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Role of Functional
Imaging in Sarcomas Dr Winnie Lam
Senior Consultant, Department of Nuclear Medicine & PET
Adj Assistant Professor, Radiological Sciences Academic Clinical Programme
5 November 2016
4th Singapore Sarcoma Symposium 2016
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• Nuclear medicine is the medical specialty that
uses the tracer principle, most often with
radiopharmaceuticals, to evaluate molecular,
metabolic, physiologic and pathologic conditions
of the body for the purposes of diagnosis,
therapy and research.
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What is Nuclear Medicine / Functional
Imaging?
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■ PET for Sarcoma Detection & Grading
■ PET in Staging and Restaging Sarcomas
■ Sentinel Lymph Node Biopsy /
Lymphoscintigraphy in Sarcomas
■ PET in Correlation to Prognosis & Monitoring
Response
■ PET-guided Biopsy within a Suspected Sarcoma
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■ Anatomical Imaging Modalities:
1. Radiographs (X-ray)
2. Computed Tomography (CT)
3. Magnetic Resonance (MR) ■ Primary diagnostic modalities
■ Exact location, size, local extent, bony destruction (biologic activity), intratumoral calcifications (phleboliths, amorphous calcification), proximity to neurovascular structures
■ CT chest for lung metastases
Imaging Techniques
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■ Functional Imaging Modalities: 1. Bone scan (gamma camera)
• Incidence of bone metastasis is low
2. Lymphoscintigraphy / Sentinel Lymph Node Imaging (gamma camera / SPECT-CT)
3. Positron Emission Tomography (PET)
■ 18F-fluorodeoxyglucose (FDG) – glucose analog
■ Complementary information in diagnosis & treatment planning
Imaging Techniques
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• Very sensitive (91%) & specific (85%) for detection
of high-grade sarcoma*
• Low positive predictive value (PPV) for nodal
metastases
• Standardized uptake value (SUV) – semi-quantitative
measure of radioactivity (FDG metabolic activity)
• Higher SUV correlated with histologic findings of
increased mitosis rate & cellularity (grade estimation) *Bastiaannet E, Groen H, Jager PL, et al. The value of
FDG-PET in the detection, grading and response to
therapy and soft tissue and bone sarcomas: a systematic
review and meta-analysis. Cancer Treat
Rev 2004;30(1):83–101.
PET for Sarcoma Detection & Grading
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• Soft tissue / bone sarcoma metastasis
predominantly (75%) to the lung
• Mixoid / round cell liposarcomas -
retroperitoneum
• Synovial sarcoma / rhabdomyosarcoma / clear
cell sarcoma / epithelioid sarcoma - LN
• Many studies on FDG PET/CT in sarcomas
compared with conventional imaging (MR, CT,
bone scan, U/S, CXR) .
PET in Staging and Restaging Sarcomas
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• Multicentre, 46 paediatric patients
• Ewing, osteo/rhabdomyosarcoma staging
• PET was superior in assessing LN involvement
& bone localizations • CT more accurate for pulmonary metastasis
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 2007;25:5435–41..
PET in Staging and Restaging Sarcomas
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• 19 paediatric patients
• Suspected sarcoma recurrence
• PET was useful for correct interpretation of
conventional imaging findings
• PET detected otherwise unknown metastasis in
2 patients Arush MW, Israel O, Postovsky S, et al. Positron
emission tomography/computed tomography with
18fluoro-deoxyglucose in the detection of local
recurrence and distant metastases of pediatric sarcoma.
Pediatr Blood Cancer 2007;49(7):901–5.
PET in Staging and Restaging Sarcomas
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• Retrospective study, 89 patients
• High-grade bone & soft tissue sarcomas
• LN involvement – PPV 27%
• Distant metastasis – Sensitivity 95%
– Specificity 95%
– PPV 87%
– NPV 98% Fuglo HM, Jorgensen SM, Loft A, et al. The diagnostic
and prognostic value of 18F-FDG PET/CT in
the initial assessment of high-grade bone and soft
tissue sarcoma. A retrospective study of 89 patients.
Eur J Nucl Med Mol Imaging 2012;39(9):1416–24..
PET in Staging and Restaging Sarcomas
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PET in Staging and Restaging Sarcomas
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• Combined FDG-PET/CT is superior to either
modality alone
• PET/CT located 282 lesions in 20 patients
• CT alone identified 242 lesions
• PET alone identified 147 lesions
Antoch G, Kanja J, Bauer S, et al. Comparison of
PET, CT, and dual-modality PET/CT imaging for
monitoring of imatinib (STI571) therapy in patients
with gastrointestinal stromal tumors. J Nucl Med
2004;45(3):357–65.
