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CA Cancer J Clin 2006; 56:366-375
doi: 10.3322/canjclin.56.6.366
© 2006 American Cancer Society
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Staging of Primary Malignancies of Bone

Robert K. Heck, Jr., MD, Terrance D. Peabody, MD and Michael A. Simon, MD

Dr. Heck is Assistant Professor, Department of Orthopaedic Surgery, University of Tennessee-Campbell Clinic, Memphis, TN.
Dr. Peabody is Professor of Surgery, Residency Director, Department of Orthopaedic Surgery, University of Chicago, Chicago, IL.
Dr. Simon is Professor of Surgery, Chief of Orthopaedic Surgery and Rehabilitation Medicine, Associate Dean of Graduate Medical Education, Department of Orthopaedic Surgery, University of Chicago, Chicago, IL.

This article is available online at http://CAonline.AmCancerSoc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 DIAGNOSTIC EVALUATION
 AJCC STAGING SYSTEM FOR...
 OTHER PROGNOSTIC FACTORS
 SUMMARY
 REFERENCES
 
Staging of bone sarcomas is the process whereby patients are evaluated with regard to histology, as well as the local and distant extent, of disease. Bone sarcomas are staged based on grade, size, and the presence and location of metastases. The system is designed to help stratify patients according to known risk factors. Proper staging helps define the prognosis for patients and helps guide their treatment. Furthermore, staging allows meaningful comparisons to be done among groups of patients.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
DIAGNOSTIC EVALUATION
 AJCC STAGING SYSTEM FOR...
 OTHER PROGNOSTIC FACTORS
 SUMMARY
 REFERENCES
 
The surgical staging system of musculoskeletal neoplasms was initially proposed by Enneking, et al.1 in 1980. As outlined by Enneking, et al.,1 the purposes of a staging system for musculoskeletal neoplasms are to "(1) incorporate the significant prognostic factors into a system that describes progressive degrees of risk of local recurrence and distant metastases to which a patient is subject, (2) stratify the stages so they have specific implications for surgical management, and (3) provide guidelines for adjunctive therapies." According to this system, malignant bone tumors were staged based on histologic grade, the intraosseous or extraosseous extent of the tumor, and the presence of distant metastases. Enneking, et al.1 showed that this system had prognostic significance and that it was able to help guide treatment. The system was evaluated and endorsed by the Musculoskeletal Tumor Society (MSTS) and later by the American Joint Committee on Cancer (AJCC). The surgical staging system (MSTS system) has remained the most widely used system by musculoskeletal oncologists to classify all patients with primary bone sarcomas. For over two decades, a time of great advances in imaging and understanding, the AJCC staging system for bone cancers had closely reflected the MSTS system and remained relatively unchanged.

According to the original MSTS staging system, low-grade bone tumors were classified as Stage I, high-grade tumors were classified as Stage II, and metastatic tumors were classified as Stage III (regardless of grade). These stages were subclassified based on the local extent of growth of the primary tumor. Bone tumors that had not grown beyond the compartment of origin (intracompartmental) had an A subclassification, whereas tumors that extended into the adjacent soft-tissue compartment (extracompartmental) had a B subclassification (Table 1). For example, a low-grade chondrosarcoma that was contained within the cortex was classified as Stage I-A. A high-grade osteosarcoma that was associated with a soft-tissue mass was Stage II-B. Because this system was designed before computed tomography (CT) and magnetic resonance imaging (MRI) were available, in some respects the A and B subclassifications served to indicate size. Furthermore, the system was designed to help guide surgical management before the advent of current multimodal treatment.


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  		TABLE 1 Musculoskeletal Tumor Society Staging System1

 
The previous AJCC staging system for primary malignancies of bone2 was almost identical to the MSTS system, with the exception of metastatic disease being classified as Stage IV (to remain consistent with the AJCC staging systems for other cancers) while Stage III was left undefined. Also, Stage IV was subdivided based on the presence of lymph node metastasis only (Stage IV-A) or the presence of distant metastases (Stage IV-B).

