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Osteosarcoma

Accurately diagnosing this bone-chilling disease

Hiller, Chelsea MPAP, PA-C; Wegler, Jennifer L. MMSc, PA-C; Forest, Christopher P. MSHS, DFAAPA, PA-C

Journal of the American Academy of PAs: December 2016 - Volume 29 - Issue 12 - p 29–35
doi: 10.1097/01.JAA.0000508202.17804.4d
CME: Oncology
Free
CME

ABSTRACT Osteosarcoma is the most common primary bone malignancy in children and adolescents. Because the incidence of osteosarcoma is low and the disease occurs in physically active patients, it may be misdiagnosed as a more benign condition, thus leading to late diagnosis. This article describes the disease's most frequent presenting complaints and initial radiographic findings, as well as its risk factors and common misdiagnoses. Clinicians should consider osteosarcoma in young patients with persistent bone pain, especially pain with weight-bearing.

Chelsea Hiller practices family medicine at the Scripps Clinic in San Diego, Calif. Jennifer L. Wegler is a clinical instructor of family medicine in the PA program at the University of Southern California in Alhambra, Calif., and practices orthopedics at Kaiser-Permanente in Baldwin Park, Calif. Christopher P. Forest is an assistant professor of clinical family medicine and director of research at the University of Southern California's Keck School of Medicine and practices urgent care and family medicine in Los Angeles, Calif. 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 December 2016.

Box 1

Box 1

Osteosarcoma is the most common primary bone malignancy, excluding malignancies arising from the marrow, such as multiple myeloma, lymphoma, and leukemia. Although osteosarcoma can be fatal, 70% to 80% of patients survive if diagnosed before the cancer metastasizes.1 However, early diagnosis can be challenging because the cancer can mimic familiar conditions such as sprains, overuse injuries, and growing pains in adolescents. Detecting osteosarcoma in the early stages, when pain has only been present for a few weeks, is essential for long-term patient survival and often allows less tissue resection at the time of surgery. To avoid missing the diagnosis of osteosarcoma, clinicians must be aware of its early signs and symptoms, radiographic features, and risk factors.

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Incidence

Osteosarcoma has a bimodal distribution, with the first peak occurring in patients ages 10 to 19 years, during the pubertal growth spurt. The second, less common peak, is in people age 65 years and older. Older patients are more likely to have a secondary osteosarcoma from a primary diagnosis of Paget disease or prior radiation therapy. The incidence of osteosarcoma is 4.4 per million per year for ages birth to 24 years, making it the eighth most common childhood cancer.2,3 In adults age 60 years and older, the incidence rate is about 4.2 per million per year.2 Nearly 1,000 new cases are diagnosed each year, 40% in patients under age 18 years.4

Box 2

Box 2

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Pathogenesis

Osteosarcoma arises from the earliest bone-forming mesenchymal cells. The tumor cells destroy normal bone and replace it with immature osteoid. The cells frequently develop into a firm tumor located in the proximal or distal end of metaphyseal bone, often with extension outside the periosteum into the soft tissue. Extremity tumors make up about 80% of all tumors.5 The most common tumor locations, in descending order, are the distal femur, proximal tibia, proximal humerus, and proximal femur. Almost 50% of osteosarcomas occur around the knee.6

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SIGNS AND SYMPTOMS

The most frequent presenting complaint is pain at the tumor site. The pain occurs as the tumor increases in size and weakens the bony architecture or causes compression on adjacent neurologic structures. Patients often describe the pain as an intermittent ache that progresses to persistent pain with a dull, aching character. Consider osteosarcoma in the differential diagnosis of patients with weight-bearing or night pain. Often, the patient will have a history of unrelated minor trauma that leads to an incidental finding of malignancy. Due to the bony destruction, 15% to 20% of patients may present with a pathologic fracture at diagnosis.1 Other symptoms include limping, if the tumor is in the lower extremity; pain when lifting, if the tumor is in the upper extremity; and tenderness, swelling, or redness at the tumor site. A soft tissue mass most often develops at the tumor site about 2 months after the inception of pain.7 Asymmetry of the affected extremity compared with the contralateral side is an important finding, so expose both extremities during the physical examination.

