PET/CT in Bone and Soft-Tissue Sarcoma

1. The clinical problem

Sarcomas are rare malignant tumours of mesenchymal tissue. They arise in soft tissue (soft-tissue sarcoma, STS) or bone (osteosarcoma, Ewing sarcoma, chondrosarcoma and rarer types), in adults and children, anywhere in the body. Their rarity and diversity are why European guidance insists that they are managed in sarcoma reference centres by a multidisciplinary team (MDT). The oncologist and surgeon ask imaging five questions: which part of the mass should be biopsied, how aggressive it is likely to be, has it spread, is preoperative treatment working, and has it come back? Magnetic resonance imaging (MRI) answers the local questions. ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) contributes most to the first, third and last.

Classification and staging in force

• World Health Organization (WHO) 2020 classification of soft tissue and bone tumours: the current pathological standard named in the 2021 European Society for Medical Oncology (ESMO) guidelines. It separates undifferentiated round cell sarcomas (CIC-rearranged, BCOR-altered and EWSR1 non-ETS fused sarcomas) from Ewing sarcoma, and lists NTRK-rearranged tumours as an emerging entity.
• Grade: for STS, histological grade is usually assigned with the three-tier French Federation of Cancer Centres (FNCLCC) system. Grade is the main driver of FDG avidity, and of metastatic risk.
• American Joint Committee on Cancer (AJCC) eighth edition: staging is now site-specific. Bone sarcomas are staged separately for the appendicular skeleton, trunk, skull and face; the spine; and the pelvis, with a three-grade system. STS is staged separately for trunk and extremity, retroperitoneum, head and neck, and visceral sites.
• Guideline view of staging: ESMO–EURACAN–GENTURIS (with the European Reference Network for rare adult solid cancers and the Genetic Tumour Risk Syndromes network) notes that available staging classifications are of limited clinical value in STS and that risk is better estimated with validated nomograms.

Where nuclear medicine changes management

• Biopsy targeting and grade: ESMO states that when preoperative treatment is an option, imaging including FDG PET/CT may help estimate malignancy grade alongside pathology.
• Distant staging: for Ewing sarcoma and, as clinically indicated, other bone sarcomas; for STS when CT is equivocal, and before resection of apparently isolated lung metastases, when abdominal CT plus bone scan or FDG PET is mandatory.
• Malignant change in neurofibromatosis type 1 (NF1): FDG PET/CT is a highly sensitive test for malignant peripheral nerve sheath tumour (MPNST) and shows which part of a large tumour to biopsy.
• Response and recurrence: FDG predicts histological response and outcome and detects recurrence accurately, although neither use is written into guidelines as routine.

2. Tracers and why they work

FDG and tumour grade

FDG is transported into cells by glucose transporters and trapped after phosphorylation by hexokinase. In sarcoma, uptake rises with cellularity, proliferation and grade. The standardised uptake value (SUV), and its maximum in the tumour (SUVmax), are therefore surrogates of grade rather than of histological type. A meta-analysis of 15 studies (441 soft-tissue lesions) found that on visual reading FDG was positive in all intermediate- and high-grade sarcomas, 74% of low-grade sarcomas and 39% of benign lesions (including 11 of 12 inflammatory lesions). With an SUV cut-off of 2.0 the rates were 89%, 33% and 19%. FDG separates high-grade sarcoma from benign disease well; it does not separate low-grade sarcoma from benign disease.

Pattern of FDG avidity by subtype, from a single-centre audit of 957 PET/CT scans in 493 patients (Macpherson 2018) and the subtype series cited below.

Lipomatous tumours

In 67 lipomatous tumours imaged before resection, mean SUVmax was 0.8 for lipoma, 2.3 for atypical lipomatous tumour, 3.0 for myxoid liposarcoma, 13.5 for pleomorphic liposarcoma and 16.3 for dedifferentiated liposarcoma; hibernoma, a benign brown-fat tumour, averaged 11.9. Low-grade and high-grade liposarcoma differed clearly (2.5 versus 12.8), but benign and malignant lesions did not, because hibernomas are hot and atypical lipomatous tumours and myxoid liposarcomas are cool. In an earlier series of 54 liposarcomas, an SUVmax above 3.6 predicted shorter disease-free survival (21 versus 44 months) better than grade or subtype. ESMO stresses that recognising the well-differentiated versus the dedifferentiated component of a retroperitoneal liposarcoma is critical to surgical planning: a focal FDG-avid solid nodule in a fatty mass is the classic target.

