Clinical question comments:What are the most appropriate imaging modalities for diagnosis and staging of bone and soft tissue tumours?/Introduction

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General comments in relation to medical imaging in sarcoma and use of PET121:23, 31 October 2013

General comments in relation to medical imaging in sarcoma and use of PET

Sarcomas are relatively rare and are a heterogeneous group of malignancies. This makes it difficult to undertake the high quality, large, prospective, randomised trials required to produce definitive, evidencebased imaging guidelines that apply to sarcomas as a group. Nonetheless we can make a number of recommendations in regard to imaging of sarcomas based on the currently available literature.

Basic concepts in relation to medical imaging in sarcoma 1. Prognosis and treatment in sarcoma depend on certain characteristics of the tumour, a number of which can be assessed with imaging. These include location, size, local extension and the presence or absence of metastases.

2. Accurate staging is central to treatment decisions. For example, localised sarcomas may be cured with surgery. If staging is not correct the patient may not receive the treatment best suited to them.

3. If surgery is not undertaken, imaging can be used to assess the response of the primary sarcoma to treatment. Imaging can also be used to assess the treatment response of metastatic lesions.

4. Imaging is also very important in assessing for local tumour recurrence, and for detecting the evolution of metastatic disease over time.

5. PET can be useful for initial grading and guidance of biopsy (Hicks & Robins 2008).

Primary tumour site Excellent, high-resolution imaging of the primary lesion site is crucial, especially when curative surgery is being considered. MRI is recommended, however, in some cases CT alone may suffice. The overall accuracy for staging primary soft tissue sarcomas is greater for combined PET/CT and conventional imaging vs PET or conventional imaging alone (Tateish et al. 2007). Sarcomas often show marked tissue heterogeneity within the tumour mass (Eary 2008) and it has been demonstrated that FDG PET/CT can be used to direct biopsy to ensure the most aggressive site within the tumour mass is biopsied (Hicks & Robins 2008, Quak 2011). This should help reduce incorrect patient management due to sampling errors. FDG PET/CT can also help in defining the overall aggressiveness of the lesion (Hicks and Robins, 2008). 95% of primary lesions in soft tissue sarcoma are FDG-avid (Charest 2009). The degree of FDG uptake correlates with tumour grade and cell type, for example liposarcomas tend to be less FDG-avid. FDG PET/CT also provides important prognostic information: low grade sarcomas tend to have lower FDG uptake, and intermediate and high grade tumours have high uptake (Brenner 2006).

Combined modality PET MRI has recently come into clinical use in some centres, and is potentially useful in this situation.

Provided a baseline PET/CT scan has been performed, PET/CT can then be used to assess response to treatment if curative surgery is not proceeded with.

Distant metastatic lesions By far the most common site of sarcoma metastasis is the lungs. CT of the thorax is the most accurate way currently available to assess for pulmonary metastasis, and is therefore crucial. Depending on tumour subtype, patient symptoms, local expertise and treatment plan, CT alone may be sufficient imaging. However, this protocol will result in a number of patients being incorrectly staged and inappropriately treated (Volker 2007). FDG PET has been shown to be a more accurate staging method than CT alone for metastatic disease outside of the lungs, and use of combined FDG PET /CT as a “single” staging modality will ensure that the number of patients who are incorrectly staged is minimised (Gerth 2007). Although this has been confirmed in a number of studies, and has been shown to improve care in some patients, it has not yet been shown in large studies to be cost effective. Given the heterogeneity of sarcomas and the relatively small numbers of patients in each tumour subtype, it may never be possible to accurately assess cost effectiveness in this situation.

In some patients there may be distant metastases (for example to bone in bone sarcomas, or within the liver in liposarcomas or intra-abdominal soft tissue sarcomas) without pulmonary metastases. If these are missed, treatment may be given inappropriately. In regard to detecting suspected bone metastases, the nuclear medicine bone scan was previously the investigation of choice. However FDG PET/CT is more accurate than bone scans in detecting bone metastases (Franzius 2000), in part because FDG PET/CT more accurately depicts bone marrow metastases. Provided whole body PET imaging is performed, bone scans can probably be omitted. Nonetheless if FDG PET is not available, a bone scan remains useful to assess suspected bone metastases. PET/CT is an excellent modality for detecting hepatic metastases in the majority of patients.

In many published series PET/CT significantly improves staging over conventional imaging, and produces an appropriate change in management in up to 32% of patients. In a prospective multicentre study Volker (2007) showed that FDG PET/CT significantly improved staging compared to conventional imaging; in this study the correct treatment was assigned to only 59% of patients staged with conventional imaging, and to 91% of patients staged with PET/CT plus conventional imaging. Australian data also show a similar magnitude of management change with the use of FDG PET (Hicks and Robins 2008). Even the most pessimistic studies in soft tissue sarcomas report that “only” 1/20 patients are staged incorrectly without FDG PET (Roberge 2012).

FDG PET/CT is recommended by the Children’s Oncology Group Bone Tumour Committee as part of the staging process in paediatric Ewing sarcoma and osteosarcoma (Meyer 2008).

