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(Radiology. 1999;211:249-256.)
© RSNA, 1999

Nuclear Medicine

Germ Cell Tumor: Differentiation of Viable Tumor, Mature Teratoma, and Necrotic Tissue with FDG PET and Kinetic Modeling1

Yoshifumi Sugawara, MD, Kenneth R. Zasadny, PhD, H. Barton Grossman, MD 2, Isaac R. Francis, MD, Michael F. Clarke, MD and Richard L. Wahl, MD

1 From the Departments of Internal Medicine, Division of Nuclear Medicine (Y.S., K.R.Z., M.F.C., R.L.W.), Urology (H.B.G.), and Radiology (I.R.F., R.L.W.), University of Michigan Medical Center, 1500 E Medical Center Dr, B1G 505C, Box 0028, Ann Arbor, MI 48109-0028. Received April 30, 1998; revision requested July 6; revision received August 10; accepted October 14. Supported in part by National Institutes of Health grants CA53172, CA56731, and CA52880, and University of Michigan Clinical Research Center grant M01RR00042 from the Hi-Tech Funding Initiative. Address reprint requests to R.L.W.


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate the feasibility of positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in patients with germ cell tumor (GCT) to monitor treatment and differentiate residual masses after chemotherapy.

MATERIALS AND METHODS: Twenty-six FDG PET studies were performed in 21 patients with GCT. FDG uptake of tumors was interpreted visually, and the lean standardized uptake value (SUVlean) was determined. Tumor kinetic rate constants (K1, k2, k3) and net rate of FDG phosphorylation (K = [K1 · k3]/[k2 + k3]) in tumors were calculated from the dynamic data by means of a three-compartment model, assuming k4 = 0.

RESULTS: Viable tumors (n = 10) showed intense FDG uptake and could easily be differentiated visually from mature teratoma (n = 6) and necrosis or scar (n = 10). The SUVlean of residual viable tumors (4.51 ± 1.34 [mean ± SD]) was higher than that of mature teratoma (1.38 ± 0.71) and necrosis or scar (1.05 ± 0.29) (P < .05). Although neither the visual interpretation nor SUVlean differentiated mature teratoma from necrosis or scar, there were statistically significant differences in the kinetic rate constants K1 and K between mature teratoma and necrosis or scar as follows: K1, 0.113 mL/min/g ± 0.026 versus 0.036 mL/min/g ± 0.005 (P < .05); K, 0.005 mL/min/g ± 0.003 versus 0.0008 mL/min/g ± 0.0001 (P < .05).

CONCLUSION: FDG PET with kinetic analysis appears to be a promising method for management of disease in patients with GCT after treatment.

Index terms: Emission CT (ECT), 60.12163 • Fluorine, 60.12163 • Germ cell neoplasm, 60.3153 • Glucose, 60.12163


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Germ cell tumors (GCTs) are rare but represent the most common neoplasms seen in young male patients, especially those aged 15–35 years (1). Although cisplatin-based combination chemotherapy regimens have achieved long-term disease-free survival and presumed cure in approximately 80% of patients (2), some patients with GCT may have residual masses after chemotherapy. Most patients with residual masses are referred for surgical exploration, but the surgical results vary according to published reports. In general, histologic findings of residual masses show viable tumor in approximately 10%–20% of cases, mature teratoma in 30%–40%, and necrosis or fibrosis in 40%–50% (3,4). Thus, approximately half of patients with residual masses after treatment of this tumor have undergone (in retrospect) unnecessary surgery. Despite this clinical problem, patient selection criteria for avoiding surgical exploration after the completion of chemotherapy remain controversial (3).

Positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) has shown utility in differentiating malignant from benign tumors of various histologic diagnoses, in staging malignant tumors, and in evaluating treatment efficacy in patients with cancer (5–10). The increased glucose metabolism in malignant versus many benign tissues allows such differentiation. Recently, it has also been reported that increased FDG uptake at PET was observed in residual viable GCTs, allowing them to be differentiated on the basis of the lower FDG uptake of teratoma and necrosis or scar (11–14). However, it is still difficult to differentiate mature teratoma from necrosis or scar with conventional visual interpretation or semiquantitative analysis of FDG uptake (13). It remains clinically desirable to avoid unnecessary surgery in patients with necrosis or scar, whereas excision of residual teratoma is theoretically important.

