18FDG-PET applications for cartilage neoplasms
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- Feldman, F., Heertum, R.V., Saxena, C. et al. Skeletal Radiol (2005) 34: 367. doi:10.1007/s00256-005-0894-y
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To assess the value of [18F]fluoro-2-deoxy-d-glucose positron emission tomography (18FDG-PET) in defining aggressive cartilage neoplasms, particularly those with problematic or borderline histologic, imaging and clinical characteristics.
Design and patients
From 2000 to 2003, 29 cartilage lesions were studied with whole-body 18FDG-PET scans (Siemens Ecat Exact, Knoxville, Tenn.). Analyses of data in 20 females and nine males, 11–85 years old, were based on maximum standard uptake values (SUVs) in regions of interest (ROIs) on axial 3.37 mm thick, 3×3 pixel images. A statistically significant maximum SUV cutoff of 2.0 was used to distinguish benign from malignant cartilage neoplasms and correlated with the postoperative histopathologic findings.
In 26 operated cases the overall sensitivity of whole-body 18FDG-PET in separating benign and malignant lesions was 90.9% (10/11), specificity 100% (18/18) and accuracy 96.6%.
Whole-body 18FDG-PET is a valuable adjunct in identifying primary, recurrent and metastatic cartilage malignancies. It supplements classic histology and morphologic imaging with functional data which may facilitate management in individual cases.
Cartilage lesions are difficult to compartmentalize histologically since their spectrum includes an often problematic, gray middle zone in which distinction between benign and malignant members may be blurred [1, 2, 3, 4]. Imaging modalities are likewise limited, but positron emission tomography (PET), with currently simplified clinical use, is providing a new functional parameter for evaluating varied histologically unrelated neoplasms [5, 6, 7]. PET, by detecting hypermetabolic foci, could thereby improve the conspicuity of residual, recurrent and metastatic tumors in view of the difficulties found with morphologically oriented imaging modalities in identifying abnormality in distorted post-treatment anatomy and large heterogeneous lesions. However, its application to musculoskeletal oncology in general and cartilage tumors in particular has not been extensively explored [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19].
The purpose of this study was to evaluate 18FDG-PET as a problem-solver specifically in cartilage lesions by utilizing its functional data to distinguish benign lesions from their malignant counterparts in view of their often problematic clinical, imaging and histologic findings.
Materials and methods
Patients and 18FDG preparation for PET scans
Patients were NPO for 6 h with fasting blood glucose levels <160 mg/dl. Intravenous access was obtained 15–30 min before injecting 0.14 mCi/kg of [18F]fluoro-2-deoxy-d-glucose (18FDG). Its preparation utilized the nucleophilic reaction of 18F-fluoride with a protected mannose molecule . Feet-first scans starting 60 min post-injection had a 60 min transmission corrected acquisition time for serial images.
Acquisition processing and display
PET studies were performed on a Siemens ECAT EXACT 921 dedicated PET scanner (Knoxville, Tenn.) with FWH=6 mm. A total of five or six bed examination (6 min emission, 4 min transmission) images used OSEM iterative reconstruction with segmented transmission attenuation corrected with Gaussian filters (cutoff 6–7 mm). Coronal, axial and sagittal 1.3 cm thick reconstructions were displayed with inverted gray-scale maps and successive 6 mm multiplanar slices of the body examined.
Image interpretation and analysis
Visual and region of interest (ROI) 3×3 pixel image analyses were based on axial whole-body 3.37 mm images. ROI data generated mean and maximum standard uptake values (SUVs), where SUV is defined as the radioactive tissue concentration in becquerels per gram divided by the body weight in grams. The maximum SUV cutoff of 2.0 between benign and aggressive lesions was based on our prior experience with various neoplasms studied with current equipment. Institutional Review Board approval was obtained for the study.
From 2000 to 2003, 29 cartilage lesions in nine males and 20 females, 11―85 years old, were referred for radiographs, CT or MRI and whole-body PET scans by various clinicians. Of 11 enchondromas, seven osteochondromas and 11 chondrosarcomas, 26 were surgically excised and histologically evaluated. Three nonoperated cases included two presumed enchondromas (cases 8 and 9) and one chondrosarcoma (case 28) with an incidentally noted breast mass preferentially referred for treatment. PET analyses based on a statistically significant (P=0.001) maximum SUV cutoff of 2.0 separated benign from malignant lesions.