Lymph node metatstases These are less common with sarcomas than with some other tumour types, but they can occur. When present, lymph node metastases carry a prognostic significance similar to that implied by the presence of distant metastases. They are extremely rare in bone sarcomas, but when present they place the patient in AJCC stage IV. Nodal metastases are uncommon in soft tissue sarcomas, but if present place the patient in stage III. Hence it is important that efforts are made to ensure that nodal metastases are not missed. PET/CT is significantly better at detecting lymph node involvement than is conventional imaging (Volker 2007). However FDG PET does carry some risk of false positive studies due to the intense local inflammatory response which can accompany some sarcomas, and positive studies within nodes need to be confirmed histologically.

References Brenner W, Eary JF, Hwang W, Vernon C, Conrad EU. Risk assessment in liposarcoma patients based on FDG PET imaging. Eur. J. Nucl. Med. Mol. Imaging 33(11), 1290–1295 (2006).

Charest M, Hickeson M, Lisbona R, Novales-Diaz JA, Derbekyan V, Turcotte RE. FDG PET/CT imaging in primary osseous and soft tissue sarcomas: a retrospective review of 212 cases. Eur. J. Nucl. Med. Mol. Imaging DOI: 10.1007/s00259-009-1203-0 (2009).

Eary JF, O'Sullivan F, O'Sullivan J, Conrad EU. Spatial heterogeneity in sarcoma 18F-FDG uptake as a predictor of patient outcome. J. Nucl. Med. 49(12), 1973–1979 (2008).

Franzius C, Sciuk J, Daldrup-Link HE, Jurgens H, Schober O. FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy. Eur. J. Nucl. Med. 27(9), 1305–1311 (2000).

Gerth HU, Juergens KU, Dirksen U, Gerss J, Schober O, Franzius C. Significant benefit of multimodal imaging: PET/CT compared with PET alone in staging and follow-up of patients with Ewing tumors. J. Nucl. Med. 48(12), 1932–1939 (2007).

Hicks R & Robins P. A comparison of conventional CT guided and metabolically(PET) guided biopsy for soft tissue sarcomas:prospective analysis of utility for tumour grading,2008. Australian PET Data Collection Project.

Meyer JS, Nadel HR, Marina N et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 51(2), 163–170 (2008).

Quak E et al. Clinical Applications of Positron Emission Tomography in sarcoma management. Expert Rev Anticancer Ther. 11(2), 195-204 (2011).

Roberge D, Vakilian S, Alabed Y et al. FDG PET/CT in Initial Staging of Adult Soft-Tissue Sarcoma. Sarcoma. Volume 2012, Article ID 960194, doi:10.1155/2012/960194.

Tateish U,Yamaguchi U, Seki K et al. Bone and Soft Tissue sarcoma:preoperative staging with fluorine 18 FDG PET/CT and conventional imaging. Radiology 2007; 245: 839-847.

Volker T, Denecke T, Steffen I et al. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J. Clin. Oncol. 25(34), 5435–5441 (2007).

It also is worth comparing the Guidelines' advice on imaging for sarcoma with the current imaging practice for sarcoma at one major teaching hospital, which are generally reflective of current practice at major oncology/paediatric oncology centres, as shown below:

FDG PET is used for:

1. Lesion evaluation. FDG PET/CT is used liberally. Has a known lesion such as a plexiform neurofibroma transformed to a sarcoma? Where is the most metabolically active site for biopsy? If minimally metabolically active, can we continue to observe rather than intervene surgically? FDG PET/CT is used more than MRI for this evaluation, but ideally both should be used.

2. Staging. This includes evaluation of tumour grade because it is well established that relative and absolute FDG uptake correlates well with tumour grade and prognosis. FDG-PET and CXR + Chest CT should always be done at baseline.

3. Treatment response. We don't do much of this monitoring for sarcoma treatment, just limited cases where neo-adjuvant chemoradiotherapy is used prior to surgery.

4. Recurrent/suspected disease. This is the other large referral group for our FDG PET/CT service. FDG PET/CT is used as the principal imaging tool in this regard, not CT.

Paediatric sarcomas are more bone-based than adult ones, and there is a much larger role for bone scintigraphy using SPECT-CT which will probably evolve into using F18 NaF PET-CT bone scans in future.

Janine Sargeant14:59, 4 October 2013

Thank you very much for your comments. We have altered the document to include reference to PET CT in both primary tumour and staging assessment. The PET-CT component of staging now reads: Combined Positron emission tomography and computed tomography (PET-CT)using 18F-fluorodeoxyglucose (FDG) can improve overall accuracy of staging soft tissue sarcomas. The degree of uptake varies with tumour grade and cell type. Whole body PET-CT can be useful for staging of STS, especially prior to radical surgery to identify unexpected metastases. However, suspicious lesions may need to be confirmed with biopsy due to a risk of false positives from inflammation. PET-CT can also guide biopsy to the most aggressive site within the primary mass. (Bastiaannet 2003, Charest 2009, Fletcher 2008, Kneisel 2006, Ricard 2011, Tateishi 2007 )

There is also an additional sentence in the primary tumour stating "PET-CT can be useful for initial grading and guidance of biopsy. "

This question did not address follow up or recurrent disease so these areas have not been added. It does also not specifically refer to paediatrics.

Dr Kirsten Gormly (talk)21:23, 31 October 2013