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Technical Developments |
1 From the Department of Medical Radiology, Division of Nuclear Medicine, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. Received September 21, 2001; revision requested December 3; final revision received March 14, 2002; accepted April 10. Supported in part by GE Medical Systems, Buc, France, and the Radium Foundation, University of Zurich, Switzerland. Address correspondence to T.F.H. (e-mail: thomas.hany@dmr.usz.ch).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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© RSNA, 2002
Index terms: Computed tomography (CT), helical, 20.12115, 60.12115, 70.12115 • Data fusion, 20.12115, 20.12163, 60.12115, 60.12163, 70.12115, 70.12163 • Images, fusion, 20.12115, 20.12163, 60.12115, 60.12163, 70.12115, 70.12163
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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In recent years, imaging with fluorodeoxyglucose (FDG) positron emission tomography (PET) for tumor staging and therapy control has been introduced. Rather than anatomic information, FDG PET provides physiologic information on glucose uptake and metabolism. FDG PET has been used successfully for detection of primary tumors, metastases, and early tumor recurrence, while the indications for PET in cardiology and neurology have existed for a longer time (4–8). The main drawback of PET in tumor imaging is the virtually complete absence of anatomic landmarks, which impedes precise localization of lesions with pathologic FDG uptake (9). Furthermore, there are some issues regarding specificity because FDG is not only taken up by many malignant tumors but also by sites of active inflammation (10).
During the early years of clinical tumor imaging with PET, the potential of multimodality image fusion was recognized since CT and magnetic resonance imaging on one hand and PET on the other yield complementary information in many diagnostic settings (9). Findings in several studies have shown that a combination of PET and CT by means of coregistration with software is more accurate than CT alone, especially in the staging of non–small cell lung cancer and detection of mediastinal lymph node metastases (9,11).
Recently, Townsend (12) introduced as proof of concept a prototype of a combined PET-CT scanner, with a single–detector row helical CT scanner and a partial-ring rotating PET scanner, that permits the acquisition of PET and CT images coregistered by means of the hardware in the same imaging session. Analysis of the results showed an improvement in lesion localization and classification, even though only restricted anatomic regions were coregistered, and spatial resolutions of both imagers used in the prototype system were suboptimal (13–15).
To our knowledge, we describe the first application for tumor staging and optimization of an in-line system that combines a full-ring-detector clinical PET scanner and a multi–detector row helical CT scanner in one machine. Both scanners are aligned so that patients can undergo imaging in either of two gantries by just moving the one system table. In this way, coverage of anatomically coregistered images from the head to the pelvic floor—as needed for tumor staging—is obtained by means of hardware arrangement rather than by means of postacquisition software coregistration.
The aim of this study was twofold: first, to determine the diagnostic improvement with hardware-fused PET-CT images compared with PET images alone in a study population of patients with tumors, and second, to determine the optimal radiation parameters to be used for nonenhanced multi–detector row helical CT for image coregistration with PET images.
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Materials and Methods |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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Data Acquisition
All imaging and data acquisition were performed with a combined PET-CT in-line system (Discovery LS; GE Medical Systems, Milwaukee, Wis) that was able to acquire CT images and PET data for the same patient in one session. A PET scanner (Advance NXi; GE Medical Systems) and a multi–detector row helical CT scanner (LightSpeed plus; GE Medical Systems) were integrated in this dedicated system. The axes of both systems were mechanically aligned to coincide. The offset along the table axis between the sensitive fields of view of the CT and PET scanners was 60 cm. The same table was used to acquire PET and CT images. As a result of mechanical limitations of this prototype table version, the table excursion permitted scanning of only six contiguous PET sections, which covered 867 mm. Coverage was adequate from head to pelvic floor in all patients examined. The PET and CT data sets were acquired with two independent computer consoles, which were connected by an interface to transfer CT data to the PET scanner. Both machines can be used independently or as a combined system.
To view the coregistered images from the system, the PET and CT data sets were transferred to an independent personal computer workstation by using digital imaging and communications in medicine. All coregistered images were viewed with dedicated software (Entegra; Elgems, Haifa, Israel). PET images were acquired during free breathing, and each image was acquired during multiple respiratory cycles; CT scans were acquired during shallow breathing. During preliminary studies (unpublished data) with 10 patients with different CT breathing protocols, we determined that the protocol used in the present study leads to good coregistration in the chest, with average mismatches of 5 mm around the diaphragm.