The efficacy of 18FDG-PET in cartilage neoplasms (H humerus, F femur, IL ilium, T tibia, P proximal, D distal)
Primarya site metastases
Chondrosarcoma site of origin
Muscle, axilla 8
Dedifferentiated to fibrosarcomaa
Dedifferentiated to fibrosarcomaa
Ilium, spine, rib, vertebra, lung 3–20
Lung, mediastinum, pelvis, femora 5
Psoas, ilium 3
Outcomes were monitored by follow-up appointments with referring physicians.
Among 16 operated benign lesions, six of nine enchondromas did not recur after 1―4 years (1 year in 1 case, 2 years in 2 cases, 3 years in 2 cases, 4 years in 1 case). Three remaining patients with enchondroma who were asymptomatic postoperatively did not return.
Among six of seven benign exostoses, none recurred after 1―4 years of follow-up (1 year in 4 cases, 2 years in 1 case, 3 years in 1 case). One patient did not return for follow-up.
PET differs from other single-photon radionuclide scans in its ability to correct for tissue attenuation signal loss and its relatively uniform spatial resolution. Regional tracer measurement in absolute units, difficult in planar and SPECT imaging, allow PET data conversion into functional images, since each pixel in an anatomic area has a numerical value measuring a physiologic parameter. While most imaging modalities depict morphology, the initial rationale for PET’s estimation of aggressiveness was the avidity of malignant cells for glucose . 18FDG ([18F]fluoro-2-deoxy-d-glucose) is a favored metabolic tracer due to its intracellular transport mechanism, indistinguishable from that of glucose, its increased uptake in cells with high metabolic rates and similarly increased utilization in malignancies. Low membrane permeability also limits FDG back-diffusion during PET, with the FDG trapped in tumor cells determining glucose utilization.
Some early studies  failed to correlate glucose metabolism and aggressiveness. Others held that 18FDG distinguished benign and malignant lesions [9, 10, 11, 12, 13]. Differences may be due to older PET technology or inclusion of bone or soft tissue tumors of diverse histology and biologic behavior. This study was therefore confined to cartilage lesions.
Clinical, imaging and histologic guidelines have inconsistently distinguished between benign and malignant cartilage lesions, with chondrosarcomas classically being held to be more often painful, palpable, proximal, larger and commoner in older patients than their benign counterparts. Large, asymptomatic, incidentally encountered lesions still pose diagnostic and management problems. Pain is also unreliable as an indicator of malignancy. Benign lesions may be symptomatic due to impingement on local anatomy while chondrosarcomas, despite age or size, may be painless and incidentally noted. Imaging criteria for malignant cartilage lesions, i.e., endosteal scalloping, remodeling, post-contrast enhancement on MRI and enlarged cartilage cap exostoses, are suggestive rather than conclusive evidence of malignancy, with variations in age and overlap continuing to be noted [1, 2, 3, 4, 20, 21].
Radiographs and CT best define mineralization and subtle periosteal changes. MRI best depicts morphology, anatomic extent and enhancement patterns which favor chondrosarcoma but are inconsistent. T1-weighted signal in cartilage, often lower than in muscle, usually increases in viable tumor on T2-weighted images. However, the converse can occur, especially in mature or heavily calcified cartilage lesions, so that inconstant MRI patterns may be less helpful than radiographs in distinguishing malignancy.
Pathologists have also had well-known difficulties in differentiating benign from low-grade cartilage tumors [1, 2, 3, 4, 20, 21], with tissue, depending on its origin and patient age, variously interpreted. Tissue from peripheral tubular bones that is considered benign may be problematic when originating in long bone intramedullary or cortical sites in multiple enchondromatoses or exostoses and in large symptomatic solitary lesions, particularly in the young with their often increased cellularity [20, 21]. 18FDG-PET, by reflecting tumor metabolism in such cases, aids in distinguishing aggressive from indolent behavior. It supplements static morphologic evaluation by helping resolve inconsistent clinical data, i.e., no pain, incidentally detected lesions, both small and large, those without extraosseous extension on MRI and “atypical or borderline histology” as in our cases 17, 18 and 21 (Table 1).