Recently, however, members of the AJCC made three major revisions to the system.3 Rather than using the intraosseous or extraosseous extent of the tumor for subdividing Stages I and II, tumor size was suggested as a better prognostic indicator. Specifically, a tumor size of less than 8 cm in any dimension was recommended as a favorable prognostic indicator. Second, tumors associated with skip metastases, defined as discontinuous disease in the same bone, were classified separately as Stage III. Finally, Stage IV tumors (those associated with distant metastases) were subdivided based on the presence of pulmonary metastases only (Stage IV-A) or metastases to other locations including bone (Stage IV-B) (Table 2).


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  		TABLE 2 Summary of Revisions to AJCC Staging System3

 

   DIAGNOSTIC EVALUATION
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSTIC EVALUATION
AJCC STAGING SYSTEM FOR...
 OTHER PROGNOSTIC FACTORS
 SUMMARY
 REFERENCES
 
An adequate history and physical examination are the first steps in evaluating a patient with a bone tumor. With few exceptions, patients with primary malignancies of bone complain of pain at the affected site. Initially, the pain often is activity related. Patients often attribute the pain to an episode of minor trauma, and many fail to promptly seek medical attention. Instead of improving, however, the pain progresses and becomes unrelated to activity. Many patients then complain of pain at rest and night pain. Often, a palpable mass is present before presentation to a physician.

Although some tumors demonstrate a sex predilection (eg, female predominance with giant cell tumors and parosteal osteosarcomas), this rarely is of diagnostic significance. Race, likewise, is of little significance with the exception that Ewing sarcoma is exceedingly rare in people of African descent. Family history occasionally can be helpful, as in cases of multiple hereditary exostosis and enchondromatosis. Age, however, may be the most important information obtained in the history because most bone tumors, both benign and malignant, occur within specific age ranges. For example, primary osteosarcoma usually occurs between the ages of 10 and 25 years; Paget osteosarcoma, 55 to 80 years; Ewing sarcoma, 5 to 25 years; primary chondrosarcoma, 30 to 60 years; and secondary chondrosarcoma, 25 to 50 years. Radiation-induced osteosarcoma typically occurs 5 to 20 years after radiation exposure.4

The physical examination should include evaluation of the patient's general health, as well as a careful examination of the part in question. A mass should be measured, and its location, shape, consistency, mobility, tenderness, local temperature, and change with position should be noted. Atrophy of the surrounding musculature should be recorded, as well as neurological deficits and adequacy of circulation. Potential sites of lymph node metastases should be palpated.

All suspected bone neoplasms should be evaluated initially with plain radiographs. Compared with any other test, conventional radiography still provides more useful diagnostic information for evaluation of bone lesions.5–14 Often, the patient's age and plain radiographic findings are sufficient to arrive at a specific diagnosis. Even if a specific diagnosis cannot be made, the aggressiveness of the lesion, and whether it is likely to be benign or malignant, usually can be determined by careful evaluation of the plain films. Inactive lesions usually have well-defined margins, often with a surrounding rim of reactive bone formation. Aggressive lesions usually have a less well-defined zone of transition between the lesion and the host bone. Cortical expansion can be seen with aggressive benign lesions, but frank cortical destruction usually is a sign of malignancy. Periosteal reactive new bone formation results when the tumor destroys cortex and may take the form of a Codman triangle, "onion-skinning," or a "sunburst" pattern. It usually is a sign of malignancy but may be present in some benign conditions such as infection or histiocytosis.

All patients with a suspected primary malignancy of bone should undergo MRI of the entire involved bone. It is the most accurate technique for determining the extent of disease both within and outside bone. MRI is the study of choice to determine the size of the tumor, as well as its anatomic relationships to surrounding tissues.5–15 It also is the best test to determine the presence of "skip" metastases (discontinuous lesions within the same bone). With regard to diagnosis, however, the MRI appearance is nonspecific, and MRI is not as useful as radiography in differentiating benign from malignant intraosseous lesions.

CT is the examination of choice for evaluating the lungs, the most common site for metastases from bone sarcomas.15–18 CT remains useful for local staging to characterize some lesions of the spine, pelvis, and scapula when plain radiographs have proven inadequate to evaluate the bony architecture. It also is useful to evaluate endosteal cortical erosion in a suspected chondrosarcoma.