Two significant obstacles that often delay diagnosis of osteosarcoma at an early stage are the high activity level of the typical adolescent patient and the physiologic changes that occur during puberty. Bone pain in active, pubescent patients often is attributed to the frequent minor trauma they incur with activity or rapid skeletal growth. Pain that persists in an adolescent, especially extremity pain and pain with weight-bearing, should be investigated further to assess for osteosarcoma.

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RISK FACTORS

Unlike more common cancers such as breast cancer and colon cancer, no screening test is recommended for osteosarcoma. Due to the low incidence, screening radiographs for adolescents are difficult to justify. Recognizing early signs, such as persistent bone pain, and monitoring patients with risk factors is essential to diagnosing osteosarcoma at an early stage.

Risk factors include age, male sex, tall stature (supporting the evidence that rapid bone growth can contribute to osteosarcoma formation), prior radiation, certain bone diseases, and inherited cancers. Due to an earlier normal pubertal growth spurt, females are diagnosed at an earlier age than males, providing evidence that a peak in sex hormones, growth hormones, and insulin-like growth factor 1 levels may influence the development of osteosarcoma. Patients with Paget disease are at greater risk, as are those with certain inherited cancer syndromes, such as hereditary retinoblastoma, Li-Fraumeni syndrome, and Rothmund-Thomson syndrome.8 Both young and old patients with multiple risk factors should be closely monitored by their primary care providers at yearly physicals, with more thorough histories and physical examinations in order to diagnose potential osteosarcomas at the earliest stage possible.

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DIAGNOSTIC EVALUATION

Radiologic evaluation plays a major role in the diagnosis and management of patients with osteosarcoma. On plain radiographs, the tumor classically has a sunburst pattern or mottled appearance secondary to new bone formation perpendicular to the shaft of the bone. A bony change often takes place in which the tumor elevates the periosteum, forming a triangle of subperiosteal bone known as Codman triangle (Figure 1). This occurs due to the aggressive nature of the tumor and its rapid growth rate. Additionally, typical radiographs of osteosarcoma show varied regions of lysis and sclerosis, cortical damage, and ossific soft tissue masses.

FIGURE 1

FIGURE 1

A principal finding of early osteosarcoma is trabecular disruption that often goes unnoticed because it can mimic simple healing bone (Figure 2). If the clinician suspects osteosarcoma, an MRI with and without gadolinium contrast may reveal abnormal extraosseous soft tissue, potentially leading to earlier diagnosis (Figure 3). MRI is superior for evaluation because it accurately determines intramedullary and soft tissue tumor extension, joint and/or growth plate involvement, and proximity of the tumor to the neurovascular structures.6 The most accurate diagnostic tool available is bone biopsy, which should be performed by an orthopedic surgeon to provide a definitive diagnosis of osteosarcoma.

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

Once diagnosed, the patient should have a total body bone scan, a chest CT, and an MRI of the entire affected bone. A bone scan looks for areas of high bone turnover and is used to detect other osseous sites of disease and for yearly surveillance in patients with a history of osteosarcoma. Chest CT is completed to identify pulmonary metastases, which are the most common metastases, and for staging purposes. An MRI is essential to characterize the osteosarcoma and for surgeons to determine the optimal angle for bone biopsy. They will later use that same tract for bony resection. MRI results can also help clinicians determine whether limb salvage surgery is possible.

Laboratory testing is of little value in the diagnosis of osteosarcoma. Baseline laboratory results, such as a complete blood cell (CBC) count and metabolic panel, should be obtained to determine the patient's overall health. Alkaline phosphatase and serum lactate dehydrogenase (LDH) levels should be obtained for prognostic purposes. Alkaline phosphatase indicates the presence of excessive bone turnover, and LDH levels reflect the tumor burden, because cells release LDH when attacked by neoplasms. Elevated alkaline phosphatase and LDH at baseline have been associated with a poor prognosis.1

The selection of diagnostic examinations should be driven by features of the patient's history and physical, which help indicate possible differential diagnoses. Areas that must be explored in more detail include a history of traumatic or overuse injuries, localized infection, inflammatory processes, developmental abnormalities, and potential diagnosis of cancer (Table 1).9