Patients fasted for at least 4 hours before the intravenous administration of 10 mCi (370 MBq) of FDG. Forty-five minutes after the injection, the combined examination started. CT data were acquired first. Patients were positioned on the table in a headfirst supine position. The acquisition was limited to 6 contiguous volumes with a transverse extent of 14.6 cm each; therefore, the start and end locations were chosen carefully to ensure coverage of a region of interest of the entire body from the level of the cerebellum to the pelvic floor. Patients’ arms were placed in an elevated position above the abdomen to reduce beam-hardening artifacts at the level of the liver.
In each patient, four CT scans were acquired with the following parameters: tube rotation time of 0.5 second per revolution; 140 kV for all scans; 10, 40, 80, and 120 mA; 22.5 mm per rotation; section pitch of 6 (high-speed mode); reconstructed section thickness of 5 mm; scanning length of 867 mm; acquisition time of 22.5 seconds for each CT scan. The effective total dose for all four scans was 10.4 mSv, which is equivalent to that for one data acquisition with the same acquisition parameters and tube current of 250 mA.
After the CT data acquisition, the table top (with the patient) was automatically advanced into the PET gantry. Acquisition of PET emission data was started at the level of the pelvic floor. Six incremental table positions, each 146 mm wide, were acquired with minimal overlap, thereby covering 867 mm of table travel. For each position (cradle), 35 two-dimensional non–attenuation-corrected scans were obtained simultaneously during 5 minutes. After emission scanning was completed, transmission scans were obtained by using two germanium 68 pin sources for the same cradle positions during 2 minutes for each position. Therefore, the total data acquisition time for PET imaging was 42 minutes. The images were reconstructed by using iterative reconstruction with two iterations and 28 subsets, which resulted in 35 two-dimensional sections over each transverse field-of-view increment of 14.6 cm. The image reconstruction matrix was 128 x 128 with a transverse field of view of 49.7 x 49.7 cm.
Image Analysis
Cases were divided according to head and neck, lung, or abdominal tumors. Head and neck or abdomen and pelvis images were read with consensus by two physicians (G.W.G., A.B.); chest images were read by three physicians (H.C.S., G.W.G., A.B.). Each group contained at least one board-certified physician for both radiology and nuclear medicine.
Image analysis was performed in five sequential steps. Initially, PET images alone were analyzed. Second, PET images and PET-CT images coregistered with 10-mA CT data were evaluated by the same readers in the same fashion as were PET images alone. In the next steps, all previous data and the fused images with increments of 40-, 80-, and 120-mA CT data were used for analysis. We chose this procedure to evaluate PET-CT images with increasing CT milliampere settings because we assumed that increasing CT image quality should result in equal or better anatomic information. The resulting PET and PET-CT data sets were referred to as PET alone, PET–10-mA CT, PET–40-mA CT, PET–80-mA CT, and PET–120-mA CT. Neither quantitative nor semiquantitative analysis of the FDG uptake was performed.
On FDG PET images, any FDG uptake that clearly exceeded the physiologic liver uptake was defined as "lesion." In each step, the readers were asked to assign the lesions observed at PET or PET-CT to one of three categories: tumor (malignancy), inflammation, or other lesion (urine, muscle, bowel, or perioral uptake). To determine the readers’ certainty of their decision for each lesion, a five-point scale was used: 1, definitively not; 2, unlikely; 3, undecided; 4, likely; or 5, definite. For lesion localization, exact anatomic location had to be indicated for each lesion. Furthermore, additional pathologic information seen at CT was also classified and localized in a manner that was identical to that for lesions taking up FDG.
To assess the clinical effect of the PET-CT examinations, staging was performed for each patient according the TNM classification system on the basis of PET images alone and the fused examinations with incremental use of CT. Results with this image-based staging for each step were then compared with the clinical and histopathologic staging data that were available.
Statistical Analysis
For statistical data analysis, the following cut-off values were used for lesion classification: values greater than 3 (undecided) were regarded as definitely positive; values less than 3, definitely negative; value of 3, undecided.
