year survival since the 1990s. A better understanding of this disease is the first step to help improve these numbers.

At the time this article was written, Emily Simpson was a student in the PA program at Mercer University in Atlanta, Ga. She now practices urgent care medicine with Georgia Emergency Associates in Savannah, Ga. Heather L. Brown is an adjunct assistant professor in the PA program at Mercer University. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of August 2018.

Figure

Figure

Box 1

Box 1

Osteosarcomas are the most common primary bone tumor and third most common cancer among children and adolescents, behind lymphomas and brain cancers.1,2 Osteosarcomas are defined by the production of osteoid, or immature bone, by malignant mesenchymal cells.1,2 With about 800 new cases diagnosed each year in the United States, this disease is rare but devastating.3 In the 1970s, the introduction of adjuvant chemotherapy following tumor resection improved overall 10-year survival from 30% to about 50%.4 However, since that change in management strategy, the survival rate has plateaued, with no improvement in overall 10-year survival since the 1990s.4,5 This lack of continued progress toward improved survival rates for patients affected by osteosarcomas indicates a clear need for better overall understanding of this disease, as well as more effective methods of diagnosis and treatment.6 This article reviews the cause, clinical presentation, diagnostic methods, and management of osteosarcoma.

Box 2

Box 2

Back to Top | Article Outline

EPIDEMIOLOGY AND CAUSE

Osteosarcomas account for 3% to 6% of all childhood cancers and about 1% of cancers in adults.1 The disease distribution is bimodal, with the first occurring in adolescence (average age of 10 to 14 years in females and 15 to 19 years in males) and the second peak occurring after age 65 years.6 In the first peak, the disease is more common in males but the sexes are evenly represented in the second peak.6 Patients in the first peak distribution are more likely to be of Asian Pacific descent; patients in the second peak are more likely to be black or white than other ethnicities.6

The cause of osteosarcoma is not well understood. In children, the disease appears to be sporadic. One-third of cases in adults occur in those with Paget disease or another cancer (Figure 1).1 Risk factors for osteosarcoma include a history of radiation or chemotherapy, history of Paget disease or other benign bone lesion, and genetic conditions, including hereditary retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomson syndrome, and Bloom and Werner syndromes.1,2 Many factors affect overall disease course and patient outcomes. These factors include age, tumor volume, axial versus appendicular location of tumor, surgical resection margin, histologic response to preoperative chemotherapy, and duration of relapse-free interval.2

FIGURE 1

FIGURE 1

Back to Top | Article Outline

PATHOPHYSIOLOGY

The exact pathophysiology of osteosarcoma is still unclear, but a relationship seems to exist between rapid bone growth and the onset of this malignancy.1 This correlation is evident when considering factors such as peak incidence of disease, most common locations where the tumors are found, and the differences in young girls' and boys' ages at diagnosis.1 A possible explanation is that problems that can lead to neoplastic development are more likely to arise during rapid bone cell proliferation at puberty.1 However, no study has shown any proof to confirm this hypothesis.1

Genetics definitely plays a role in osteosarcoma development, and research has sought to find a specific gene that may be responsible. The p53 gene, which is involved in the normal development and physiology of bone, is thought to be a possible contributor to tumor formation.2 Luetke and colleagues indicate that the p53 gene is linked to Li-Fraumeni syndrome, a risk factor for osteosarcoma.2 However, this gene link has not been definitively proven. Additionally, a significant proportion of patients with osteosarcoma also have mutations in the RB gene, traditionally associated with development of retinoblastoma, despite not clinically displaying signs or symptoms of retinoblastoma itself.7

Back to Top | Article Outline

CLINICAL PRESENTATION

An example of a typical patient presentation is a teenage male athlete with a 3-month history of pain in his right proximal anterior tibia. Often, the patient history includes a minor trauma, such as a kick to the tibia. The patient usually has associated pain and decreased range of motion. On physical examination, the patient may have tenderness in the area, skin warmth, and a small palpable mass anterior to the bone in the pretibial area.