The elevated glucose utilization in tumors is a result of a combination of increased blood flow and glucose transport, increased glucose phosphorylation (enhanced hexokinase activity), and decreased rates of dephosphorylation (15). Therefore, dynamic FDG PET kinetic studies of tumors can be performed to produce numeric estimates of rate constants of FDG (16,17). In general, based on the method initially shown by Sokoloff et al (18), the three-compartment model analysis has been used to quantify cerebral glucose metabolism in humans (19). Recently, this method has also been cautiously applied to some tumors in humans (8,16,20–22).

In the present study, we applied standard three-compartment model kinetic analysis to FDG PET studies in patients with untreated and treated GCT, in addition to conventional visual interpretation and semiquantitative analysis of FDG PET images. Thus, we evaluated the feasibility of FDG PET in patients with GCT, not only for monitoring treatment efficacy but also for differentiating residual masses after chemotherapy. One of our goals was to determine if the kinetic modeling approach would be useful in differentiating mature teratoma from necrosis or scar.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patient Population
Twenty-one male patients, aged 19–42 years (mean age, 29 years), with primary or metastatic GCTs were studied (Table). Fifteen of 21 patients presented with metastatic lesions from testicular GCTs, whereas six patients presented with primary GCTs in the retroperitoneum (patients 3 and 9) or the mediastinum (patients 10, 11, 13, and 20). Written informed consent was obtained from all patients for the studies, which were performed with institutional review board approval. FDG PET studies were performed at the time of diagnosis (five studies) and when residual masses remained after standard cisplatin-based chemotherapy (21 studies, including two after radiation therapy and two after autologous bone marrow transplantation). In five patients, FDG PET studies were repeated after the completion of chemotherapy or as follow-up (mean interval, 280 days). A total of 26 studies was performed in the 21 patients. To define the precise location and size of lesions, all patients also underwent computed tomography (CT), magnetic resonance (MR) imaging, or both before FDG PET (mean interval after CT or MR imaging to FDG PET, 16 days). Histologic confirmation was obtained in 21 lesions (mean interval after FDG PET, 14 days), and the other five lesions were assessed as viable clinically (ie, newly diagnosed or regrowing tumor depicted at CT or MR imaging with increased tumor markers of {alpha}-fetoprotein, ß-human chorionic gonadotropin, or both).


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  		Patient Characteristics and FDG PET Results
 
FDG PET Scanning
FDG was produced by means of a standard nucleophilic fluorination method, as previously described (23). FDG PET studies were performed with either an Ecat 931 scanner (15 scanning planes, 10-cm longitudinal field of view) or an Exact 921 scanner (47 scanning planes, 15-cm longitudinal field of view) (Siemens Medical Systems, Iselin, NJ). The reconstruction x-y resolution with the Hanning filter cutoff value of 0.3 was approximately 1.2 cm full width at half maximum for both scanners. All patients fasted for at least 4 hours before FDG PET. Before tracer injections, at least one 10-minute transmission scan was obtained with use of a germanium-68 ring or rod source to allow attenuation correction of the emission images. Immediately after intravenous tracer injection (approximately 370 MBq of FDG), sequential dynamic scans at the level of suspected tumors were obtained throughout 60 minutes. These dynamic scans generally included six 10-second scans, three 20-second scans, two 90-second scans, one 5-minute scan, and five 10-minute scans, although in some instances, more frames were obtained. After completion of sequential dynamic scanning, static scans, including multiple levels, were obtained with a 2–10-minute acquisition time per scanning level according to the patient status and field of view.