Since lesion classification and location were taken to be relevant for correct diagnosis in malignant lesions, the clinical or pathologic stage was used as the standard of reference. The clinical stage was determined on the basis of histologic proof of the primary lesion and of crucial secondary lesions. In cases of extended disease, no further work-up was performed. The pathologic stage was determined on the basis of findings in macro- and micropathologic specimens obtained at surgery with curative intent.
If lesion location and classification for a tumor were identical to the standard of reference, lesions were graded as true-positive (TP). A false-negative (FN) classification resulted if location or classification of a lesion differed from the standard of reference and influenced the stage of disease. Lesions classified as tumors in one of the examinations (PET alone, PET–10-mA CT, PET–40-mA CT, PET–80-mA CT, or PET–120-mA CT) were counted as false-positive (FP) when the standard of reference was negative. All inflammatory or other lesions were regarded as true-negative (TN) results, and false classification of such lesions as tumors was counted as a FP result.
Calculation of sensitivity and specificity ratios for tumor detection was based on a lesion-by-lesion analysis in relation to the standard of reference. Furthermore, the accuracy based on the lesion-by-lesion analysis was calculated. To calculate sensitivities and specificities, we dealt with the undecided lesions in the following way: All lesions that remained undecided and were not tumorous according to the standard of reference were excluded from the calculations. Undecided lesions that were tumorous and remained undecided were called FN. In addition, a McNemar test (
2 test) was used to compare the accuracies in tumor detection in a stepwise approach by comparing the accuracy for each step with that of the following step. A P value less than .05 was considered to indicate a statistically significant difference.
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Results |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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Of the seven patients with lung lesions who underwent follow-up examinations, five had recurrent disease—small cell lung cancer, n = 1; mesothelioma, n = 1; non–small cell lung cancer, n = 3—and two were free of disease.
Fourteen patients presented with an ear, nose, and throat carcinoma. Eleven patients were seen for initial staging (unknown primary tumor, n = 1 [stage TxN1M0]; laryngeal carcinoma, n = 1 [stage IV]; hypopharyngeal carcinoma, n = 3 [all stage IVA]; oral carcinoma, n = 5 [stage II, n = 2; stage IVA, n = 2; stage IVC, n = 1]; and nasopharyngeal carcinoma, n = 1 [stage IVC]), and three patients were seen for restaging (nasopharyngeal cancer, n = 1; oral cavity cancer, n = 2). Histologically, 13 tumors were squamous cell carcinomas and one was a schwannoma.
Tumors in 13 patients were examined because of suspicion for recurrence: colon carcinoma, n = 3; rectal carcinoma, n = 1; malignant melanoma, n = 1; breast carcinoma, n = 2; seminoma, n = 1; uterine carcinoma, n = 1; cervical carcinoma, n = 1; Hodgkin disease, n = 1; non–Hodgkin disease, n = 1; and endomyometritis, n = 1. In these patients, full pathologic staging was performed after surgery. Clinical staging, including histologic proof of the primary tumor, was performed in the remaining 40 patients. In cases of extended disease in 35 of these 40 patients, only the most crucial lesions were examined histologically. Five patients were free of disease, but no histologic proof was available.
Lesion-by-Lesion Analysis
Overall, 285 lesions were identified. Additionally, two lesions were added by virtue of the standard of reference; these lesions were not seen with all imaging modalities but were positive at pathologic examination (one patient with lung carcinoma stage N2 and one patient with an oral cavity tumor with a second tumor). Thus, 287 lesions were analyzed (average for each patient, 5.4 lesions; range, 1–14 lesions).
With PET alone, 137 lesions were regarded as tumors, 40 as inflammatory changes, and 44 as other lesions (Table 1). In a comparison of these results with the standard of reference, 123 of the 137 tumor lesions were TP; six, FP; and eight, FN. The eight FN lesions were classified as tumors but were not properly localized by the readers (Table 2). Hence, 123 TP, 84 TN, and 13 FN lesions were determined. By excluding the 61 undecided lesions, a sensitivity of 90% and a specificity of 93% were calculated for detection of tumor lesions compared with the standard of reference (Table 3).