Almost all bone sarcomas demonstrate increased activity on technetium bone scan; however, the same is true of most benign bone tumors. Its main use, therefore, is to determine the presence of multiple lesions or skeletal metastases.16–18 Angiography, which previously was used to determine the relationship of a neoplasm to the vessels, has been supplanted by MRI. Positron emission tomography (PET) is still considered investigational in the field of musculoskeletal oncology. It may prove to be useful in staging (especially for detecting nonpulmonary metastases), evaluating the response to preoperative chemotherapy, helping to direct subsequent treatment, and helping to detect recurrent local or metastatic disease during follow up. Currently, the role of PET remains undefined.19–31

Bone tumors should be completely evaluated before biopsy is done. The differential diagnosis, extent of the lesion, and potential resectability of the lesion can affect the type of biopsy, the placement of the biopsy incision, and the diagnostic management of the tissue obtained. A complete evaluation helps to narrow the differential diagnosis and to bring about a more accurate pathological diagnosis. Furthermore, studies such as CT, MRI, and bone scan can be adversely affected by postoperative changes in the tissues. If a lesion is suspected to be a bone sarcoma, the biopsy should be performed by a surgeon who is well educated in techniques of musculoskeletal oncology to minimize the many risks that are associated with a poorly performed biopsy.32,33 The biopsy preferably is done by the surgeon who will perform the definitive procedure (resection or amputation) or by a surgeon working in close conjunction with this person. Similarly, if a radiologist will be performing an image-guided needle biopsy, this procedure should be planned in conjunction with the treating surgeon. Histologic analysis is then performed to determine the histologic type of tumor as well as its grade.

Patients suspected of having a primary malignancy of bone, therefore, should be evaluated with radiographs of the involved bone and chest. An MRI (or a CT in some cases) of the lesion delineates the extent of the lesion in the bone, as well as soft tissue involvement and the relationship to other anatomic structures. A bone scan should be obtained to detect any other areas of skeletal involvement, and a CT scan of the chest should be obtained to detect pulmonary metastases. The biopsy of a suspected bone sarcoma should be done after staging is complete, and only by the surgeon who will perform the definitive procedure or by an individual working in close conjunction with this surgeon.


   AJCC STAGING SYSTEM FOR BONE TUMORS
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSTIC EVALUATION
 AJCC STAGING SYSTEM FOR...
OTHER PROGNOSTIC FACTORS
 SUMMARY
 REFERENCES
 
The present AJCC system for bone sarcomas3 (Tumor-Node-Metastasis [TNM] system) is based on tumor grade and size and the presence and location of metastases. Stage I tumors are low grade. Stage II tumors are high grade. Stages I and II are subdivided based on size. Stages I-A and II-A are less than or equal to 8 cm in their greatest linear measurement. Stages I-B and II-B are greater than 8 cm in size. Stage III tumors are those that have "skip" metastases, which are defined as discontinuous lesions within the same bone. Stage IV-A includes patients with pulmonary metastases only, whereas Stage IV-B includes patients with nonpulmonary metastases (eg, bone, liver, lymph node) (Tables 3 and 4).


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  		TABLE 3 Definition of TNM and Grade [G]3

 

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  		TABLE 4 Stage Grouping3

 
In a study comparing staging systems for bone sarcomas, Heck, et al.34 showed statistically significant differences in the prognoses among groups of patients with Stage I, Stage II, and Stage IV disease. With the numbers available, the authors were unable to show a significant difference between the A and B subclassifications of Stages I, II, and IV (Figure 1). Similarly, the authors were able to demonstrate significant differences among Stages I, II, and III of the MSTS system, but were unable to demonstrate differences between the subclassifications of Stages I and II. As discussed later in this manuscript, multiple studies have shown grade, size, presence, and location of metastases to be of prognostic significance. The authors are not aware, however, of a study that specifically demonstrates compartment status to be of prognostic significance.