TABLE 1

TABLE 1

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TREATMENT

Until the 1970s, amputation was the treatment of choice, with a 5-year survival of less than 20%.4 With the advent of MRI, clinicians were able to visualize the tumor with more accuracy, making it possible to salvage the extremity. When determining whether to perform amputation or limb salvage surgery, surgeons take into account the location and size of the tumor, metastatic existence, and patient's response to chemotherapy. Studies show that functional outcomes and quality of life are similar for patients who undergo either amputation or limb salvage surgery. Currently, limb salvage involving wide surgical resection of the tumor is performed in 80% of patients, and is the preferred treatment in patients with long bone tumors because it provides slightly better long-term function and less need for walking support.1,10 Early diagnosis can help patients avoid amputation and can reduce the extent of tissue resection necessary when limb salvage surgery is performed.

In recent years, the combination of adjuvant chemotherapy and surgical intervention has resulted in a cure rate exceeding 70% for patients without metastases.11 Chemotherapy originally was introduced in osteosarcoma management to address the high rate of metastasis in patients. This resulted in a significant improvement in overall survival, which doubled to 80% when adjuvant chemotherapy was part of the treatment plan in patients without metastases.11

Systemic therapy also increases long-term survival. Cohort studies demonstrate that survival benefits are maintained over 25 years in patients with high-grade, operable osteosarcoma when they are treated with adjuvant chemotherapy. Patients who received chemotherapy had more than twice the 25-year overall survival as patients who did not.11 However, due to the increased exposure to toxic agents, patients who receive chemotherapy or radiotherapy have a greater risk of death from secondary neoplasms, especially hematologic malignancies, than the general population. Other possible complications causing eventual death are infection and cardiovascular diseases. Although patients treated for an original diagnosis of osteosarcoma have a significant increase in mortality from nonrecurrent causes, the most common cause of death in patients diagnosed between ages 15 to 39 years remains disease progression and recurrence.12

The most effective chemotherapy protocol for osteosarcoma is unknown; however, the principal agents used in various combinations are high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide. Studies show no definite benefit of one regimen over another. Choice of regimen partially depends on whether the patient is being treated through a clinical trial or one particular institution.1 Generally, chemotherapy is administered before and after surgery. Neoadjuvant chemotherapy is useful in determining the degree of tumor necrosis at the time of resection. Tumors with greater than 90% necrosis are deemed good responders and patients have a better long-term prognosis.1

Disease recurrence occurs in 30% to 40% of patients with extremity tumors even after complete surgical resection and chemotherapy, usually 2 to 3 years after treatment has ended.13,14 Most recurrence is the lungs; other common sites are local recurrence at or near the site of the original tumor and skeletal metastasis.5 A bone scan, chest CT, and serial radiographs of the affected bone should be regularly scheduled in the critical months and years following diagnosis. After 5 years, annual history and physical examinations as well as radiographs of the chest and primary site of osteosarcoma are used for follow-up.14 The most important predictors of local recurrence are the degree of tumor necrosis following preoperative chemotherapy and the presence of positive surgical margins.15 Additional surgery is most frequently performed following recurrence. Chemotherapy is used as a treatment for recurrence, particularly when the metastases cannot be completely excised or in cases of significant tumor burden.13

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PROGNOSIS

Prognostic factors, such as age, sex, body mass index (BMI), location of the primary tumor, and metastasis, must all be considered when making a diagnosis of osteosarcoma. These factors establish survival rates and inform the clinician which patient characteristics to identify and observe. Patients with multiple risk factors for poor outcomes often have more aggressive treatment protocols.

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Age

Though cancer is typically regarded as a disease of older adults, primary osteosarcoma is known to occur more often in younger patients.3 Whether age has an effect on patient survival is controversial. Although one randomized controlled trial found no significant difference in survival between age groups (age 18 years and younger versus older than age 18 years, or younger than age 35 years versus age 35 years and older), researchers found that patients with osteosarcoma in the extremities were younger on average than patients with tumors located elsewhere.16 Extremity tumors generally require a more straightforward surgical treatment with fewer complications, leading to better outcomes. A study conducted by the Children's Oncology Group based on 1,054 patients and with analysis restricted to localized disease found poorer 10-year event-free survival and overall survival for patients ages 18 to 30 years compared with patients under age 18 years.17 Age was not found to be a factor for survival in patients with metastatic disease, and no increased rate of metastasis was found in older patients. According to the National Cancer Data Base Report, the survival rates for patients with osteosarcoma are 60% in patients under age 30 years, 50% in those ages 30 to 49 years, and 30% in those age 50 years and older.3 The Children's Oncology Group study suggested the difference in survival between age groups could be due to other factors, including tumor histology, compliance with chemotherapy, participation in clinical trials, increased toxicity, and chemotherapy metabolism.17

