Primary malignant musculoskeletal tumors are an inhomogeneous group of lesions originating from mesenchymal tissues.
Primary malignant musculoskeletal tumors are an inhomogeneous group of lesions originating from mesenchymal tissues.
Soft-tissue sarcomas can derive from fatty tissue (liposarcoma), muscles (leiomyosarcoma, rhabdomyosarcoma), connective tissue (fibrosarcoma), blood vessels (angiosarcoma), and neurogenic tissue (malignant peripheral nerve sheath tumor, malignant schwannoma). Bone sarcomas arise from either bony tissue (osteosarcoma) or cartilage (chondrosarcoma).
Sarcomas are relatively rare compared with colon cancers, bronchial tumors, or malignant breast lesions. The incidence of sarcoma is about one or two new cases per 100,000 individuals per year. Osteosarcomas and the Ewing's sarcoma family, which includes peripheral neuroectodermal tumors, are important childhood cancers. Adults most often present with osteosarcoma and chondrosarcoma.
The majority of musculoskeletal tumors arise in the extremities, with the lower limbs affected more frequently than the upper limbs. Men and boys are affected more often than women and girls. Younger patients generally have better outcomes, and new surgical limb salvage procedures are now delivering excellent functional results.
Prompt diagnosis of these tumors is crucial, as prognosis and therapeutic options are much more promising at the early stages of malignancy. Diagnosis is often delayed, however, owing to a lack of specific clinical symptoms and misinterpretation of radiological findings. Several lesions may be detected incidentally on imaging studies. Typical symptoms include pain, palpable mass, and pathological fractures.
Staging is performed according to systems set out by the Musculoskeletal Tumor Society System and the American Joint Committee on Cancer.1 Criteria used for staging include tumor extent (T-stage), presence of lymph node metastases (N-stage), presence of distant metastases (M-stage), and histological grading (G). Approximately 15% to 20% of patients with osteosarcoma present with pulmonary metastases at initial staging. Metastases can occasionally occur in the bone, lymph nodes, brain, or soft tissue as well.
Imaging plays a major role in the diagnostic workup, treatment, and post-therapy evaluation of patients with musculoskeletal tumors. Classification of the lesion as malignant or benign, biopsy guidance, local staging, treatment response, and follow-up are all based mainly on imaging.
Several imaging modalities have been used for the diagnosis of musculoskeletal tumors. Plain-film radiography and ultrasound are generally used first, because of their availability and low cost. X-rays will typically be requested for suspect bone lesions and ultrasound for soft-tissue lesions. If these modalities show normal or indeterminate findings, but the patient has persisting symptoms, then additional imaging studies will often be required.
Sarcoma staging was performed with CT prior to the growth of clinical MRI. CT now has a more limited role, though it remains useful when assessing cortical involvement or cortically based lesions such as osteoid osteoma, periosteal reaction, matrix mineralization, and lesions in flat bones.
MRI is now considered the reference standard for local staging of musculoskeletal tumors, due to the modality's superior anatomic resolution and its delineation of bony structures, soft tissue, vessels, and nerves. MRI can determine the intra- and extracompartmental extent of the tumor and its relationship to critical neurovascular structures. The modality is also highly sensitive to bone marrow lesions.
Three-phase bone scintigraphy may also be used to evaluate bone tumors. The rise of MRI and PET, however, means that the importance of the conventional bone scan is decreasing. Coregistered PET/CT studies have gained widespread acceptance over the past few years for general oncology applications,2 but experience in patients with musculoskeletal tumors remains limited at present.3
There is no gold standard MRI protocol for imaging sarcomas. The majority of examinations are performed on 1.5T or 3T systems. The most commonly used sequences are T1- and T2-weighted (fast/ultrafast) spin-echo imaging, T1-weighted imaging with fat saturation, short-tau inversion recovery, and gadolinium-enhanced T1-weighted MRI. The acquisition of sagittal, axial, and coronal orientations will depend on the type and site of the tumor and physicians' preferences. Most MRI protocols include at least one sequence covering the entire affected bone/limb with a large field-of-view for identification of skip lesions.
Commercially available MRI systems already exhibit superior image quality in terms of signal-to-noise ratio and contrast-to-noise ratio. Further¬more, a large variety of new sequences are constantly being evaluated. Research into new MRI techniques, such as diffusion-weighted imaging, MR elastography, and MR spectroscopy, is currently being assessed. These techniques are really in their infancy, however, in terms of clinical use.