Figure 1
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  		FIGURE 1 Probability of Survival Based on the New AJCC Staging System.34

In all, 245 patients at 1 institution (I-A, 45; I-B, 26; II-A, 55; II-B, 76; III, 5; IV-A, 26; IV-B, 12) were included. There were significant (P < 0.001) differences among patients with Stage I, Stage II, and Stage IV disease. There were no significant differences between patients with Stages I-A and I-B disease (P = 0.15), between patients with Stages II-A and II-B disease (P = 0.14), or between patients with Stages IV-A and IV-B disease (P = 0.21). Reprinted from Heck RK, Stacy GS, Flaherty MJ, et al.34 with permission from Lippincott Williams & Wilkins.

 
Similar to other cancers, it is well established that the presence of metastases at diagnosis is the most important indicator of poor prognosis in patients with primary malignancies of bone.35–43 Furthermore, it has been shown that the location of metastases also is extremely important for these patients. Patients with nonpulmonary metastases, such as bone, lymph node, or hepatic metastases, have a much worse prognosis than patients with only pulmonary metastases.38,44–48 This fact is appropriately reflected by the recent subdivision of Stage IV into Stage IV-A (pulmonary metastases only) and Stage IV-B (nonpulmonary metastases). Patients with high-grade bone sarcomas who present with bone metastases continue to do very poorly despite very aggressive modern multimodal treatment. Conversely, patients with bone sarcomas who present with only pulmonary metastases have been shown to have a 25% to 50% chance of long-term survival.15,36,38,45,49 One caveat, however, is that patients with low-grade lesions, such as low-grade hemangioendothelioma or low-grade chondrosarcoma, probably are not appropriately classified as having Stage IV-B disease even if multiple bones are involved because these patients have relatively good prognoses. Stage IV-B is probably best reserved for patients with high-grade tumors and nonpulmonary metastases.34

Grading of bone sarcomas is somewhat subjective and is based on the degree of cellularity and extent of anaplasia. Grading is best done by a pathologist specifically trained in this area. Low-grade sarcomas typically have cytologic features similar to the tissue of origin. High-grade sarcomas, on the other hand, may appear completely undifferentiated. Necrosis and mitotic figures are more common in high-grade tumors, but these parameters are not used in grading. Cartilage and vascular tumors are graded from one to three; most other sarcomas are graded from one to four. Some tumors are not typically graded; for example, Ewing sarcomas are all considered high grade, whereas adamantinomas are low grade.4

It is well established that tumor grade is an extremely important prognostic indicator for patients with primary malignancies of bone. Low-grade osteosarcomas are associated with a much better prognosis than conventional high-grade osteosarcomas.42,50–53 Low-grade chondrosarcomas have a better prognosis than high-grade chondrosarcomas.54–59 Dedifferentiated chondrosarcomas (high grade) are associated with an extremely poor prognosis.55,60–64 Similarly, low-grade chordomas are associated with a much better prognosis than their high-grade counterpart, dedifferentiated chordomas.65–75 Adamantinoma, a low-grade tumor, is associated with a relatively good prognosis.76–78 Grade has been shown to be of prognostic significance for malignant fibrous histiocytoma of bone and fibrosarcoma of bone.79–81 Finally, Ewing sarcoma and other high-grade sarcomas of bone carry prognoses similar to that of high-grade osteosarcoma.38–41,43,82–86 Thus, the strategy of using grade to separate Stage I and Stage II tumors has remained unchanged for over 25 years and remains appropriate.

Stages I and II are subdivided based on the local growth of the tumor. This subdivision was previously defined by the intra- or extracompartmental status of the tumor. The current AJCC system, however, uses a linear size measurement to make this separation. The strategy of using compartmental status to subclassify tumors was based on the surgical concept that a patient with a small tumor with extraosseous extension may require a more extensive operative procedure than a patient with a large tumor that remains entirely intraosseous. The MSTS system was a surgical staging system that originally was designed to help guide surgical treatment. It was therefore argued that only by recognizing compartmental status can we do any meaningful analysis among groups of patients and their respective operative procedures.87 The same reasoning, however, can be applied to the strategy of using tumor size to help stage tumors in the AJCC system. A large extraosseous tumor usually requires a much more extensive operative procedure than does a small extraosseous tumor. Because most bone sarcomas are extraosseous on diagnosis, compartmental status does little to subdivide Stages I and II in the MSTS staging system. This especially is true for high-grade bone tumors because most are classified as MSTS Stage II-B. Furthermore, the MSTS system was originally devised at a time when plain radiographs were the only imaging study used for staging. Compartment status was a surrogate for size before the availability of axial imaging. The current availability of axial imaging improves the ability to measure size accurately before treatment. Although size and compartment status have a bearing on the operative procedure and are interrelated, size will likely prove to be a better prognostic indicator because it is an objective measure of the complex interaction between the tumor and host. In addition, many current cancer staging systems use size as a prognostic indicator.