PET/CT in Staging Gastrointestinal
Stromal Tumours (GIST)
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• Commonly used in breast ca & malignant melanoma
• Radiopharmaceutical : Tc-99m Sulfur Colloid
• Dose 0.2mCi and volume 0.1ml
• Sentinel LN : LNs that first receive lymphatic drainage
from tumour
• Can have more than one sentinel lymph node
• Efficient tool to reduce postoperative long-term
morbidity (lymphoedema) without compromising local
control of disease
Sentinel Lymph Node Biopsy /
Lymphoscintigraphy in Sarcomas
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Sentinel Lymph Node Biopsy /
Lymphoscintigraphy in Sarcomas
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Sentinel Lymph Node Biopsy /
Lymphoscintigraphy in Sarcomas
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Lymphoscintigraphy plus SPECT-CT
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• Prospective study, 28 patients • Rhabdomyosarcoma, epithelioid sarcoma, synovial sarcoma, soft
tissue Ewing’s sarcoma, fibrosarcoma, other soft tissue sarcomas • Median of 2.4 sentinel nodes / patient • SLNB identified tumour in 7/28 (25%), including 3 with normal
PET/CT • PET/CT demonstrated hypermetabolic LN in 14
– Sensitivity 57% – Specificity 52% – PPV 29% – NPV 79%
• SLNB can safely guide rational selection of LNs for biopsy • SLNB can identify therapy-changing nodal disease not
appreciated with PET/CT Wagner LM, Kremer N, Gelfand MJ,, et al. Detection of lymph node metastases in pediatric and adolescent/young adult sarcoma: Sentenel lymph node biopsy versus
fludeoxyglucose positron emission tomography imaging-A prospective trial. Cancer 2016 Aug 26. doi: 10.1002/cncr.30282. [Epub ahead of print]
SLNB plus SPECT-CT vs FDG PET in
Paediatric & Adolescent/Young Adult
Sarcoma
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• Significant association between FDG uptake &
several pathologic markers:1
– Histopathological grade
– Tumour cellularity
– Proliferative activity (mitotic figure counts)
– Overexpression of p53
– Ki67 values in GIST2
1. 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;6:1279–87.
2. Kamiyama Y, Aihara R, Nakabayashi T, et al. 18F-fluorodeoxyglucose positron emission tomography: useful technique for predicting
malignant potential of gastrointestinal stromal tumors. World J Surg 2005;29(11):1429–35.
PET and Prediction of Prognosis
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• 238 patients with FDG-PET before
chemotherapy / surgical resection
• PET result compared with OS & DFS
• SUVmax & FDG heterogeneous distribution
can distinguish between higher-risk patients &
lower-risk patients Eary JF, O’Sullivan F, O’Sullivan J, et al. Spatial heterogeneity
in sarcoma 18F-FDG uptake as a predictor of
patient outcome. J Nucl Med 2008;49(12):1973–9.
PET and Prediction of Prognosis
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• Assessment of tumour response based on
changes in tumour size is not particularly helpful
in sarcomas.
Tabacchi E, Fanti S, Nanni C. The Possible Role of PET Imaging Toward Individualized Management of Bone and Soft Tissue Malignancies. PET Clin 2016; 285-296.
PET in Monitoring Response to Therapy
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• PET allows detection of tumour regression /progression before morphologic alterations on CT & MR
• Metabolic response precedes volumetric decrease of tumours
• PET findings can aid in decision making about maintaining / modifying therapy
• Reduction in FDG uptake of >35% from pretherapy value predictive of histologically assessed treatment response
Benz MR, Czernin J, Allen-Auerbach MS, et al. FDGPET/
CT imaging predicts histopathologic treatment
responses after the initial cycle of neoadjuvant
chemotherapy in high-grade soft-tissue sarcomas.
Clin Cancer Res 2009;15(8):2856–63.
PET in Monitoring Response to Therapy
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• Study of early response in GISTs • FDG-PET able to differentiate metabolic responders (11)
from metabolic nonresponders (4) after 1 week of imatinib treatment compared with clinical & radiologic response according to RECIST
• Mean SUVmax decreased in responders (65%), increased in nonresponders
• FDG-PET also correlated with clinical disease course (PFS)
• No significant difference in FDG uptake between scans 1 & 8 weeks after treatment initiation
• FDG response to imatinib is genuinely an early response
Jager PL, Gietema JA, van der Graaf WT. Imatinib mesylate for the treatment of gastrointestinal stromal tumours: best monitored with FDG PET. Nucl Med
Commun 2004;25(5):433–8.
