Intratumoral heterogeneity of F-18 FDG uptake differentiates between gastrointestinal stromal tumors and abdominal malignant lymphomas on PET/CT
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Gastrointestinal stromal tumors (GISTs) and malignant lymphomas (MLs) in the abdomen are often observed as tumors of unknown origin on F-18 FDG PET/CT. The purpose of this study was to evaluate the intratumoral metabolic heterogeneity of F-18 FDG uptake on PET to determine if it might be helpful to discriminate between these tumors.
The F-18 FDG PET/CT findings of 21 large abdominal tumors were retrospectively evaluated (9 GISTs and 12 MLs). Intratumoral heterogeneity was evaluated by visual scoring (visual score: 0, homogeneous; 1, slightly heterogeneous; 2, moderately heterogeneous; 3, highly heterogeneous) and by the cumulative standardized uptake value (SUV) histograms on transaxial PET images at the maximal cross-sectional tumor diameter. Percent tumor areas above a threshold from 0 to 100% of the maximum SUV were plotted and the area under curve of the cumulative SUV histograms (AUC-CSH) was used as a heterogeneity index, where lower values corresponded with increased heterogeneity. Correlation between the visual score and the AUC-CSH was investigated by the Spearman’s rank test.
GISTs exhibited heterogeneous uptake of F-18 FDG, whereas MLs showed rather homogeneous uptake on visual analysis (visual score: 2.67 ± 0.50 and 0.58 ± 0.79, respectively; p < 0.001). The AUC-CSH was significantly lower for the GISTs than for the MLs (0.41 ± 0.14 and 0.64 ± 0.08, respectively; p < 0.001). Significant correlations were observed between the visual score and the AUC-CSH (ρ = −0.866, p < 0.001).
GISTs exhibited significantly heterogeneous intratumoral tracer uptake as compared with the MLs. Evaluation of the intratumoral heterogeneity of F-18 FDG uptake may help in the discrimination between these tumors.
KeywordsF-18 FDG PET Intratumoral heterogeneity Gastrointestinal stromal tumor Malignant lymphoma Cumulative standardized uptake value histograms
Gastrointestinal stromal tumors (GISTs) and malignant lymphomas (MLs) in the abdomen are often observed as tumors of unknown origin on F-18 fluorodeoxyglucose (FDG) PET/CT examinations. Characteristics of tumors are often determined by the intensity of F-18 FDG uptake, usually by the maximum standardized uptake value (SUVmax). SUVmax is calculated based on the hottest uptake of the tumor and does not reflect the activity throughout the tumor. Heterogeneous F-18 FDG uptake is sometimes encountered in large abdominal tumors. For example, GISTs often exhibit heterogeneous uptake as compared with other types of tumors, even if the SUVmax is on the same level. On the other hand, homogeneous uptake has often been observed in MLs. Thus, evaluation of the intratumoral heterogeneity of F-18 FDG uptake may provide us with additional information about the tumor characteristics. A recent study reported that the detection of intratumoral metabolic heterogeneity on baseline F-18 FDG-PET is useful for predicting the response to concomitant radiochemotherapy in esophageal cancer . However, no study has reported evaluation of the intratumoral distribution of F-18 FDG on PET to differentiate among tumors of unknown origin. Intratumoral metabolic activity is not uniform and may differ depending on the characteristics of the tumor cells such as the cellular proliferative activity and the state of the microenvironment such as presence/absence of hypoxia . We evaluated the intratumoral heterogeneity of F-18 FDG uptake on PET, which was considered to reflect the tumor characteristics. The purpose of this study was to evaluate the intratumoral metabolic heterogeneity in GISTs and MLs on PET images to determine if it might be helpful in discriminating between these two types of tumors.