Image Analysis
Tumor uptake of FDG on the last frame (at 50–60 minutes) of dynamic scans or on static scans was assessed visually. For areas with a corresponding abnormality also depicted on CT or MR images, qualitative grades were assigned: grade 2, intense uptake; grade 1, equivocal uptake; grade 0, no uptake. In cases of more than one lesion depicted at FDG PET, the lesion with the greatest FDG uptake was chosen for analysis. If the lesions did not show intense uptake on FDG PET images, the largest lesion that was also depicted at CT or MR imaging (and for which histologic confirmation was usually obtained after surgical resection) was also chosen for analysis.

For quantitative analysis of FDG uptake in tissue, a small square (4 x 4 pixels, approximately 1.7 x 1.7 cm) region of interest (ROI) was placed on the 50–60- or 60–70-minute postinjection images. In cases of intensely increased FDG uptake (grade 2), this 16-pixel ROI was placed by means of an automated algorithm on the area of maximal FDG uptake within a larger ROI that included the mass lesions. In cases of equivocal or no uptake of FDG (grades 1 or 0), the ROI was placed in the center of the lesion by referring to the CT or MR images. An ROI was not placed in cases of a small lesion (less than 2.0 cm in diameter on CT or MR images) with grade 0 FDG uptake. To generate tissue time-activity curves, the ROIs over all planes that included mass lesions were reviewed in reference to the CT or MR images and were copied to every dynamic scan. Then, the counts were averaged for two (Ecat 931) or three (Exact 921) contiguous sections with the highest activity (24). For a more weight-independent index of standardized uptake value (SUV) in this maximal uptake ROI, we calculated SUVlean. As described previously (25), SUVlean is decay-corrected tissue activity divided by the injected dose per patient body weight corrected by predicted lean body mass.

A standard three-compartment metabolic model (18,19) was used to assess FDG kinetics in tissue. To define the blood input function noninvasively, blood time-activity curves were generated with a 16-pixel ROI in the left atrium or with a four-pixel ROI in the abdominal aorta, according to the level of dynamic scanning, as previously described (24). To reduce the partial volume effect, the maximal counts per pixel within the aorta were averaged over three contiguous planes and then divided by the recovery coefficient, which was obtained with the method defined by Germano et al (26). The generated kinetic parameters were rate constants for FDG transport from blood to tissue (K1) (in milliliters per minute per gram), return from tissue to blood (k2) (per minute), and phosphorylation of FDG to FDG-6 phosphate (k3) (per minute). The latter rate was assumed to be negligible (k4 = 0), as previously described (8), although this was also verified by means of modeling (19). Each rate constant was obtained from the dynamic data by means of a nonlinear least-squares curve-fitting algorithm (27). This kinetic model also produced an estimate of net FDG phosphorylation rate in tissue (K) as follows: K = (K1 · k3)/(k2 + k3) (in milliliters per minute per gram). This index is equal to the influx constant (Ki), which is determined by means of a graphic analysis of unidirectional FDG influx, as defined by Patlak et al (28). Kinetic analysis was not performed in cases of difficult ROI selection (ie, no FDG uptake or a very small lesion), patient motion during dynamic scanning, or no dynamic data acquisition at the tumor level. Kinetic data were available for 15 studies in 13 patients.

Statistical Analysis
Lesion categories were based on histologic findings for 21 lesions and on clinical observations for five lesions. At histologic examination, resected material was categorized as viable if any component of viable cancer cells was present and as mature teratoma if there was no evidence of viable cancer cells but a component of mature teratoma was present. Other lesions were categorized as necrosis or scar.

In the different lesions, differences in SUVlean and the kinetic rate constants were compared by means of analysis of variance followed by the Mann-Whitney U test. The data are presented as the mean plus or minus SD. A P value less than .05 was considered statistically significant.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Patient characteristics and the results of FDG PET studies are shown in the Table. All viable tumors (10 cases, including five clinically diagnosed lesions) showed intense (grade 2) FDG uptake, whereas mature teratoma (six cases) and necrosis or scar (10 cases) showed equivocal (grade 1) or no (grade 0) FDG uptake. Newly diagnosed tumors all showed obvious intense uptake at FDG PET. After effective chemotherapy, FDG uptake decreased substantially (patients 2, 3, and 6), even though residual masses remained at CT (Figs 1, 2).