Cartilage tumours

Most conventional chondrosarcomas are low grade (atypical cartilaginous tumour / grade 1), which ESMO allows to be curetted or watched in the long bones, whereas grade 2–3 tumours and all pelvic or axial chondrosarcomas need wide excision. Biopsy under-grades these tumours, so FDG adds information. In 31 patients, mean SUV was 3.4 in grade 1, 5.4 in grade 2 and 7.1 in grade 3; an SUV above 4 predicted relapse (sensitivity 90%, specificity 76%). In 95 chondroid lesions, the best SUVmax cut-offs were 2.6 for enchondroma versus low-grade chondrosarcoma (sensitivity 68%, specificity 86%), 3.7 for low-grade versus grade 2–3 (83%, 84%) and 7.7 for grade 2–3 versus dedifferentiated chondrosarcoma (92%, 90%). These are single-centre thresholds and should be quoted with their source.

NF1 and malignant peripheral nerve sheath tumour

Plexiform neurofibromas in NF1 are common and usually mildly avid; MPNST is aggressive and usually much hotter. In 69 patients (85 lesions) imaged at 90 and 240 min, FDG PET/CT had a sensitivity of 97% and specificity of 87% for MPNST, and the authors recommended early plus 4-h imaging with an SUVmax cut-off of 3.5 on the delayed images. In 49 patients, normalising to the liver improved specificity: a tumour-to-liver ratio (TLR) above 2.6 and an SUVmax above 3.5 were both 100% sensitive, but specificity was 90.3% with the ratio versus 79.8% with the SUVmax cut-off. Uptake varies within a large plexiform tumour, so the whole lesion must be examined and the hottest region biopsied.

When FDG fails and what replaces it

• Low-grade tumours: atypical lipomatous tumour, myxoid liposarcoma and grade 1 chondrosarcoma can overlap with benign lesions; MRI and histology decide.
• Small lung metastases: partial-volume effects hide sub-centimetre nodules; the CT component, read in lung windows, and a dedicated chest CT decide.
• Benign avid lesions: giant cell tumour, chondroblastoma, schwannoma, hibernoma and inflammation mimic sarcoma; histology decides.
• Fibroblast activation protein (FAP) tracers: sarcomas express FAP on tumour cells and associated fibroblasts, so FAP inhibitor (FAPI) PET is being studied as a complement; it is investigational (section 8).

3. Indications by clinical scenario

4. Evidence at a glance

Abbreviations: PFS, progression-free survival; SUV1 and SUV2, SUVmax before and after neoadjuvant chemotherapy; RCT, randomised controlled trial; HR, hazard ratio; TLR, tumour-to-liver ratio; PPV, positive predictive value.

5. Patient preparation and acquisition

Preparation follows the European Association of Nuclear Medicine (EANM) FDG tumour guideline version 2.0: at least 4 h without food or sugary drinks, glucose checked before injection, and an uptake time of 60 min (acceptable range 55–75 min), kept identical on serial scans because SUV depends on it. What differs in sarcoma is below.

1. Field of view: sarcomas start in the limbs, so extend the scan to include the whole limb carrying the primary, and usually vertex to toes. The EANM guideline defines whole-body imaging as the top of the head through the feet.
2. Injection site: inject away from the primary and its draining nodes, and record the site, so that extravasation or reactive nodes are not mistaken for disease.
3. Before biopsy when possible: a PET done to choose the biopsy target must precede the biopsy; afterwards, record the biopsy route and date, because the track and haematoma take up FDG.
4. Young patients: brown fat uptake is more common in the young and in cold rooms. Keep the patient warm from 30–60 min before injection until the end of the scan, as EANM recommends. Expect symmetrical physeal uptake around the knees and elsewhere in adolescents.
5. NF1: acquire early (about 90 min) and delayed (about 4 h) images, as in the largest prospective series; SUVmax differs between the two time points, and the published cut-off of 3.5 applies to the delayed images.
6. Response studies: same scanner, reconstruction and uptake time as baseline; scan after the last cycle of neoadjuvant chemotherapy and before surgery, matching the protocol of the series whose thresholds you intend to use.
7. History for the reader: dates of surgery, biopsy, radiotherapy and chemotherapy; growth factor support; any fracture or prosthesis; and, in NF1, which lesion is painful or growing.

6. Interpretation

What to measure

• SUVmax of the hottest solid part of the primary, with its location described so that the biopsy can target it; note necrotic or cystic regions that would give a non-diagnostic core.
• Heterogeneity: a focal hot nodule in a cool fatty or cartilaginous tumour suggests dedifferentiation; say so explicitly.
• In NF1: SUVmax on early and delayed images and the TLR for each symptomatic or growing lesion; list lesions above the thresholds.
• Distant disease: lungs (on the CT, in lung windows), bone and marrow, nodes (uncommon in most adult STS, so confirm an avid node before it upstages the patient), and soft tissue elsewhere, including the opposite limb.

Thresholds that have been published

All are single-centre, retrospective or small prospective derivations; SUV depends on scanner, reconstruction and uptake time. Quote the source and use them to support, not replace, the visual read.