Materials and methods
Characteristics of the patients and extent of the lesions
58.1 ± 13.6
59.2 ± 10.8
GIST (n = 9)
Gastric 3, small intestine 3, peritoneum 2, unknown 1
Liver 3, peritoneum 3, both liver and peritoneum 1
ML (n = 12)
Non-Hodgkin’s lymphoma (diffuse large B-cell type 6, follicular type 6)
Stage (Ann Arbor)
I: 1, II: 2, III: 6, IV: 3
After at least 4 h of fasting, the patients received an intravenous injection of F-18 FDG (approximately 3.7 MBq (0.1 mCi)/kg body weight). PET/CT exams were performed about 60 min after the administration of F-18 FDG. Imaging was performed with an integrated PET/CT scanner (GEMINI GXL, Philips). Whole-body images were acquired generally from the top of the skull to the mid-thighs. PET images were acquired under the following acquisition conditions: 3D emission scan, 2 min scan/bed position × 9–11 positions, and 4.0-mm slice thickness/interval. The PET images were reconstructed with the 3-dimensional (3D) line-of-response row-action maximum-likelihood algorithm using standard protocol parameters (relaxation parameter of 0.04). The spatial resolutions at the center of the PET were 5.2 mm full width at half maximum (FWHM) in the transaxial direction and 6.0 mm FWHM in the axial direction. The acquisition conditions for the CT (16-slice CT) were as follows: breathhold during normal expiration from the level of the lung apex to the lower poles of the kidneys, without intravenous or oral contrast medium, 120 kVp and 50 effective mAs, 5.0-mm slice thickness/4.0 mm interval. The CT scan data were used for the attenuation correction as well as image fusion. The matrix size was 144 × 144 (4 mm × 4 mm for each pixel) for PET and 512 × 512 (1.17 mm × 1.17 mm for each pixel) for CT.
Single tumor lesion (primary site in GISTs or the largest lymph node in MLs) was selected in each patient and transaxial PET image at the maximal cross-sectional tumor diameter was used for evaluation of the intratumoral metabolic heterogeneity. Visual assessment was performed by two experienced nuclear medicine physicians who were unaware of the patients’ histories or diagnosis, using a visual scoring system, as follows: 0, homogeneous uptake; 1, slight heterogeneous uptake; 2, moderate heterogeneous uptake; 3, highly heterogeneous uptake. The decision on the visual score was based on the consensus of the two observers.
The data between the two groups were compared by Mann–Whitney’s test. Correlation between the visual score and other parameters were assessed by calculation of the Spearman’s rank correlation coefficient. Probability values of less than 0.05 were considered to denote statistical significance.
Results of visual and ROI analysis of the GIST and ML groups
2.67 ± 0.50
0.58 ± 0.79
7.4 ± 2.6
11.0 ± 6.4
9.0 ± 3.6
12.6 ± 6.0
0.58 ± 0.30
0.31 ± 0.09
0.41 ± 0.14
0.64 ± 0.08
Tumor area (cm2)
118.6 ± 102.1
40.1 ± 31.6
Correlation between the visual score and other parameters
Coefficient of correlation
Tumor area (cm2)
Results of visual and ROI analysis in the DLBCL and FL groups
1.00 ± 0.89
0.17 ± 0.41
15.0 ± 7.1
7.0 ± 0.7
17.0 ± 5.9
8.3 ± 0.8
0.36 ± 0.10
0.27 ± 0.04
0.60 ± 0.08
0.68 ± 0.04
Tumor area (cm2)
51.9 ± 39.8
28.3 ± 16.6
GISTs are mesenchymal neoplasms with a spectrum of histologic appearances and biologic activity  and arise from anywhere in the gastrointestinal tract (from the esophagus to the rectum) . It has been reported that F-18 FDG PET is useful for evaluating the therapeutic responses of these tumors to drugs, such as imatinib . We evaluated the intratumoral heterogeneity of F-18 FDG uptake to discriminate them from other abdominal tumors for diagnosis. A previous study reported heterogeneous enhancement in large GISTs on enhanced CT . Focal areas of low attenuation on CT in small GISTs represent varying pathological conditions, including solid tumor, hemorrhage, hemorrhage with necrosis, cystic degeneration, fluid in ulcers, and fibrous septum . Large GISTs (>6 cm) frequently show central areas of necrosis or hemorrhage, resulting in a cystic appearance [4, 9]. In our study, areas of lower F-18 FDG uptake in GISTs often corresponded to the low-attenuation areas on CT and were considered to reflect the aforementioned pathological features. However, heterogeneous F-18 FDG uptake was observed in solid portions of the GISTs, which corresponded to areas of homogeneous density on CT.