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  		Figure 1a. Patient 2. Images in a 37-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumors (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy. d depicts dramatically decreased FDG uptake (SUVlean decreased from 8.04 to 2.17) despite residual masses seen on the CT scan (arrowheads in c). Histologic examination of residual masses revealed mature teratoma. In d, the two intense foci of FDG activity represent labeled beads at the skin surface near the midline and left side of the abdomen.

 


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  		Figure 1c. Patient 2. Images in a 37-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumors (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy. d depicts dramatically decreased FDG uptake (SUVlean decreased from 8.04 to 2.17) despite residual masses seen on the CT scan (arrowheads in c). Histologic examination of residual masses revealed mature teratoma. In d, the two intense foci of FDG activity represent labeled beads at the skin surface near the midline and left side of the abdomen.

 


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  		Figure 1b. Patient 2. Images in a 37-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumors (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy. d depicts dramatically decreased FDG uptake (SUVlean decreased from 8.04 to 2.17) despite residual masses seen on the CT scan (arrowheads in c). Histologic examination of residual masses revealed mature teratoma. In d, the two intense foci of FDG activity represent labeled beads at the skin surface near the midline and left side of the abdomen.

 


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  		Figure 1d. Patient 2. Images in a 37-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumors (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy. d depicts dramatically decreased FDG uptake (SUVlean decreased from 8.04 to 2.17) despite residual masses seen on the CT scan (arrowheads in c). Histologic examination of residual masses revealed mature teratoma. In d, the two intense foci of FDG activity represent labeled beads at the skin surface near the midline and left side of the abdomen.

 


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  		Figure 2a. Patient 3. Images in a 28-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumor (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy depict a residual mass at CT (arrowheads in c), but the mass shows no FDG uptake in d. Note that intravenous contrast material was not used for the CT study owing to renal dysfunction after chemotherapy. The right kidney shows intense FDG uptake (arrow in d), presumably due to chemotherapy-related abnormality. Histologic examination of the residual mass revealed necrotic tissue.

 


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  		Figure 2c. Patient 3. Images in a 28-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumor (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy depict a residual mass at CT (arrowheads in c), but the mass shows no FDG uptake in d. Note that intravenous contrast material was not used for the CT study owing to renal dysfunction after chemotherapy. The right kidney shows intense FDG uptake (arrow in d), presumably due to chemotherapy-related abnormality. Histologic examination of the residual mass revealed necrotic tissue.

 


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  		Figure 2b. Patient 3. Images in a 28-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumor (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy depict a residual mass at CT (arrowheads in c), but the mass shows no FDG uptake in d. Note that intravenous contrast material was not used for the CT study owing to renal dysfunction after chemotherapy. The right kidney shows intense FDG uptake (arrow in d), presumably due to chemotherapy-related abnormality. Histologic examination of the residual mass revealed necrotic tissue.

 


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  		Figure 2d. Patient 3. Images in a 28-year-old man. (a) CT and (b) FDG PET scans obtained before chemotherapy depict retroperitoneal tumor (arrows), with intense FDG uptake in b. (c) CT and (d) FDG PET scans obtained after chemotherapy depict a residual mass at CT (arrowheads in c), but the mass shows no FDG uptake in d. Note that intravenous contrast material was not used for the CT study owing to renal dysfunction after chemotherapy. The right kidney shows intense FDG uptake (arrow in d), presumably due to chemotherapy-related abnormality. Histologic examination of the residual mass revealed necrotic tissue.