If size is to be used in the staging system, the next issue to be considered is how the size of the tumor should be measured. Recent studies that have shown size to be a statistically significant prognostic factor for osteosarcoma and Ewing sarcoma have used various parameters to determine the definition of a large tumor. Parameters that have been used include an absolute tumor volume greater than 60 cc,88 66 mL,39 100 mL,38,55 150 mL,89–91 200 mL,83 300 mL,37 580 cc,40 and 700 mL; relative size greater than one-third the size of the involved bone36; and linear size greater than 8 cm,42,43,86 9 cm,92 and 10 cm.54,93 Although it is argued that absolute tumor volume is the most accurate prognostic indicator,90 an accurate measurement of this parameter is more difficult to obtain. Likewise, relative tumor size may be difficult to determine in flat bones. A simple linear measurement, however, is easy to obtain from an MRI scan taken before chemotherapy and is readily reproducible. Furthermore, a linear cutoff of 8 cm fairly evenly divides the tumors into the A and B subclassifications of the new AJCC system.34 This is in contrast to the high proportion of high-grade tumors that were classified as Stage II-B disease in the MSTS system.

Patients with skip metastases are classified as having Stage III disease in the new AJCC system. Skip metastases in this staging system are defined as "two or more discontinuous lesions in the same bone." It is still somewhat controversial exactly how this should be interpreted. It is well established that osteosarcoma patients with skip metastases have a very poor prognosis.94–97 Conversely, strict adherence to the definition will result in some patients with multifocal low-grade lesions, such as hemangioendotheliomas and some chondrosarcomas, being classified as having Stage III disease if multiple lesions occur in one bone. These patients obviously have a much better prognosis than those with high-grade skip metastases. This can result in a very disparate group of patients, some of whom have a relatively good prognosis and some of whom have a dismal prognosis. In one study, three of five patients diagnosed as having AJCC Stage III tumors actually had low-grade tumors. All three of these patients had Stage I-A disease according to the MSTS system, and all three have remained disease-free.34 Thus, it is likely that only patients with high-grade discontinuous tumors should be classified as having Stage III disease.


   OTHER PROGNOSTIC FACTORS
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSTIC EVALUATION
 AJCC STAGING SYSTEM FOR...
 OTHER PROGNOSTIC FACTORS
SUMMARY
 REFERENCES
 
In a critical review of the literature on nonmetastatic osteosarcoma, Davis, et al.98 concluded that histologic response to chemotherapy was the only potential prognostic variable that maintained statistical significance by multivariate analysis. It is our opinion, however, that a staging system should not be based on treatment-related variables. Instead, it should be based only on parameters that can be evaluated at the time of diagnosis. Regardless, it is well accepted that patients with osteosarcoma36,42,88–90,99,100 and Ewing sarcoma43,83,84,86 whose tumors demonstrate greater than 90% necrosis after neoadjuvant chemotherapy have a relatively good prognosis when compared with patients with a poor response. It is still unclear, however, exactly how this fact should impact the treatment of individual patients. Although some institutions have incorporated chemotherapy protocols that customize postoperative regimens based on the results of the preoperative regimens,101–104 the authors are not aware of a study that has proved this strategy to be advantageous. Nevertheless, extent of necrosis remains a good prognostic indicator. Furthermore, it is an extremely important parameter for clinical studies evaluating chemotherapy regimens.