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Sex

Males are more likely to be diagnosed with osteosarcoma; however, whether male sex is a negative predictor of outcome is somewhat debatable. In a recent retrospective study of patients ages 13 to 74 years, female patients had longer survival times than male patients by an average of 94 months.16 This significance is not consistent across all studies. Another study of children demonstrated that although females outlived males, they had more negative consequences from therapy than males. Females suffered more renal toxicity after two rounds of chemotherapy and received more blood and platelet transfusions. Females also were more likely to receive IV antibiotics and antifungal medications during the first course of chemotherapy.18 Differences in toxicity levels could be related to variations in enzymes, drug metabolism, and drug clearance between sexes.19 Although statistically males are more frequently diagnosed with osteosarcoma, whether sex has an effect on survival has not been established.

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BMI

The prevalence of obesity is rising in the United States. Not only does a high BMI (greater than the 85th percentile for weight) have detrimental effects on overall health, it also has the potential to alter the outcomes of patients with osteosarcoma.18 The comorbidities that occur with obesity, such as subclinical diabetes and persistent inflammation, can impair survival.

Difficulty in effectively dosing chemotherapeutic agents in children with a high BMI and high body surface area (BSA) could contribute to the difference in survival. Obesity can affect renal clearance and hepatic metabolism of many chemotherapeutic drugs. Recent guidelines developed by the American Society of Clinical Oncology recommend using body weight and BSA to determine dosing for adults with abnormal BSA when the aim of treatment is cure.20 These guidelines may be useful for chemotherapy dosing in children.

A current study of children demonstrates that high BMI is associated with greater renal toxicity after the second course of chemotherapy, most frequently causing electrolyte abnormalities.18 Patients with higher BMI also had a higher rate of wound complication following tumor resection. Wound complication then delays further chemotherapy. A high BMI ultimately led to worse overall survival rates: 69.7% in the high BMI group compared with 80.5% in the normal BMI group.18 Although BMI is not unanimously associated with poor outcome, it causes many comorbidities that make it more difficult for patients to recover from a disease such as osteosarcoma.

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Location of primary tumor

A primary tumor in the pelvis is an uncommon location (5% of cases), and patients with these tumors are at higher risk of relapse and death than patients with extremity tumors. Local recurrences of pelvic tumors range from 11% to 44%.21 In a recent cohort study of adolescents and young adults, patients with nonpelvic tumors had more than twice the 5-year event-free survival than patients with pelvic tumors.21 In fact, patients with pelvic tumors had similar 5-year event-free survival compared with patients with metastatic nonpelvic osteosarcoma. Survival is poorer due to the deep location of pelvic tumors, which makes them more difficult to treat and to visualize on plain radiographs. As a result, more pelvic tumors are diagnosed at a later stage. Due to the regional anatomy, pelvic tumors are more difficult to completely excise with adequate margins. Also, pelvic surgery puts patients at risk for injuries to vital organs or to nerves necessary for the movement of extremities or bowel and movement bladder function. Resecting part of the pelvis causes a shortage of muscular and bony architecture, requiring a more invasive surgery involving multiple surgical sites.

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Metastasis

Patients who have metastatic osteosarcoma at diagnosis have a poor overall survival rate. On average, 5-year overall survival for patients with all metastatic lesions is 20% to 40%.1 In a retrospective study of patients ages 13 to 74 years, those with localized disease survived 84 months longer on average compared with patients with metastasis.16 In a different study conducted by the Children's Oncology Group, adolescents and young adults with metastasis at diagnosis had a 36% 5-year overall survival compared with 74% for patients without metastasis.17 Although 15% to 20% of patients have detectable metastases at diagnosis, more than 80% have micrometastatic disease at initial diagnosis that cannot be detected with current imaging methods.3,16 This explains why the addition of systemic chemotherapy has drastically improved overall survival rates in all patients.