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With PET–40-mA CT, no tumor classifications were changed (Tables 1, 2). Three additional lesions were TN. Hence, 133 TP, 112 TN, and five FN lesions were determined. The undecided lesions were reduced to 36. By excluding the undecided lesions, a sensitivity of 96% and a specificity of 99% were calculated for detection of tumor lesions compared with the standard of reference (Table 3).
With PET–80-mA CT, two additional lesions were defined as tumor and three additional lesions were TN (Tables 1, 2). By excluding the undecided cases, a sensitivity of 98% and a specificity of 99% were calculated for detection of tumor lesions compared with the standard of reference (Table 3).
Differences in accuracy were significant between the PET–CT techniques and PET alone. Within the PET-CT results, no significant difference was seen (Table 3).
Patient-by-Patient Data Analysis
With PET alone in 38 (72%) (36 with disease and two without disease) of the 53 patients, correct clinical and pathologic staging was achieved. Thirteen lesions were FN, which resulted in understaging of disease in 11 patients (four with lung carcinoma, four with head and neck tumors, and three with other lesions). Six lesions were FP, which resulted in overstaging of disease in three patients (one with follow-up of a lung tumor, one with head and neck tumors, and one with other lesions). Understaging of disease was a result of the following causes. In patients with lung tumors, one IIIA tumor was interpreted as IB (additional ipsilateral metastases were found at mediastinoscopy), and three lung carcinomas were staged as IIIA but were not treated surgically (two stage IIIB tumors and one stage IV tumor) (Figs 1, 2). In patients with ear, nose, and throat tumors, disease in two patients with T4 stage IV hypopharyngeal carcinoma was interpreted as stage III (one tumor was localized incorrectly and one tumor was not seen). With PET alone, one meningioma was not detected, one disseminated colon carcinoma was interpreted as localized in the liver, one tumor in the cervix was missed, and an endomyometritis was interpreted to be the bladder. Disease was overstaged in the following cases: A cancer localized in the liver was called disseminated, an inflammatory lesion was called a secondary tumor in a patient with laryngeal carcinoma, and one tracheobronchial lymph node after lobectomy and lymphadenectomy was called recurrence of tumor instead of an inflammatory node.
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With PET–40-mA CT, disease in 49 patients (92%, 47 with and two without disease) was diagnosed correctly. Five lesions were FN, which resulted in understaging of three tumors (two lung carcinomas and one head and neck tumor). One lesion was FP, which resulted in overstaging of one tumor. Understaging of disease was a result of one bronchial carcinoma stage IIIA that was interpreted to be stage IB and one bronchial carcinoma stage IIIB that was interpreted to be stage IIIA; in addition, the ear, nose, and throat tumor was not seen. Overstaging of disease occurred in a patient after lobectomy and lymphadenectomy when one tracheobronchial lymph node was called recurrence of tumor.
Finally, with PET–80-mA CT and PET–120-mA CT, disease in 49 patients (92%, 47 patients with and two without disease) was diagnosed correctly (Fig 3). Three lesions were FN, which resulted in understaging of disease in the same four patients and overstaging of disease in the same patient.
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Discussion |
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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Physiologic accumulations of FDG occur in the muscular, gastrointestinal, and renal excretory systems, and increased accumulations in inflammatory lesions are well known (16,17). These circumstances lead to uncertainty in lesion classification. With PET alone, 21% of all lesions were classified as undecided and thus could not be specified. By using low-dose CT for image coregistration, an additional 7% of all lesions could be classified specifically as a result of change in localization (12 of 22 lesions).
A reduction in FN results significantly increased the accuracy of PET-CT compared with that with PET alone. Essentially, this reduction was achieved when tumor lesions that were localized incorrectly could be localized correctly (Table 2). PET–80-mA CT reduced the number of undecided lesions to 34 (12%) of 285 lesions. However, PET–120-mA CT did not further improve lesion classification. Therefore, we believe that PET–80-mA CT should be used for optimal reduction of the number of undecided lesions. Our results confirm the findings of other authors who reported improvement in lesion localization, classification, and treatment by using software registration (11,13). Readers can more easily classify lesions as having pathologic or physiologic FDG uptake whenever a lesion that takes up FDG can be assigned to a precise anatomic structure.