Tumor location also has been shown to be of prognostic significance in several studies, although this parameter has never been reflected in bone cancer staging systems. In general, axial, pelvic, and proximal femoral locations are associated with a worse prognosis than more distally based tumors.36,38,42,55,88,93,99,105 The reasons for this are most likely multifactorial. It is difficult to differentiate the effects of size from the effects of location because proximal tumors tend to be larger than distal tumors at presentation. It is possible that proximally located tumors behave in a more aggressive manner because of a better blood supply, increased temperature conducive to growth, or better access to venous circulation for metastases. It also is possible that proximal tumors might simply escape detection longer than distal tumors, thus allowing them to grow larger and develop micrometastases before diagnosis. Furthermore, the surgeon's ability to resect a bone sarcoma with adequate margins has a bearing on the patient's prognosis.36,37,44,46,55,57,59,88 Although treatment-related variables should not be considered in a staging system, it is obvious that many spinal and pelvic tumors cannot be completely resected with adequate margins.

Another prognostic factor that is not reflected in the staging system is the total metastatic burden. Although the staging system appropriately distinguishes patients with pulmonary metastases only from patients with nonpulmonary metastases, there is no allowance for the number or size of the metastases. Although the presence of a single bone metastasis at presentation portends a poor prognosis,38,44–48 the same is not true for a solitary resectable pulmonary metastasis. Patients with one or a few small resectable pulmonary metastases might have a probability of long-term survival over 50%.45,46,49,106 Conversely, patients with numerous, large, or unresectable pulmonary metastases have a much worse prognosis.15,45,46,48,107 Thus, Stage IV-A is a very disparate group of patients, some of whom have a very good prognosis and some of whom have a very poor prognosis.

The AJCC staging system is strictly an anatomic system. Whereas anatomic size is currently used to subclassify Stages I and II, it is possible that future classification systems will use other parameters to measure the total tumor burden. Multiple studies have suggested that serum lactate dehydrogenase (LDH) levels can be used to evaluate tumor activity. Furthermore, pretreatment serum LDH levels have been shown to have prognostic significance for patients with osteosarcoma100,108 and Ewing sarcoma.38,41,82,109

Finally, multiple studies have shown that molecular abnormalities can be correlated with outcome in patients with osteosarcoma and Ewing sarcoma. For example, studies have shown that increased P-glycoprotein expression in tumor cells has prognostic significance for patients with osteosarcoma.91,110,111 P-glycoprotein is the product of the multidrug resistance 1 gene. It is an adenosine triphosphate–dependent pump capable of removing chemotherapeutic agents such as doxorubicin from tumor cells. A high level of c-erbB-2 proto-oncogene, which codes for human epidermal growth factor receptor 2, also has been shown in a study to be associated with a poor outcome in patients with osteosarcoma.112 Other molecular markers that have been shown to be associated with worse outcomes in patients with osteosarcoma include overexpression of heat shock protein 27,113 telomerase expression,114 vascular endothelial growth factor expression,115 expression of CD44 isoforms,116 and overexpression of the proliferative marker Ki-67.117 Ewing sarcoma patients with the EWS-FL1 type 1 translocation have a better prognosis than patients with other types of translocations.40 Also for Ewing sarcoma patients, p53 expression,39,118–120 INK4A deletion,85 or p16/p14ARF deletion120 (all cell-cycle regulators) have been associated with a poor outcome. Future studies in this area will greatly increase our understanding of the pathogenesis of these tumors. It is likely that future staging systems and treatment protocols will reflect this new knowledge.


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSTIC EVALUATION
 AJCC STAGING SYSTEM FOR...
 OTHER PROGNOSTIC FACTORS
 SUMMARY
REFERENCES
 
Staging is the process whereby patients are evaluated with regard to the histology, as well as the local and distant extent, of disease. This process helps to define the prognosis for patients and helps guide their treatment. Proper staging also allows for meaningful comparisons to be made among groups of patients. This is especially important when studies are performed in an attempt to develop new treatment strategies. The previous AJCC system for bone cancers closely reflected the more commonly used MSTS staging system. It still is unclear whether or not the recent changes in the system will better serve physicians who treat patients or others who perform research in the field of musculoskeletal oncology. The current AJCC staging system is based on tumor grade and size and the presence and location of metastases. It is a strictly anatomic system. New discoveries in the field of molecular biology will likely contribute greatly to future tumor classification systems and treatment protocols.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 DIAGNOSTIC EVALUATION
 AJCC STAGING SYSTEM FOR...
 OTHER PROGNOSTIC FACTORS
 SUMMARY
 REFERENCES
 

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