Patients typically present with a complaint of several months of localized pain, which usually is noticed after an injury.1,8 The pain may come and go but never fully resolves and often is reported to be worse at night.1,7 The diagnosis may be delayed in adolescents as pain may be inappropriately attributed to athletics or rapid bone growth. Patients may present with complaints of systemic symptoms, such as weight loss, fever, fatigue, or malaise, although usually they do not.1,8 Physical examination typically reveals a soft-tissue mass that is tender to palpation.1,8 The patient also may have appreciable warmth, skin vascularity, or pulsations over the lesion.8 Joint involvement and decreased range of motion will be apparent on physical examination.8 Most commonly, these tumors originate in the metaphysis of the long bone, most often the distal femur, followed by the proximal tibia, proximal humerus, and middle and proximal femur (Figure 2).1 Unusually, osteosarcoma can originate in the axial skeleton, frequently originating in the pelvis. However, tumors in these locations generally are found in adults.2 The presence of lymphadenopathy in a patient with osteosarcoma is an important indication of possible distant metastasis.8

FIGURE 2

FIGURE 2

Up to 20% of patients diagnosed with osteosarcoma will have demonstrable metastatic disease at the time of disease confirmation.1 Wang and colleagues note that “occult micrometastases are presumed to be present in the majority of those who appear to have clinically localized disease since before the age of adjuvant chemotherapy, over 80% of patients with osteosarcomas developed metastatic disease despite achieving local tumor control.”1 As is consistent with most neoplastic disease, patients who present with more advanced disease and presence of distant metastases generally have a poorer prognosis, and this also appears to be true with osteosarcoma.2 When distant metastases do occur, the most common site is in the lungs, but metastases also can occur in other bones and the lymph nodes.1,2

Back to Top | Article Outline

DIAGNOSTIC APPROACH

Clinicians should employ a methodical, stepwise procedure when evaluating a patient for osteosarcoma (Table 1). Whenever a patient presents with a tender mass overlying a bone, with or without a history of injury, or pain persisting past the expected duration after an acute injury, the first step is to get a plain radiographic image of the bone as well as serum laboratory tests.1 The radiograph will show a sunburst pattern, which is classically seen in osteosarcoma lesions, representing a soft-tissue mass that has new bone growth around the edges of the tumor and extension of the mass through the periosteum.1,8 The affected bone will show areas of radiopaque and radiolucent bone indicating lytic bone lesions, periosteal reaction of the bone cortex, and new periosteal bone formation.l Destruction of the normal trabecular bone pattern and indistinct margins around the area of the tumor (a “moth-eaten” appearance) will be visible on radiograph.1,7 Although these findings help to confirm a suspicion of osteosarcoma, no radiographic findings are pathognomonic for osteosarcoma.1,8

TABLE 1

TABLE 1

Initial workup of suspected osteosarcoma should include several blood studies to determine prognosis and assess the patient's condition before administering chemotherapy.8 Obtain a complete blood cell count, including a differential and platelet count, aminotransferases (ALT and AST), albumin, blood urea nitrogen, creatinine, and electrolyte levels.8 Elevated serum levels of lactase dehydrogenase generally mean a poorer prognosis for patients.8

Historically, serum alkaline phosphatase (ALP) has been used as a diagnostic and prognostic tool for osteosarcomas, with higher levels of ALP indicating higher disease burden.7,9 This test is still viewed as a reliable test for diagnosis in adults.9 However, serum ALP levels vary in children and adolescents depending on age, sex, and puberty, rendering serum ALP unreliable as a diagnostic test for these patients.9 Because serum acid phosphatase (ACP) varies along the same pattern as serum ALP in this age group, Shimose and colleagues hypothesized that the ratio of ALP to ACP could be a better option to help diagnose osteosarcomas in children and adolescents (Table 2).9 The study retrospectively looked at 538 participants ages 1 to 18 years with either a malignant bone tumor, a benign bone tumor, or nontumor bone lesion, and found minimal variation with age in the ratio of ALP to ACP in patients with nontumor lesions.9 The study further demonstrated that the sensitivity and specificity of the ALP:ACP ratios were superior in diagnosis of osteosarcoma, leading the study authors to conclude that the ALP:ACP ratio is a more useful tool than serum ALP for diagnosing osteosarcoma in children and adolescents.9

TABLE 2

TABLE 2

Because radiographic findings are not pathognomonic for osteosarcoma, definitive diagnosis requires a bone biopsy.1 Needle biopsy has a diagnostic accuracy of 90% but many facilities prefer incisional biopsy to increase accuracy and reduce sampling errors.7 An MRI of the entire involved bone is indicated for surgical planning. Also, a radionuclide bone scan with technetium is the study of choice for evaluating the entire skeleton for other neoplastic lesions, and also provides valuable information about the extent of local tumor burden in patients.1,7