PET in Monitoring Response to Therapy
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• Case story of significant reduction in SUVmax (from
13 to 4) 24 hours after a single dose of imatinib (400
mg) Shinto A, Nair N, Dutt A, et al. Early response
assessment in gastrointestinal stromal tumors with
FDG PET scan 24 hours after a single dose of imatinib.
Clin Nucl Med 2008;33(7):486–7.
• Comparison with morphologic therapy assessment
• SUVmean decrease of 60% on day 8 of imatinib
• Partial response according to RECIST after 23
weeks Heinicke T, Wardelmann E, Sauerbruch T, et al. Very
early detection of response to imatinib mesylate
therapy of gastrointestinal stromal tumours using
18fluoro-deoxyglucose-positron emission tomography.
Anticancer Res 2005;25(6C):4591–4.
PET in Monitoring Response to Therapy
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Donswijk ML, Hess S, Mulders T, et al. [18F]Fluorodeoxyglucose
PET/computed tomography in gastrointestinal malignancies. PET Clin
2014;9:435
PET in Monitoring Response to Therapy
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• Progression / secondary resistance to imatinib as re-emergence of FDG uptake
• Suggest more complex interrelation with heterogeneous intratumoral & intertumoral clonal dedifferentiation:
• After cessation of imatinib, flares of FDG uptake observed in lesions that were metabolically inactive during therapy
• Some lesions may still be responsive to initial treatment, whereas some clones progress to resistance
• This may provide basis for combination therapy for different TKIs, like imatinib & sunitinib, instead of traditional complete switch in therapy
• Literature favours use of FDG-PET as primary method for treatment assessment in GISTs
Van den Abbeele AD. The lessons of GIST–PET and PET/CT: a new paradigm for imaging. Oncologist 2008;13(Suppl 2):8–13.
PET in Monitoring Response to Therapy
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• Clinical trial of novel IGF1R antibody in Ewing
sarcoma
• PET was superior to anatomic imaging in
identification of response
• Early signal with FDG-PET on day 9 was the
best predictor of benefit (OS) Koshkin VS, Bolejack V, Schwartz LN, et al. Assessment of Imaging Modalities and Response Metrics in Ewing Sarcoma: Correlation with Survival.
J Clin Oncol 2016 Aug 29. pii: JCO681858. [Epub ahead of print]
PET in Monitoring Response to Therapy
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• Source of misinterpretation: – Infectious/inflammatory diseases
– Postsurgical change
– Postradiotherapy inflammation .
PET in Monitoring Response to Therapy
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• PET/CT-guided biopsy combines anatomic information from CT with PET metabolic characterization
• Large malignant lesions can be heterogeneous • FDG PET/CT to guide biopsy of highest metabolic
activity, reducing probability of tumour grade underestimation & consequential inappropriate approach
• PET-guided biopsy enables evaluation of lesions with exclusively FDG uptake without corresponding anatomic findings on CT
• When biopsy results are inconclusive / inconsistent with clinical & radiologic pictures, patient may benefit from PET-guided second biopsy
PET/CT in Biopsy
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• Histology of biopsy site of 8 malignant lesions
(as suggested by FDG-PET) showed the most
pleiomorphism & highest mitotic index within the
sarcoma Hain SF, O’Doherty MJ, Bingham J, et al. Can FDG
PET be used to successfully direct preoperative
biopsy of soft tissue tumors? Nucl Med Commun
2003;24(11):1139–43.
PET/CT in Biopsy
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• Benign skeletal lesions with intense FDG
uptake: – Osteochondromas
– Giant cell tumours
– Chondroblastomas
– Langerhans cell histiocytosis
– Desmoid tumours
– Fibrous dysplasia .
Pitfalls
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1. FDG PET provides metabolic information about primary tumour (T)
but its main advantage is evaluation of LN involvement (N), distant
metastasis (M), and local relapse.
2. PET/CT does not provide anatomic details, so cannot be used to
evaluate local infiltration.
3. Sentinel Lymph Node Biopsy can guide rational selection of LNs
for biopsy in sarcoma patients & identify therapy-changing nodal
disease not appreciated with PET/CT.
4. SUVmax before therapy is prognostic & useful for therapy
assessment as compared with posttherapy SUVmax.
5. After radiotherapy, some false positives may occur because of RT-
related inflammation (reduces with time after RT).
6. PET has lower sensitivity than CT in detecting lung metastases (CT
can be acquired on PET/CT tomographs).
7. Some benign diseases especially in the bone can be
hypermetabolic (false positive).
What the Referring Clinician Needs to
Know
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Department of Nuclear Medicine & PET