 
The SUVlean of all 10 viable tumors ranged from 3.19 to 12.23 (mean, 7.12 ± 3.33). The SUVlean of all five newly diagnosed tumors (range, 6.62–12.23; mean, 9.73 ± 2.49) was higher than that for all five residual viable tumors after chemotherapy (range, 3.19–6.64; mean, 4.51 ± 1.34) (P < .05). The newly diagnosed tumors (size range, 2.0 x 2.0 cm to 12.0 x 9.0 cm; mean, 6.5 x 5.2 cm) were slightly larger than the residual viable tumors (size range, 1.3 x 1.3 cm to 6.0 x 5.0 cm; mean, 3.7 x 3.1 cm), but the differences were not significant. In contrast, the SUVlean of all five mature teratomas ranged from 0.50 to 2.17 (mean, 1.38 ± 0.71), whereas that of the seven lesions diagnosed as necrosis or scar ranged from 0.73 to 1.50 (mean, 1.05 ± 0.29). The SUVlean of mature teratomas and necrosis or scar was significantly lower than that of residual viable tumors (P < .05), whereas there were no significant differences between the SUVlean of mature teratomas and that of necrosis or scar (Fig 3). The SUVlean could not be calculated reliably in one mature teratoma and in three cases of necrosis or scar, all of which were small lesions (diameter less than 2.0 cm) with no visible FDG uptake. The mature teratomas (size range, 1.5 x 1.5 cm to 11.0 x 7.0 cm; mean, 4.4 cm ± 2.9) were larger than the cases of necrosis or scar (size range, 1.0 x 1.0 cm to 5.0 x 4.5 cm; mean, 2.8 x 2.5 cm), but the differences were also not significant.



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  		Figure 3. The SUVlean (SUL) of residual viable tumors, mature teratomas, and necrosis or scar. The SUVlean of viable tumors is significantly higher than that of mature teratomas or necrosis (P < .05), whereas there are no significant (ns) differences between the SUVlean of mature teratomas and necrosis. Error bars indicate the means plus or minus SDs.

 
Kinetic rate constants were calculated in 15 of 26 FDG PET studies. There were no significant differences in rate constants between the newly diagnosed tumors and the residual viable tumors after chemotherapy. The K values of newly diagnosed tumors were higher than those of residual viable tumors (0.050 mL/min/g ± 0.019 vs 0.023 mL/min/g ± 0.013, P < .05), similar to the differences in their SUVlean. In cases after chemotherapy, the comparisons of the rate constants (K1, k2, k3) and the K values in the three histologic types (viable tumor, n = 4; mature teratoma, n = 3; necrosis or scar, n = 4) are shown in Figure 4. The K1 values of necrosis or scar were lower than those of viable tumors or mature teratomas (0.036 mL/min/g ± 0.005 for necrosis or scar vs 0.119 mL/min/g ± 0.049 for viable tumors or 0.113 mL/min/g ± 0.026 for mature teratomas, P < .05) (Fig 4a). There were no differences in the k2 values for the three groups (0.282 min-1 ± 0.307, 0.301 min-1 ± 0.116, 0.176 min-1 ± 0.042, respectively) (Fig 4b). The k3 values of mature teratomas and necrosis or scar were lower than those of viable tumors (0.063 min-1 ± 0.049 in viable tumors vs 0.012 min-1 ± 0.007 in mature teratomas and 0.004 min-1 ± 0.002 in necrosis or scar, P < .05) (Fig 4c). There were significant differences in the K values for the three groups (0.023 mL/min/ g ± 0.013 in viable tumors vs 0.005 mL/min/g ± 0.003 in mature teratomas vs 0.0008 mL/min/g ± 0.0001 in necrosis or scar, P < .05, respectively) (Fig 4d).



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  		Figure 4a. Kinetic rate constants of (a) K1, (b) k2, (c) k3, and (d) K. The differences in K1 and K are significant between mature teratomas and necrosis or scar. Error bars indicate the means plus or minus SDs.

 


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  		Figure 4b. Kinetic rate constants of (a) K1, (b) k2, (c) k3, and (d) K. The differences in K1 and K are significant between mature teratomas and necrosis or scar. Error bars indicate the means plus or minus SDs.

 


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  		Figure 4c. Kinetic rate constants of (a) K1, (b) k2, (c) k3, and (d) K. The differences in K1 and K are significant between mature teratomas and necrosis or scar. Error bars indicate the means plus or minus SDs.

 


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  		Figure 4d. Kinetic rate constants of (a) K1, (b) k2, (c) k3, and (d) K. The differences in K1 and K are significant between mature teratomas and necrosis or scar. Error bars indicate the means plus or minus SDs.