Patients should be further evaluated for potential metastases to the bony skeleton by positron emission tomography scanning.1,10

Once this evaluation is completed, the extent of disease related to bone sarcoma can be quantified using the Musculoskeletal Tumor Society staging system, which is based on tumor aggressiveness and compartmental localization.7,10 Stage I indicates a low-grade tumor, stage II indicates a high-grade tumor, and stage III indicates distant metastasis or lymph node involvement. The letter A can be added to a stage number to indicate that the tumor is only in the original tissue compartment; B indicates local extension of disease. Some clinicians use the more traditional TNM staging criteria for osteosarcomas.10

Back to Top | Article Outline

MANAGEMENT

After the diagnosis is confirmed, patients with osteosarcoma are treated with a multispecialty approach by orthopedics and oncology practitioners. The standard of care for osteosarcomas consists of neoadjuvant chemotherapy before surgery, surgical resection (including all known resectable metastases), and adjuvant chemotherapy postoperatively.2

For children and adults up to age 40 years, the chemotherapy of choice is the MAP regimen, a combination of high-dose methotrexate, doxorubicin, and cisplatin.5,11 The benefit of high-dose methotrexate in older adults is unproven, so doxorubicin and cisplatin only are used in patients age 40 years and older.11 Appropriate choice of chemotherapeutic agents is critical, as salvage treatment for patients failing initial or alternate regimens (such as two-drug combinations) has not been shown to be successful.5

Patients undergo neoadjuvant chemotherapy for 8 to 10 weeks before surgery.2,5 This therapy has been shown to increase overall survival rates.5 The more vigorous the response of the tumor to the preoperative chemotherapy, the better the overall patient prognosis.2 Following this initial regimen of chemotherapy, patients undergo tumor removal surgery, which is necessary for a definitive cure.2

Although limb amputation was once the rule rather than the exception, limb loss poses serious long-term repercussions, especially in children. Today, 80% of patients undergo limb-sparing procedures.2 Limb-sparing surgery carries a significantly higher rate of localized recurrence compared with amputation, and patients and families should be made aware of this risk when discussing treatment options.2 Retaining the limb doubles the chance of localized recurrence, which is generally much more aggressive than the primary cancer was originally.2 Local recurrence also is related to size of tumor margins, and although there is no accepted standard to the width of healthy tissue to excise around these tumors, wider margins generally are thought to be better.2

Postoperatively, chemotherapy is delayed for up to 21 days to allow for surgical wound healing, and then another 12 to 29 weeks of adjuvant chemotherapy is administered.2,12 Radiation, although used as adjuvant treatment in other types of cancers, including other types of primary bone tumors such as Ewing sarcoma, does not have a place in osteosarcoma management except in the few patients who are unable to undergo successful tumor resection with widely negative margins.13

Back to Top | Article Outline

RECURRENCE

Despite treatment of localized disease that adheres to accepted standards and current management guidelines, osteosarcoma recurs in 30% to 40% of patients.2 Research has shown that the original size of resected tumor mass is an unreliable predictor of tumor recurrence in successfully treated patients.14 Most disease recurrence occurs within 2 to 3 years of initial treatment, and patients rarely experience a recurrence after 5 years following the completion of initial treatment.2 Recurrence carries a poor prognosis, with only 23% to 29% of patients surviving for longer than 5 years past the second diagnosis.2 Limb amputation usually is the treatment of choice when disease recurs locally to the original tumor location.14

Metastases most often occur in the lung (90%) and less commonly in distant bony sites and lymph nodes.2 In patients with isolated lung metastases, surgical resection alone is considered adequate therapy; otherwise, chemotherapy is used for any nonlocal recurrence that occurs after completion of initial therapy.8

Back to Top | Article Outline

ADDITIONAL CONSIDERATIONS

Clinicians who manage patients with osteosarcoma also must address the psychosocial and long-term effects of the disease on patients and families. Patients who suffer from osteosarcomas are typically children and adolescents, and dealing with major illness during this period of development can lead to depression and anxiety as they experience resentment, worry, fear, and anger.15

Patients may have a fear of dying, face multiple hospitalizations and anxiety-producing interventions, lose mobility, lose function in the affected limb, and develop alopecia and scars.16 This often makes it difficult for patients to handle social situations and connect with their peers, which puts them at risk for becoming psychosocially maladjusted.16 Working with a multidisciplinary team (including physical and occupational therapy) and specialized support services can help patients deal with the many psychosocial issues that are inevitable with a childhood cancer diagnosis. Encourage patients and families to use their facility's support programs and counseling services.