MRI has several possible roles in the evaluation of malignant musculoskeletal tumors. The tumor's blood supply can be imaged using contrast-enhanced dynamic (perfusion) MRI. Gadolinium-enhanced MRI can also assist in the differentiation of benign and malignant lesions in certain cases, such as cystic myxoid sarcomas. Another possible indication is differentiation of high- and low-flow hemangiomas. This distinction is used to decide whether the patient should undergo embolization or surgery. Dynamic contrast-enhanced MRI can also be used to differentiate slowly enhancing lesions; for example, hematoma and hemorrhagic sarcoma, as well as cystic and aneurysmatic lesions.4
MRI is an important tool for biopsy guidance, ensuring that the needle is directed into the vascularized, viable part of the tumor. This approach should avoid unrepresentative or misleading histologies. It may be best to perform MRI prior to biopsy, given that hematoma and edema caused by intervention can complicate diagnoses.5 The overlap in enhancement patterns between malignant and benign lesions, however, means that MRI cannot replace biopsy altogether for unclear musculoskeletal lesions.
Early studies showed that MRI was unable to distinguish benign musculoskeletal masses from malignant lesions in many cases. An accuracy of 55% was reported, with the presence of malignant lesions overestimated by 39%.6 Other investigators have examined this same question separately for soft-tissue masses and bone tumors. MRI has been reported to have a sensitivity of 66% and a specificity of 58% when differentiating benign soft-tissue masses from malignant tumors. These results suggest that MRI has limited clinical value for definitive diagnoses. A slightly different picture can be found when considering malignant bone tumors-here, the sensitivity rises to 86% and the specificity to 67%.7 Some researchers now suggest that MRI should be used to estimate the tumor's biological activity rather than its status as benign or malignant. This could be achieved using contrast-enhanced or perfusion MRI to evaluate typical enhancement patterns in relation to their time-activity curve.7 Presurgical monitoring during neoadjuvant chemotherapy is another possible indication for MRI. This could help define the optimal time point for surgery. Dynamic contrast-enhanced and diffusion-weighted MRI promise to distinguish between therapy-induced changes and viable persistent tumor.8,9 Metabolic imaging with PET/ CT or PET/MRI may, however, be a better tool for assessing treatment response. Although whole-body MRI is becoming more widespread, it is time-consuming and could lead to contrast protocols being compromised.
Histopathologic classification is a vital step in the management of sarcomas. Tumor grade will have a significant impact on prognosis. Sarcomas can be extremely heterogeneous, and biopsies should be directed toward the most aggressive part of the lesion. PET/CT can identify the most metabolically active tumor part (Figure 1).
Fluorine-18 FDG uptake, measured semiquantitatively as the maximum standardized uptake value, has been shown to correlate with histopathologic grading in sarcomas.10 This approach has certain limitations, however, due to overlap of FDG uptake in benign and malignant soft-tissue and bone sarcomas.11,12 Although FDG uptake of sarcomas is typically higher than that of benign lesions, some nonmalignant tumors can be avidly FDG-active, leading to misinterpretations. Examples include fibrous dysplasia, chondroblastoma, and inflammatory lesions such as Brodie abscess.13,14
MRI is clearly superior to PET alone for viewing the anatomic details of tumor extent. Adding CT to PET helps overcome this weakness, particularly with reference to the bony anatomy. PET/CT studies can also reveal periosteal reactions, cortical destruction, calcifications, and other important details. The staging accuracy of combined PET/CT has been shown to be significantly higher than PET alone in bone and soft-tissue sarcoma.3
PET/CT is increasingly being used to monitor treatment response in a variety of cancers, including lymphoma, gastrointestinal stromal tumors, and lung cancer. Evaluation of therapy response is important for sarcomas as well. The percentage of tumor necrosis found in histology after chemotherapy has been shown to be a powerful predictor of outcome in sarcoma patients.15 Although MRI is often used for this indication, it is limited in its ability to differentiate between viable and nonviable tumor parts. FDG uptake offers a much better reflection of the number of viable tumor cells (Figure 2).16,17
Another important advantage of a combined PET/CT protocol is the possibility of obtaining high-resolution CT images of the lung. Lung metastases occur in a significant number of sarcoma patients. Their detection may alter the prognosis significantly. Small lung metastases may not be seen on FDG-PET because of their small size and respiratory motion. This is especially true for metastases in the basal parts of the lungs. PET/CT protocols in sarcoma patients should consequently include a diagnostic lung CT examination.18
Integrated whole-body PET/MR scanners are not yet available commercially, and their clinical value remains subject to speculation. PET/MR studies are currently derived from software-based fusion of PET and MR images obtained on separate scanners.19,20 We have found this process to be difficult and time-consuming. Identical patient positioning is crucial to obtain a perfect match, but variance in scanner geometries and examination protocols make this tricky to achieve in practice. More studies are needed to evaluate the possible value of integrated PET/MR scanners in sarcoma patients. These investigations should be based on prospective coregistration of images, not retrospective fusion.
Adequate modality selection is crucial for the successful diagnosis and treatment of malignant musculoskeletal tumors. MRI is the most important "second-step" imaging tool if x-ray or ultrasound findings are suspicious for a bone or soft-tissue tumor. MRI can help assess a lesion's malignancy, reveal its extension, and guide the required biopsy. CT and bone scintigraphy may be helpful in selected cases.