The question remains of whether there is added clinical value in having easily available coregistered anatomic data together with PET images. To evaluate the effect on staging, which is clinically more relevant, pathologic staging with pathologic correlation was warranted. However, one of the major limitations of the present study was the missing pathologic correlation in 40 cases because most of those patients had extensive disease and did not undergo further pathologic staging before nonsurgical treatment. With PET alone, disease in 71% of all cases could be staged correctly. This number probably represents findings in the heterogeneous patient population.
Those cancer types in which FDG PET is known to have a limited sensitivity, as in gynecologic malignancies, have been included. Interestingly, disease in those cases could be diagnosed correctly by adding the CT information. After the morphologic information of low-dose CT was added, disease in 90% of the cases was diagnosed correctly. With use of a higher CT dose, only minor diagnostic improvements were seen. We believe that especially in those cases, which showed FN results with PET imaging alone as a result of missing FDG uptake and morphologic changes, such as in normal-sized mediastinal lymph nodes, use of higher radiation doses or contrast material–enhanced CT would not have improved the sensitivity of PET-CT.
The gain in diagnostic information is generated not only with PET but also with CT. Malignancies with variable FDG uptake, such as meningiomas or carcinomas of the uterus, may be detectable as a result of morphologic changes rather than pathologic FDG uptake. In almost all types of cancer, however, contrast-enhanced CT is performed for tumor staging. We have used a subsecond multi–detector row helical CT scanner for data acquisition. This system was implemented by the manufacturer to allow optimal flexibility when using the system. Potential advantages of such a CT examination in patients with cancer include the possibility of acquisition of data from the entire trunk in a short time. In cancer CT, data acquisition with single–detector row CT may provide similar results. For other applications (ie, cardiologic imaging of the coronary artery tree), high-speed CT scanners will be mandatory.
In the present study, germanium scanning for transmission correction was used in accordance with our study protocol. Kinahan et al (18) showed that essentially noiseless transmission scanning and CT-based scatter and attenuation correction can be performed. Therefore, attenuation correction could be reduced from 12 minutes to 23 seconds with CT data, and a reduction in acquisition time from 42 minutes to around 31 minutes could be achieved. Reduction of emission scanning to 4 minutes would further reduce the scanning time to less than 25 minutes. Additional extension of the transverse field of view to cover anatomy from the head to the upper thigh could be accomplished within 30 minutes. The radiation burden with low-dose CT is significantly higher than that with germanium scanning but lower than that with diagnostic contrast-enhanced CT. An additional total-body radiation exposure of 2 mSv (80 mA, 0.5 seconds per evolution, 140 kV) for diagnostic purposes is acceptable in patients. After analyzing the data of the present study, we are using only 80-mA CT for transmission correction.
One of the biggest dilemmas from the technical point of view is the question whether to acquire a breath-hold data acquisition. Obviously, a certain misalignment between PET and CT images has to be expected, especially in the region of the diaphragm. However, intrapulmonary tumor lesions with local pathologic FDG uptake must have a soft-tissue correlate in the CT images and thus can be identified easily. On the other hand, small intrapulmonary lesions that are beyond PET resolution might not be detected with FDG PET but only with a thorough analysis of CT images. Our results did not show any evidence that any intrapulmonary or thoracic-wall metastases were missed. Therefore, we allowed shallow breathing during the CT data acquisition (19).
In conclusion, our results show that PET-CT fusion in a combined scanner with low-dose CT at 80 mA can significantly increase diagnostic accuracy regarding lesion classification compared with that with PET alone. On the basis of our data, staging of disease in patients with cancer is improved with PET-CT compared with that with PET alone, but this has to be evaluated in extensive clinical studies.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, T.F.H., G.K.v.S.; study concepts, T.F.H., G.K.v.S.; study design, all authors; literature research, T.F.H.; clinical studies, T.F.H., H.C.S., G.W.G.; data acquisition, T.F.H., H.C.S., G.W.G.; data analysis/interpretation, all authors; statistical analysis, T.F.H., G.K.v.S.; manuscript preparation, all authors; manuscript definition of intellectual content, T.F.H., A.B., G.K.v.S.; manuscript editing, T.F.H.; manuscript revision/review, T.F.H., G.K.v.S.; manuscript final version approval, all authors.
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TOPABSTRACTINTRODUCTIONMaterials and Methods Results DiscussionREFERENCES |
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