Clinicians also must acknowledge and address patients' potential long-term medical consequences, including future fertility issues, possible hearing and learning disabilities, cancer recurrence, and new cancers (such as leukemia) as a result of treatments.15

Be open and discuss potential lifelong health effects with patients. Encourage them to be vigilant and seek care if any problems arise in the future. Make sure to stress the importance of regular follow-ups and recommended screening tests, which are frequent in the first few years after diagnosis and initial treatment and become annual after a documented disease-free period of 5 years.15 Encourage patients and families to continue to maintain a therapeutic relationship with their pediatric oncology specialists throughout adolescence and early adulthood, and transition to adult practitioners as needed. Advise all patients to keep a detailed record of all of their care, to facilitate continuity of care throughout their recovery and beyond.15,16

Back to Top | Article Outline

CONCLUSION

Increasing patient survival rates for osteosarcoma depends on clinicians being able to recognize the disease early and manage it appropriately. More research is needed on the cause of osteosarcoma and its progression, the role of genetics, better testing options for earlier and more accurate diagnosis, and treatments that can reduce patient morbidity and mortality.

Back to Top | Article Outline

REFERENCES

1. Wang L, Gebhardt M, Rainusso N. Osteosarcoma: epidemiology, pathogenesis, clinical presentation, diagnosis, and histology. http://www.uptodate.com/contents/osteosarcoma-epidemiology-pathogenesis-clinical-presentation-diagnosis-and-histology. Accessed April 25, 2018.
2. Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment—where do we stand? A state of the art review. Cancer Treat Rev. 2014;40(4):523–532.
3. American Cancer Society. What are the key statistics about osteosarcoma? http://www.cancer.org/cancer/osteosarcoma/detailedguide/osteosarcoma-key-statistics. Accessed April 25, 2018.
4. Berner K, Johannesen TB, Berner A, et al Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma. Acta Oncol. 2015;54(1):25–33.
5. Anninga JK, Gelderblom H, Fiocco M, et al Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand. Eur J Cancer. 2011;47(16):2431–2445.
6. Mirabello L, Troisi RJ, Savage SA. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer. 2009;125(1):229–234.
7. Baker LH. Bone tumors: primary and metastatic bone lesions. In: Goldman L, Ausiello D, eds. Cecil Medicine. Philadelphia, PA: Elsevier; 2008:1520–1522.
8. Cripe T. Pediatric osteosarcoma clinical presentation. http://emedicine.medscape.com/article/988516-clinical#a0217. Accessed April 25, 2018.
9. Shimose S, Kubo T, Fujimori J, et al A novel assessment method of serum alkaline phosphatase for the diagnosis of osteosarcoma in children and adolescents. J Orthop Sci. 2014;19(6):997–1003.
10. Patel S, Benjamin R. Soft tissue and bone sarcomas. In: Kasper DL, Fauci AS, Hauser SL, et al. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill Education, Inc.; 2015.
11. Janeway K, Maki R. Chemotherapy and radiation therapy in the management of osteosarcoma. http://www.uptodate.com/contents/chemotherapy-and-radiation-therapy-in-the-management-of-osteosarcoma. Accessed April 25, 2018.
12. Imran H, Enders F, Krailo M, et al Effect of time to resumption of chemotherapy after definitive surgery on prognosis for non-metastatic osteosarcoma. J Bone Joint Surg Am. 2009;91(3):604–612.
13. DeLaney TF, Park L, Goldberg SI, et al Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys. 2005;61(2):492–498.
14. Poudel RR, Kumar VS, Bakhshi S, et al High tumor volume and local recurrence following surgery in osteosarcoma: a retrospective study. Indian J Orthop. 2014;48(3):285–288.
15. American Cancer Society. Living as an osteosarcoma survivor. http://www.cancer.org/content/cancer/en/cancer/osteosarcoma/after-treatment/follow-up.html. Accessed April 25, 2018.
16. van Riel CA, Meijer-van den Bergh EE, Kemps HL, et al Self-perception and quality of life in adolescents during treatment for a primary malignant bone tumour. Eur J Oncol Nurs. 2014;18(3):267–272.
Keywords:

osteosarcoma; bone; children; pediatric; limb-sparing; chemotherapy

Copyright © 2018 American Academy of Physician Assistants