The role of PET/CT in malignant musculoskeletal tumors is not yet clearly defined. This modality can certainly provide important information for biopsy guidance, tumor staging, and therapy response.
Coregistered PET/MR images may be able to combine the benefits of MRI with those of PET/CT, though this needs further evaluation. Integrated PET/MRI systems promise to reduce the time required for scanning and image fusion and thus reduce patients' radiation burden. No imaging modality can yet replace the need for biopsy in ambiguous cases.
DR. STROBEL is a dual-board-certified radiologist and nuclear medicine physician, and DR. HANY is a dual-board-certified radiologist and nuclear medicine physician, at the University Hospital Zurich, in Switzerland. Both are consultants in nuclear medicine. DR. VEIT-HAIBACH is a resident in the department of nuclear medicine at the same institution.
1. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer staging manual, 6th ed. New York: Springer-Verlag, 2002.
2. Antoch G, Saoudi N, Kuehl H, et al. Accuracy of whole-body dual-modality fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: comparison with CT and PET. J Clin Oncol 2004;22(21):4357-4368.
3. Tateishi U, Yamaguchi U, Seki K, et al. Bone and soft-tissue sarcoma: preoperative staging with fluorine 18 fluorodeoxyglucose PET/CT and conventional imaging. Radiology 2007;245(3):839-847.
4. Verstraete KL, Van der Woude HJ, Hogendoorn PC, et al. Dynamic contrast-enhanced MR imaging of musculoskeletal tu¬mors: basic principles and clinical applications. J Magn Reson Imaging 1996;6(2):311-321.
5. Verstraete KL, Lang P. Bone and soft tissue tumors: the role of contrast agents for MR imaging. Eur J Radiol 2000;34(3):229-246.
6. Ma LD, Frassica FJ, Scott WW, Jr., et al. Differentiation of benign and malignant musculoskeletal tumors: potential pitfalls with MR imaging. Radiographics 1995;15(2):349-366.
7. Barile A, Regis G, Masi R, et al. Musculoskeletal tumours: preliminary experience with perfusion MRI. Radiol Med (Torino) 2007;112(4):550-561.
8. Dyke JP, Panicek DM, Healey JH, et al. Osteogenic and Ewing sarcomas: estimation of necrotic fraction during induction chemotherapy with dynamic contrast-enhanced MR imaging. Radiology 2003;228(1):271-278.
9. Lang P, Wendland MF, Saeed M, et al. Osteogenic sarcoma: noninvasive in vivo assessment of tumor necrosis with diffusion-weighted MR imaging. Radiology 1998;206(1):227-235.
10. Folpe AL, Lyles RH, Sprouse JT, et al. (F-18) fluorodeoxyglucose positron emission tomography as a predictor of pathologic grade and other prognostic variables in bone and soft tissue sarcoma. Clin Cancer Res 2000;6(4):1279-1287.
11. Aoki J, Watanabe H, Shinozaki T, et al. FDG PET of primary benign and malignant bone tumors: standardized uptake value in 52 lesions. Radiology 2001;219(3):774-777.
12. Aoki J, Watanabe H, Shinozaki T, et al. FDG-PET for preoperative differential diagnosis between benign and malignant soft tissue masses. Skeletal Radiol 2003;32(3):133-138.
13. Strobel K, Bode B, Lardinois D, Exner U. PET-positive fibrous dysplasia-a potentially misleading incidental finding in a patient with intimal sarcoma of the pulmonary artery. Skeletal Radiol 2007;36(Suppl 1):S24-S28.
14. Strobel K, Hany TF, Exner GU. PET/CT of a Brodie abscess. Clin Nucl Med 2006;31(4):210.
15. Raymond AK, Chawla SP, Carrasco CH, et al. Osteosarcoma chemotherapy effect: a prognostic factor. Semin Diagn Pathol 1987;4(3):212-236.
16. Schulte M, Brecht-Krauss D, Werner M, et al. Evaluation of neoadjuvant therapy response of osteogenic sarcoma using FDG PET. J Nucl Med 1999;40(10):1637-1643.
17. Shapeero LG, Vanel D. Imaging evaluation of the response of high-grade osteosarcoma and Ewing sarcoma to chemotherapy with emphasis on dynamic contrast-enhanced magnetic resonance imaging. Semin Musculoskelet Radiol 2000;4(1):137-146.
18. Daldrup-Link HE, Franzius C, Link TM, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. AJR 2001;177(1):229-236.
19. Somer EJ, Benatar NA, O'Doherty MJ, et al. Use of the CT component of PET-CT to improve PET-MR registration: demonstration in soft-tissue sarcoma. Phys Med Biol 2007;52(23):6991-7006.
20. Somer EJ, Marsden PK, Benatar NA, et al. PET-MR image fusion in soft tissue sarcoma: accuracy, reliability and practicality of interactive point-based and automated mutual information techniques. Europ J Nucl Med Mol Imaging 2003;30(1):54-62.