Thomas F. Hany, MD

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.

 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,

 but experience in patients with musculoskeletal tumors remains limited at present.

There is no gold standard MRI protocol for imaging sarcomas. Most 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 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 and contrast-to-noise ratios. 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.

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.

 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 

 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, sensitivity rises to 86% and specificity to 67%.

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.

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.

 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.

 This approach has certain limitations, however, due to overlap of FDG uptake in benign and malignant soft-tissue and bone sarcomas.

 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.

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 PET/CT has been shown to be significantly higher than PET alone in bone and soft-tissue sarcoma.

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.

 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).

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.

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.

 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 

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 may be able to combine the benefits of MR with those of PET/CT, though this needs further evaluation. Integrated PET/MR 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. 



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 tumors: 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.



Articles

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).

Imaging helps in diagnosis of musculoskeletal masses

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.

 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.

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.

 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%.

 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%.

 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.

 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.

 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).

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.

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.

 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.

Imaging aids diagnosis of musculoskeletal masses

Integrated PET/CT scanners entered clinical practice in 2001. Their quasisimultaneous acquisition of complementary anatomic and functional information has revolutionized diagnosis and treatment monitoring for many oncological diseases.

PET/CT has the advantage of acquiring whole-body examinations in a single step. This enables referring oncology physicians to plan therapy according to the imaging and complementary laboratory results. Defining the extent of disease according to existing guidelines is not easy, however. These guidelines are generally based on experiences with stand-alone CT and PET systems and long follow-up studies. Questions then arise: Do we need combined PET/CT response criteria, and for which cancers might these be useful?

CT-based evaluations of therapy use changes to tumor size and/or characteristic contrast enhancement patterns to indicate changes to underlying morphology. Either Response Evaluation Criteria for Solid Tumors (RECIST)1 or World Health Organization criteria for solid tumors can be used to define therapy response. These criteria have also been adapted for other solid tumors, such as pleural mesothelioma.2

RECIST has become the most widely used response tool in routine clinical applications, following evidence that unidimensional and bidimensional criteria show no relevant differences in response evaluation or prognostic impact.3 Contrast-enhancement patterns can also play an important role in monitoring treatment response. Central necrosis of lesions and cystic degeneration are widely accepted parameters, and they were used routinely prior to PET/CT imaging.

PET uses radioisotope tracers to depict metabolic changes indicative of malignancy. Fluorine-18 FDG is used most widely for general oncological tasks. A high proportion of experience in diagnosis and therapy response with PET is based on F-18 FDG. Other PET tracers under investigation include carbon-11 methionine, F-18 tyrosine, and F-18 DOPA.

Measurements of functional information generally include a standardized uptake value (SUVmax). This measurement is regarded as the gold standard. Alternative methods, such as total lesion glycolysis or tumor volume defined by PET measurements, are currently the subject of trials. Therapy monitoring with FDG-PET is generally based on consensus criteria from the European Organisation for Research and Treatment of Cancer (EORTC).4 The criteria have not been revised since their introduction in 1999, though they have been adapted for several tumor entities. Combined PET/CT response criteria are likely needed to assess tumor regression properly.

Combined PET/CT evaluation has already been shown to have a huge impact on the diagnosis of several cancers and is expected to expand to other applications.

Lymphoma. The imaging subcommittee of the International Harmonization Project in lymphoma has produced a new guideline on PET and PET/CT response criteria for Hodgkin's disease and aggressive non-Hodgkin's lymphoma.5 The "basic" EORTC parameters had previously defined progressive metabolic disease, stable metabolic disease, partial metabolic response, and complete metabolic response in terms of percentage differences between actual SUVmax and baseline SUVmax. The new criteria take CT parameters into account as well.

The guidelines state that contrast-enhanced CT may serve as an adequate alternative for therapy assessment. They recommend that either contrast-enhanced CT or PET/CT be used, at least for initial staging. The PET component of PET/CT, however, is still highlighted as the leading response tool. CT parameters are used partly to define the location of lesions and extent of involvement for certain indications, such as hepatic and splenic lesions and lymph nodes.

Some problems related to combined response evaluation are not discussed. Gross disease will shrink and glucose metabolism decrease, causing a reduction in SUV in most patients. Residual morphological tissue (up to 2-cm diameter, short axis) without metabolic activity can be found during therapy or at the end of treatment in some patients, however. This is especially the case for patients starting treatment with large lymph node masses. If PET is taken to be the main response tool, then these residual masses are not considered relevant. An assessment based on CT alone would have classified these patients as partial responders. PET/CT, on the other hand, classifies them as complete metabolic responders (Figure 1).

Data evaluating the clinical significance of these residual nonactive masses are not yet available. Prospective studies are needed to determine if these patients relapse early or tend to have a higher overall relapse rate.

Colorectal cancer. Contrast-enhanced abdominal CT is generally performed in patients with colorectal cancer. The presence and extent of liver metastases, or other distant metastases, are of particular interest. The therapeutic strategy is different in rectal cancer. Diagnosis of a T3-stage cancer and any N-stage disease will be followed by neoadjuvant radio/chemotherapy. Pelvic MRI is considered the reference standard in these patients.

PET has already been shown to be more accurate than contrast-enhanced CT in staging colorectal cancer. This is especially true for M-staging, owing to PET's superior detection of distant metastases. PET has additionally shown potential in monitoring treatment response in patients with hepatic metastases.6

PET/CT colonography has shown superior results in TNM-staging compared with CT alone.7 Combining PET and CT criteria could still be useful for the evaluation of rectal cancer after radio/chemotherapy and for the assessment of hepatic metastases. Decreases in metabolic activity and lesion size, according to EORTC and RECIST criteria, correlate in most cases. Histological evaluation of residual masses with normalized FDG uptake, however, reveals viable tumor tissue in the majority of cases (Figure 2).