 

   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Findings in this study demonstrate that untreated viable GCTs show intense FDG uptake and that the uptake is reduced after effective chemotherapy, as previously described for other types of tumors (6,8). Second, in the cases of residual masses after chemotherapy, FDG PET could differentiate viable tumors, which have increased FDG uptake, from mature teratomas and necrosis or scar, on the basis of qualitative visual interpretation or SUVlean calculations; however, it was not consistently possible to differentiate mature teratomas from necrosis or scar on this basis. These results are in agreement with our preliminary findings and with other recently published reports (11–13). Finally, the FDG kinetics in mature teratomas were significantly different from those in necrosis or scar.

Our study results show that FDG PET, especially with kinetic modeling, can provide useful and additional information in the management of disease in patients with GCTs, particularly in cases of residual masses after chemotherapy. If FDG PET shows intense FDG uptake (and high SUVlean) in the residual mass, viable tumor is very likely present; patient treatment could be salvage chemotherapy, surgical resection, or both. When FDG PET does not show obvious uptake in the residual mass and SUVlean is low, but the rate constant K1 is substantial (K1 > 0.06 mL/min/g), patient treatment could be surgical resection, as teratoma seems likely. However, when K1 of the residual mass is also low, the patient potentially could be observed without surgery and followed up with periodic CT or MR imaging, FDG PET, or both. More extensive clinical studies are warranted to prospectively confirm the accuracy of this method of kinetic analysis of FDG in tumors.

Although increased FDG uptake was seen in all viable tumors in this study, a few viable tumor cells might not be detected at FDG PET. In some other conditions, false-positive cases of inflammatory tissues accumulating FDG have been reported (14). For example, if there is intercurrent infection in a mass, distinguishing inflammatory tissue from residual viable tumor could be difficult on the basis of FDG uptake. In general, FDG uptake in a mass after chemotherapy suggests residual tumor is present.

Mature teratoma is found in approximately 30%–40% of cases of a residual mass in patients with GCT after chemotherapy. The tumor is generally removed surgically, despite its histologically benign features, since it may grow (29), has a risk of malignant transformation (30), and may result in late recurrence (31). Thus, differentiation of mature teratoma from necrosis or scar is essential, but it has been difficult on the basis of conventional CT findings (32) or the usual qualitative interpretation of FDG PET images (13). Microscopically, mature teratoma may have tissues derived from all three germ layers (ie, ectoderm, mesoderm, endoderm). Macroscopically, hemorrhage and necrosis are also commonly seen in mature teratoma (33).

We believe that the rate constant for FDG transport from blood to tissue (K1) may be substantially preserved in mature teratoma, as it is in other viable tumors with the same histologic features; as a result, the rate constant K1 would be higher in mature teratoma than in necrosis or scar (Fig 4a). In addition, the rate constant for FDG transport from tissue to blood (k2) of mature teratoma is slightly higher than that of necrosis or scar, although the difference was not significant in this small series, and reasonably large variances exist (Fig 4b). On the other hand, the rate constant that likely reflects hexokinase activity in tissue (k3) (21,22) was lower in mature teratoma than in viable tumor and appeared to be similar to that in necrosis or scar (Fig 4c). As a result, the net FDG phosphorylation rate in tissue (ie, K = [K1 · k3]/[k2 + k3]) shows low values in mature teratoma. In this study, these K values also correlated well with SUVlean (r = 0.947, P < .001) (Fig 5). The SUVlean was very low in cases of extremely low K values ({approx}0) (in the cases of necrosis or scar, which are shown around the y intercept in Fig 5). As a result, the differences between mature teratomas and necrosis or scar were not significant for SUVlean, but they were significant for K. These results may be partly supported by those in previous reports, which demonstrated that parametric images of the influx constant (Ki) obtained from graphic analysis (28) had better lesion contrast than did summed or dynamic images (16,34). Thus, for necrosis or scar, K can range downward to essentially zero, but SUVlean does not reach as low as zero.