A study that evaluated 461 cases of extremity and pelvic osteosarcoma in all ages found that metastatic disease and tumor size greater than 5 cm at recurrence was associated with poorer overall survival.22 The estimated 5-year survival rate after recurrence went from 88% to 11% when tumors were 5 cm or larger; this is mostly due to the limited treatment options for larger tumors. Metastasis at diagnosis and at recurrence remains the most negative predictor of outcome.

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ENSURING ACCURATE DIAGNOSES

At initial presentation, osteosarcoma is often misdiagnosed as a more common condition. A recent study found that 80% of patients were originally misdiagnosed after having 1 to 3 weeks of pain. The initial diagnoses given to patients with an ultimate diagnosis of osteosarcoma included growing pains, stress fractures, sprains, and infections.7 Although the most likely diagnoses are investigated first, they should not be the only ones considered. Radiology and additional testing can be helpful in distinguishing between the multitudes of possible diagnoses (Table 1).

Diagnosing osteosarcoma early is crucial to early treatment and improved patient survival. Reasons for diagnostic delay include not obtaining a radiograph at the time of the original complaint, not considering malignancy and failing to identify bony changes that suggest malignancy on initial radiograph, and failing to repeat the radiograph at follow-up, regardless of initial diagnosis. Additionally, patients may have a delayed presentation, making it difficult to employ early identification and treatment. Overall, the disease may be too rare or insufficiently studied to elicit clinical suspicion—that is, osteosarcoma fails to be on the differential diagnosis list of many providers.

Primary care providers have a key role in the diagnosis and workup of a potential osteosarcoma due to the consistency of care and established relationships with their patients. Specific steps can aid in the diagnosis and should be implemented whenever an adolescent, particularly one ages 10 to 19 years, presents with symptoms greater than 1 month's duration of bone pain, limping, or redness or swelling near the area of pain. Unless the patient sustained a recent injury, these symptoms should lead to an increased level of suspicion. First, the clinician should obtain a radiograph of the entire area in question. If it reveals a sunburst appearance or some level of periosteal elevation, the diagnosis of osteosarcoma should be seriously considered. Following a suspicious or equivocal radiograph, the provider should order an MRI with contrast of the entire affected bone and simultaneously refer the patient for an orthopedic oncology consult. Obtaining an MRI early minimizes the need for imaging by the specialist and, in turn, can lead to an earlier diagnosis of osteosarcoma.23 The orthopedic oncologist and orthopedic surgeon will then determine if the MRI result warrants a bone biopsy. The ultimate responsibility of the primary care provider is to initiate the steps toward diagnosis.

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CONCLUSION

To improve diagnosis, clinicians must consider osteosarcoma as a plausible diagnosis in any child with persistent bone pain or limping. Because no screening methods exist for osteosarcoma, practitioners should be suspicious for osteosarcoma and must use their judgment when ordering radiographs. Additional imaging should be performed, specifically MRI, on patients presenting with pain and abnormalities on plain radiographs resembling trabecular disruption or vague osteosclerosis or osteolysis.

For patients diagnosed with osteosarcoma, follow-up radiographs and CT scans are essential to monitor for recurrence, especially in the first 2 to 3 years after the conclusion of treatment. Although nonmodifiable prognostic factors cannot be avoided, clinicians can aim to lower the occurrence of metastasis by diagnosing osteosarcoma in the early stages. The only way to complete this task is to eliminate assumptions and thoroughly investigate each complaint of pain in the most vulnerable patient populations.

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REFERENCES

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18. Altaf S, Enders F, Jeavons E, et al. High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2013;60(12):2042–2046.
19. Klimm B, Reineke T, Haverkamp H, et al. Role of hematotoxicity and sex in patients with Hodgkin's lymphoma: an analysis from the German Hodgkin Study Group. J Clin Oncol. 2005;23(31):8003–8011.
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Keywords:

osteosarcoma; sunburst; bone tumor; pediatric; limp; chemotherapy

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