Cartilage, like other individual cell types, should be considered separately. Unique properties shared by its benign and malignant counterparts include relative hypovascularity, gelatinous extracellular matrix and predominant anaerobic glycolysis [14). Vascularity and metabolism, even of aggressive cartilage lesions, seldom reach the SUVs of osteosarcoma, fibrosarcoma or Ewing tumor [12, 13, 14], excepting mesenchymal variants (case 22; Fig. 4), dedifferentiated lesions (cases 19 and 20; Fig. 7) and their metastases. Well-differentiated grade 1 or 2 chondrosarcomas and large, mature, heavily calcified or focally necrotic lesions may have relatively lower SUVs reflecting hypometabolism despite their size [12, 15, 16, 17]. Necrotic foci may also be ringed by “donut-like” viable peripheral tissue (Fig. 7). FDG, by “mapping” haphazardly distributed hypermetabolism, particularly in large heterogeneous lesions, can more reliably assess tumor grade than tissue obtained from undirected sampling [12, 15, 16, 17].
Recent PET analyses of known chondrosarcomas indicated that maximum SUV and histopathology, when combined, are useful parameters for tumor grading and outcome prediction for local relapse and metastases . As in clinical and conventional imaging observations, tumor diameter “was not a significant discriminator of outcome” . The current study also noted that FDG uptake increased with tumor grade. PET changed management in six current patients (cases 8, 9, 17, 18, 20 and 28).Biopsy or surgery was eliminated due to hypometabolism in two enchondromas (cases 8 and 9). Excision, rather than allograft placement occurred in two others (cases 17 and 18). Two serendipitous PET-defined breast lesions (cases 20 and 28), referred for preferential care, influenced management.
Single-site CT, MRI and ultrasound (excepting Doppler) chiefly define static morphology.
While low-grade chondrosarcoma is particularly difficult for conventional radionuclide scanning , PET can simultaneously detect primary tumors, local residua, recurrence and metastases earlier via metabolic activity both before and after treatment, regardless of post-treatment anatomic distortion.
Timelier treatment adjustments may then result [22, 23, 24]. PET also documents diverse physiologic dynamics of primary and metastatic lesions (cases 19, 22 and 23). Focal recurrences or metastases may change their aggressiveness or dedifferentiate with resultant higher SUVs than primary foci (cases 19 and 20) (Table 1).
Limitations of PET
Variables affecting SUV include small lesions, volume averaging, scan initiation time and duration post-injection, tumor type, patient weight and blood glucose, with varying results in the same patients on different days. Values for separating benign from malignant lesions also vary in different institutions (from a maximum SUV of 1.3  to 4  due to diverse equipment, protocols and histology of lesions, so that SUV criteria cannot be strictly compared . In the current study a maximum SUV cutoff of 2.0 was considered statistically significant (P=0.001).
While glucose metabolism generally increases in malignancies , tumor SUVs may overlap with those of inflammatory lesions (osteomyelitis, eosinophilic granuloma), lesions with a high giant cell content (giant cell tumor, aneurysmal bone cyst, osteoblastoma, Paget disease) and fibrous lesions (fibrous dysplasia). However, these entities may be excluded by radiographs, history and clinical data [15, 26, 27]. Experience with lesions of shared histology in general and cartilage lesions in particular also aid in optimizing PET evaluation.
18FDG-PET is a valuable adjunct in identifying aggressive cartilage lesions: directly in primary and locally recurrent sites or indirectly on whole-body scans by detecting unsuspected metastases. PET may eliminate biopsy in incidentally noted hypometabolic lesions(case 8 and 9) or guide it in histologically problematic or heterogeneous cartilage lesions by defining hypermetabolic foci for selective sampling which may be further facilitated by PET/CT. PET can be advantageous in elderly or high-risk cases, especially in detecting small or scattered foci in deep pelvic or retroperitoneal soft tissues (cases 24, 25 and 27). Interval whole-body scans, by characterizing new lesions metabolically, may aid in decreasing the repeated interventional or imaging studies often required for initial staging or follow-up.
18FDG-PET served as an objective and quantitative modality in distinguishing benign and malignant cartilage neoplasms. It supplied a functional criterion with which to further assess or supplement morphologic imaging and histopathology. PET may be useful as a predictor of biologic behavior of cartilage lesions as a group or of its individual members. Inter-institutional coordination of SUVs from larger cohorts is needed to provide more uniform criteria for the evaluation of SUVs and to allow optimal management.