Data on the relationship among FDG avidity, the size and number of lesions after neo-adjuvant chemotherapy, and patient outcome are not yet available. A combination of CT- and PET-based criteria could consequently help when planning treatment strategies for patients with colorectal cancer.

Breast cancer. CT plays no role in diagnosing primary breast cancer, though it can be used to detect distant bone and soft-tissue metastases. PET has again shown encouraging results in the detection of lymph nodes and distant metastases. PET/CT has performed better than PET alone when diagnosing metastatic and recurrent breast cancer.8

The evaluation of bone metastases during therapy is rather complicated. Osteoblastic metastases may initially be overlooked on PET in certain cases, due to an absence of FDG uptake. These same metastases will be clearly visible on CT.9,10 How should they be evaluated? Analysis of these metabolically inactive masses should seemingly be based on morphological criteria. But RECIST criteria regard bone metastases as nonmeasurable lesions, which makes post-therapy follow-up challenging.

Osteolytic metastases, on the other hand, are detected easily on CT and PET. PET can often detect these metastases earlier than CT; an uptake is visible, but no morphological change can be seen at that time. The metastases' size remains stable after therapy, but they become more sclerotic and lose their metabolic activity. How should they be handled? Some authors claim if a metastasis changes from lytic to blastic and is no longer FDG-avid, then it has been cured. But these metastases may still be viable for several indications.

There is a clear need for combined PET/CT evaluation criteria in patients whose breast cancer has metastasized, particularly if these lesions are in the bone.

Gastrointestinal stromal tumor. Several studies have been published concerning therapy response in gastrointestinal stromal tumors.11,12 Most studies found PET/CT to be more accurate at assessing therapy response than either CT alone or PET alone. PET/CT also provided relevant prognostic information. Patients with an absence of elevated glucose metabolism after initiation of treatment survived for a statistically significantly longer period than did patients with detectable glucose uptake.

The CT part of the PET/CT study was less accurate in terms of evaluating therapy response when RECIST criteria were applied, mainly because liver metastases of gastrointestinal stromal tumors do not shrink much when treated, even in long-term survivors. A significant number of patients will thus not be regarded as responders. Alternative CT-based criteria for assessing the response of gastrointestinal stromal tumors to treatment have been proposed. These advocate that a 10% reduction in tumor size or a 15% decrease in tumor density should be enough to qualify a patient as a partial responder. A figure of 25% was used in previous studies.13

PET-specific criteria and modified morphological parameters may be included in an optimized combined PET/CT response assessment for gastrointestinal stromal tumors. These findings could also lead researchers to explore other tumor entities using disease-adapted response criteria.

Ear, nose, and throat cancers. The primary methods for the detection and characterization of ear, nose, and throat cancers are CT and MRI, based on international guidelines.14 FDG-PET has already shown remarkable results for the detection of tumors and lymph nodes in ENT cancer.15,16 Diagnosis can be impaired by artifacts and inflammatory lesions, however. Detection of pathologically involved cervical lymph nodes on CT is based on typical contrast enhancement patterns as well as size criteria.17 FDG-PET defines tumor response as a decrease in FDG uptake of more than 25%. Any remaining pathological focal glucose metabolism is taken to indicate tumor persistence.

Interpretation of CT is often complex. Lesions may decrease in size, but contrast enhancement may still be present owing to the widening of extracellular space in radiotherapy scar tissue.

Small lesions that have shrunk can easily be overlooked on morphological imaging alone. The use of multislice CT technology, particularly 64-slice CT, means that functional perfusion studies can be integrated into a clinical routine protocol. CT perfusion can be useful in detecting and determining therapy response in several tumor entities.18,19

Evaluations of therapy response on PET/CT are likely to rely more on PET in cases in which the interpretation of CT findings are difficult or PET and CT findings are not concordant. Because most advanced ENT cancers are treated with radio/chemotherapy, the time at which post-therapy FDG-PET/CT is performed is important. We find that four to six weeks after completion of treatment is sufficient.

Mesothelioma. CT-based modified RECIST criteria and PET evaluation with EORTC-based criteria have each been found to be valuable in assessing the response of pleural mesothelioma to treatment.2,20 Data comparing modified RECIST and EORTC criteria in the same patient, and their possible correlation to clinical outcome, are not yet available.

Decreasing FDG uptake during therapy may be taken as a sign of response. Concurrent CT measurements, however, may not change enough to be considered significant (Figure 3).

CT criteria may need some fine-tuning to classify patients' response appropriately, as in the case of gastrointestinal stromal tumors. Reliable definition of combined PET/CT response criteria, through further studies, will help to ensure correct stratification of patients into the appropriate response classes and ensure that therapy can be cost-effective and enhance patients' quality of life.

As more and more PET/CT systems are being installed worldwide, clinical experience of combined modality cancer imaging is growing exponentially. We may expect future studies to examine the role of PET/CT in following up cancers additional to the ones mentioned above.

Novel approaches in quantifying therapy response that go beyond standard RECIST or EORTC criteria are needed, as seen in the cases of lymphoma, gastrointestinal stromal tumors, and mesothelioma. These will have to be evaluated for dual-modality imaging. Visualization tools that can display and analyze baseline and follow-up studies simultaneously, together with new techniques for evaluating response (e.g., CT perfusion) may follow. These may be incorporated in future therapy response protocols too.

DR. VEIT-HAIBACH, DR. STROBEL, and DR. HANY are radiologists and nuclear medicine physicians in the department of medical radiology, division of nuclear medicine, at Zurich University Hospital.

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Thomas F. Hany, MD

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