Pitfalls and mimics

Wording the conclusion

• Answer the question asked first: stage (with the AJCC site group), the biopsy target, or malignant change in NF1.
• Give the SUVmax of the hottest part and where it is, for example 'SUVmax 11.4 in the anteromedial solid component, 3 cm from the skin; central necrosis'.
• Separate definite metastases from indeterminate findings and say which test resolves each: 'three 4–6 mm lung nodules without uptake, below PET resolution; assess on dedicated chest CT'.
• In NF1, list each assessed lesion with early and delayed SUVmax and TLR, and state which exceed the thresholds.

7. Response assessment and follow-up

Bone sarcomas: FDG and histological response

In osteosarcoma and Ewing sarcoma the percentage of necrosis in the resected tumour after neoadjuvant chemotherapy is a strong prognostic factor; a good response is conventionally at least 90% necrosis, and EURAMOS-1 defined poor response as 10% or more viable tumour. Two series from one institution tested FDG against it. In 36 Ewing sarcoma family tumours, a good PET response was defined as SUV2 below 2.5 or SUV2/SUV1 of 0.5 or less; these agreed with histology in 68% and 69%, and 4-year PFS was 72% with SUV2 below 2.5 versus 27% above it. In 40 extremity osteosarcomas, agreement with histology was 58% for SUV2 and 68% for the ratio, and 4-year PFS was 73% versus 39%.

So FDG predicts outcome, but it is not a substitute for pathology. Nor is there yet a validated action: in EURAMOS-1, 618 poor histological responders were randomised to add ifosfamide and etoposide to postoperative MAP (cisplatin, doxorubicin, high-dose methotrexate); event-free survival did not improve (HR 0.98) and toxicity rose. An early metabolic response would need its own trial before it changes treatment.

Soft-tissue sarcoma

In 42 patients with high-grade STS scanned before and after neoadjuvant therapy, the fall in FDG uptake predicted histopathological response (at least 95% necrosis) far better than the change in size: area under the curve 0.93 versus 0.60. A decrease of 60% or more had a sensitivity of 100% and specificity of 71%, whereas size-based Response Evaluation Criteria in Solid Tumours (RECIST) had a sensitivity of only 25%. Many sarcomas do not shrink when they respond, and some swell with haemorrhage or necrosis, which is why metabolic response is attractive here. It remains a research tool.

Which criteria

No sarcoma-specific PET response criteria are recommended by guidelines. State what you measured (SUVmax or SULpeak, the same region, the same uptake time), the percentage change, and the threshold of the series you are applying. Do not call a response 'complete' because a necrotic tumour is cold centrally; describe residual rim uptake.

Follow-up and recurrence

• ESMO schedules: high-grade bone sarcoma is followed with examination, imaging of the primary site and chest X-ray or CT, roughly every 2–3 months for 2 years, 6-monthly to year 5 and 6–12-monthly to year 10. Intermediate- and high-grade STS may be seen every 3–4 months for 2–3 years, then twice yearly to year 5 and yearly after; low-grade STS 6-monthly for 5 years, then yearly. PET is not part of routine follow-up.
• PET versus MRI at the operated site: MRI is the local surveillance test. In the meta-analysis of soft-tissue lesions, FDG performed similarly for primary and recurrent lesions, and the limited head-to-head data showed no difference from MRI. PET helps when MRI is degraded by metal or confounded by postoperative and radiation change, and it restages the whole body before salvage surgery.
• Accuracy for recurrence: in Ewing sarcoma, pooled sensitivity was 89.9% and specificity 92.6%.
• Timing: early after surgery or radiotherapy, inflammatory uptake is expected; interpret against dates and prefer a later scan when the question allows.

8. Theranostics and emerging tracers

FAP is attractive in sarcoma because the tumour cells themselves, not only the stroma, can express it. The trials so far are small, uncontrolled and from few centres; FAP-directed therapy should be offered only within trials or formal compassionate-use programmes after multidisciplinary review.

9. Structured report example

10. Take-home points

1. Think grade: FDG is reliably positive in intermediate- and high-grade sarcoma, unreliable in low-grade tumours and positive in a substantial minority of benign lesions.
2. Report the hottest solid part and where it is; it is the best biopsy target and flags dedifferentiation in fatty and cartilaginous tumours.
3. Adult STS is staged with CT; PET solves problems. Ewing sarcoma is staged with PET/CT or whole-body MRI; bone sarcomas otherwise as clinically indicated.
4. Never let a negative PET clear small lung nodules; the CT decides.
5. In NF1, use delayed images, SUVmax 3.5 and the tumour-to-liver ratio 2.6, and send the biopsy needle to the hottest part.
6. Metabolic response after neoadjuvant chemotherapy predicts outcome but has not been shown to guide treatment; histology remains the reference.
7. Giant cell tumour, schwannoma, hibernoma, inflammation and postoperative change are hot; low-grade and myxoid sarcomas can be cool.
8. FAP-targeted imaging and therapy are promising and investigational.

Test yourself

5 quick questions. Pick an answer to see the explanation.

References

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