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  		Figure 5. Relationship between SUVlean (SUL) and K, which have a strong correlation. The SUVlean is low, but not zero, in the cases of extremely low ({approx}0) values of K (the regression line has a y intercept).

 
Limitations in our study include the small number of patients, which is consistent with the relative infrequency of this tumor even at a tertiary care hospital. The patient population was mixed (some patients were studied before and some after treatment). Further, the number of tumors after treatment was quite small (ie, teratoma in three patients and necrosis or scar in four). Therefore, more patients must be studied to confirm our observations.

To obtain the blood input function for kinetic modeling by means of noninvasive FDG PET, we employed time-activity curves generated for the left atrium or abdominal aorta at dynamic scanning. Our results were good for the abdominal aorta with use of modern PET scanners and correction for the partial volume effect (ie, incomplete count recovery) with the method defined by Germano et al (26). However, overcoming the problem of count spillover from surrounding tissue into aortic activity remains challenging (35). Other challenges to the application of a simple three-compartment model to quantitate metabolism in tissue are those that result from tissue heterogeneity (36) and the tissue vascular compartment (16,20). Indeed, both viable GCT and mature teratoma have been reported to show heterogeneous features, and they often have measurable vascular compartments (33). Also, as expected, individual rate constants (K1, k2, k3) have been reported to show moderately large variance, although the influx constant (Ki), which is equal to K in this study, obtained with this noninvasive method is less sensitive to errors (24).

Another limitation in this study was that small residual tumors (ie, diameter less than 2 cm) had lower FDG uptake than did surrounding normal tissues. If ROIs could be placed precisely on such small lesions—by referring to other morphologic images such as CT, MR, or fusion images—the activity in those ROIs might be seen to reflect activity from surrounding normal tissue, which can also demonstrate substantial FDG uptake (37). However, such ROIs could not be placed; therefore, we did not perform kinetic analysis in very small lesions, and it remains difficult to differentiate mature teratoma from necrosis or scar in such cases. However, findings in some studies suggest that residual masses less than 1.5 cm in diameter, less than 20 mL in volume, or both can be managed with observation rather than adjunctive surgery owing to their high probability of representing necrosis or scar (3,32). On the other hand, we could detect viable tumor less than 2 cm in diameter at FDG PET on the basis of the increased FDG uptake (ie, patient 19, SUVlean = 4.15). Although it has some limitations, we believe FDG PET will be useful in the management of disease in patients with residual masses after treatment of GCT, since it may add useful metabolic information to other morphologic imaging findings.

In summary, untreated viable GCTs have increased FDG uptake, as do residual viable GCTs after treatment. Although both mature teratomas and necrosis or scar have low FDG uptake, FDG transport (K1) and the net rate of FDG phosphorylation (K) for mature teratomas are significantly higher than those for necrosis or scar. Although these findings should be confirmed in larger series, our observations suggest that FDG PET with kinetic analysis will be a useful tool in the management of disease in patients with GCT.


   Acknowledgments
 
The authors thank Paul V. Kison, BS, for his technical assistance.


   Footnotes
 
2 Current address: Department of Urology, M.D. Anderson Cancer Center, Houston, Tex. Back

Abbreviations: FDG = 2-[fluorine-18]-fluoro-2-deoxy-D-glucose GCT = germ cell tumor ROI = region of interest SUV = standardized uptake value

Author contributions: Guarantor of integrity of entire study, R.L.W.; study concepts, R.L.W., H.B.G.; study design, R.L.W., H.B.G., I.R.F.; definition of intellectual content, R.L.W., H.B.G., Y.S.; literature research, Y.S., R.L.W.; clinical studies, R.L.W., H.B.G., I.R.F., M.F.C.; data acquisition, Y.S., K.R.Z.; data analysis, Y.S., K.R.Z., R.L.W.; statistical analysis, Y.S., K.R.Z, R.L.W.; manuscript preparation, Y.S., K.R.Z., R.L.W.; manuscript editing, Y.S., R.L.W., H.B.G.; manuscript review, R.L.W., Y.S.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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