MLs are malignant neoplasms composed of monoclonal proliferations of lymphocytes derived from either B cells or T cells at various stages of their differentiation . The molecular characteristics and biologic behavior of these tumors differ according to the histologic subtype. MLs can be divided into aggressive and indolent types according to the clinical course. The ML subtypes included in our study were FL (indolent type) and DLBCL (aggressive type). On CT images, MLs typically show homogeneous attenuation on non-contrast images, related to the inherent hypercellularity of the lymphoma masses . Intratumoral necrosis is rarely seen before chemotherapy. In our study, both FLs and DLBCLs exhibited a homogeneous density on CT, without any areas of low attenuation.
FLs generally show low-to-moderate F-18 FDG uptake on PET . Typical FL accounts for most cases of low-grade FLs and represents a homogeneous disease entity with definitive morphological characteristics, phenotype, and gene aberrations . DLBCLs generally exhibit marked elevation of F-18 FDG uptake on PET/CT . In our study, DLBCLs showed markedly high uptake and FLs had moderate uptake, which corresponded to the previous study.
In many previous F-18 FDG PET studies, the tumor characteristics were usually evaluated by the 3D-SUVmax, which reflected only a single voxel with the maximum uptake, and few PET studies have focused on the intratumoral distribution of F-18 FDG [1, 3, 15]. The CSH method that we applied in our study was recently reported for parameterizing heterogeneous intratumoral F-18 FDG uptake in non-small cell lung cancer PET studies . This method can be applied for 2D-ROI analysis to evaluate large tumors. The heterogeneity of F-18 FDG uptake may be greatly affected by the tumor size and spatial resolution of PET. Our inclusion criteria of the tumor were measuring more than 5 cm in the major-axis maximal diameter, which is approximately 10 times as large as FWHM in the transaxial direction. Therefore, tumor size was large enough to evaluate by the transaxial PET slice at the maximal diameter as a representative image of the entire tumor.
The results of visual scoring evaluation were significantly correlated with the AUC-CSH, which showed the better correlation than the CV. Our evaluation by visual analysis corresponded to the quantitative method to characterize the intratumoral metabolic heterogeneity.
There were no significant correlations between the visual score and the 2D-SUVmax, which suggested that the 2D-SUVmax does not reflect the intratumoral metabolic heterogeneity, although higher 2D-SUVmax may be associated with a greater likelihood of metabolic heterogeneity. In our study, DLBCLs, which showed the highest 2D-SUVmax, showed homogeneous uptake as compared with GISTs. F-18 FDG PET evaluation revealed that while FLs and GISTs were on the similar 2D-SUVmax levels, they exhibited significant differences in intratumoral heterogeneity of F-18 FDG uptake.
The limitations of our study was that we did not account for the difference in the tumor volume between the GISTs and MLs; the GISTs showed a higher average tumor volume than the MLs. In general, larger tumors may be expected to show more heterogeneous F-18 FDG uptake on PET. In our study, the visual score was significantly correlated with the tumor area, which suggested that tumor volume might be one of the major determinants of intratumoral metabolic heterogeneity.
In this F-18 FDG PET/CT study, GISTs exhibited significantly more heterogeneous intratumoral uptake as compared with MLs. We used a 2D-ROI analysis method for evaluating the intratumoral tracer distribution, the results of which showed a good correlation with the results of the visual assessment. Evaluation of the intratumoral metabolic heterogeneity on F-18 FDG PET images may help discriminate between these tumors.
The authors thank the staff of the Department of Nuclear Medicine, Osaka University Hospital, for their excellent technical assistance.
Conflict of interest
The authors declare that they have no conflict of interest and no source of funding.
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