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Departments of Nuclear Medicine and Endocrine Tumors (S.L., J.L., E.B., M.S.), Radiology (C.D., R.S.), Medical Physics (G.B.), Epidemiology (A.A.), and Pathology (B.C.), Institut Gustave Roussy, 94805 Villejuif Cédex, France
Address all correspondence and requests for reprints to: Martin Schlumberger, M.D., Department of Nuclear Medicine and Endocrine Tumors, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: schlumbg{at}igr.fr.
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Abstract |
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Methods: Twenty-eight consecutive patients with adrenocortical cancer referred from November 2003 to December 2004 to the Institut Gustave Roussy were included. Mean time between PET/CT and TAP-CT was 16 d. Independent readers analyzed images of each modality. The gold standard was progression on follow-up TAP-CT or pathology.
Results: A total of 269 lesions in 57 organs were depicted in 22 patients. The sensitivities for the detection of distinct lesions and the diagnosis of metastatic organs were 90 and 93% for PET/CT and 88 and 82% for TAP-CT, respectively. Twelve percent of the lesions were seen on PET/CT only and 10% on TAP-CT only. Eighteen percent of the metastatic organs were diagnosed with PET/CT only and 7% with TAP-CT only. Thirty-eight percent of the local relapses were seen only with PET/CT. PET/CT depicted three false-positive lesions. Treatment modalities were modified by PET/CT findings in five cases among which one was falsely positive. Tumor size and mitotic rate were significantly associated with FDG uptake. The intensity of FDG uptake (maximum standardized uptake value > 10) and the volume of FDG uptake (>150 ml) were significant prognostic factors for survival.
Conclusions: We show that FDG-PET/CT is complementary to TAP-CT and of special interest in the diagnosis of local relapses.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Imaging modalities are performed in patients in complete remission for early diagnosis of recurrence because of the potential impact on survival and, in patients with metastatic disease for complete staging, evaluation of tumor progression and response to therapy. For these reasons, patients with ACC are submitted to serial and extensive imaging evaluations, including thoracoabdominopelvic (TAP) computed tomography (CT) and bone scintigraphy (BS). F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is now widely used as a diagnostic and prognostic tool for many cancers (14, 15, 16, 17, 18, 19). It also appears to be useful for the diagnosis of malignancy of adrenal tumors (20, 21, 22, 23, 24). In a limited series of ACC patients, abnormal uptake of FDG was reported (25, 26, 27), but the exact role of PET in these patients has not yet been precisely defined.
The aims of this prospective study were therefore to evaluate the diagnostic value of PET using an integrated PET/CT system in comparison with TAP-CT and to record modifications of therapeutic options and to evaluate the prognostic value of PET on survival in patients with metastatic disease.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Twenty-eight consecutive patients with confirmed ACC referred to the Institut Gustave Roussy from November 2003 to December 2004 were enrolled in this study. TAP-CT was part of their usual work-up, to which PET/CT was added. BS was performed in three patients with bone pain. Mean time between PET/CT and TAP-CT was 16 d (range 0–44 d). Our institutional review board approved the study, and all patients gave written informed consent.
Imaging techniques
FDG PET. All imaging and data acquisitions were performed on an integrated PET/CT Biograph LSO system (Siemens Medical Solutions, Erlangen, Germany) using a single table serving for both the attenuation correction CT and PET elements. PET/CT scanning was performed after an iv injection of 5 MBq/kg FDG, followed by a 60- to 120-min uptake phase. All patients had fasted for 6 h and capillary glycemia was normal in all patients (mean 5.0 mmol/liter; range 3.7–6.9). During the image acquisition, patients maintained their arms above their head and no specific breathing instructions were given.
The PET elements of the system are based on a full-ring tomograph (ECAT ACCEL, CPS Innovation, Knoxville, TN). Emission data were acquired for 4 min at each bed position from the top of the head to the midthigh. Three-dimensional mode was used for PET image acquisition. PET data were reconstructed on a 128 x 128 matrix, using an iterative algorithm (FORE and AWOSEM) with two iterations, eight subsets, and a 5-mm FWHM gaussian postfilter. Reconstruction data were acquired with a single slice spiral CT (Somatom Emotion, Siemens Medical Solutions) without iv contrast agent. CT parameters were set to 80 mA and 110 kV, slice thickness of 5 mm, and pitch 1.5. CT data were reconstructed using filtered back projection with a smooth filter on a 512 x 512 matrix.
Maximum standardized uptake value (SUVmax) and FDG uptake tumor volume were determined in patients with abnormal FDG uptake. SUVmax was automatically extracted using e.Soft tools (Siemens Medical Solutions) dedicated to image analyses. The FDG uptake-related tumor volumes were estimated by a semiautomated image-intensity threshold volume calculated through a segmentation method, using an e.Soft-dedicated three-dimensional segmentation tool (Siemens Medical Solutions), as previously described (28, 29). Background level of activity was first determined in each organ. Contours of organs with abnormal FDG uptake were then manually drawn, excluding regions of physiological uptake. With the threshold technique, the total area of pixels with uptake value greater than a defined background to tumor ratio was summed to evaluate the FDG uptake-related tumor volume. The background to tumor ratio chosen was 4 for lung parenchyma lesions and 2 otherwise. FDG uptake-related tumor volume is the sum of FDG uptake-related tumor volumes in each organ with abnormal FDG uptake.
TAP-CT scanning. TAP-CT with spiral CT was performed after oral administration of contrast medium and iv injection of iodinated contrast material with slice thickness varying from 5 to 10 mm.
BS.
Bone scans were recorded 2–4 h after iv injection of 500–700 MBq 99mTc-hydroxymethylene diphosphonate, using a large field-of-view 
-camera with a low-energy and high-resolution collimator.
Image quantitative analysis. Images of each modality were analyzed by two readers (S.L., C.D.), blindly and independently. An abnormal PET/CT was defined by nonphysiological FDG uptake in at least one site or by the detection of at least one site without FDG uptake detected on the attenuation correction CT. An abnormal TAP-CT was defined by the detection of at least one tumor site. The standard basis for diagnosis was either tumor progression on follow-up TAP-CT or tumor pathology in three cases. Numbers of involved organs and distinct lesions visualized by PET, PET/CT, and TAP-CT were recorded. Lung, mediastinum, thyroid, liver, pancreas, bones, testis, axillary lymph nodes, and local relapse were considered as distinct organs. Peritoneum and abdominal lymph nodes were considered as a single organ. When more than 15 lesions were depicted in a given organ, 16 were considered for the statistical analysis. PET, PET/CT, and TAP-CT results were compared per patient, per involved organ and per number of detected lesions. Modifications of therapeutic options based on PET/CT results were recorded.
Statistics
Data were analyzed using SAS statistical software (SAS Institute, Cary, NC). Sensitivities of PET, PET/CT, and TAP-CT and their 95% confidence intervals (95% CI) were calculated and compared using the McNemar test for matched proportions. Associations between FDG uptake (present or absent) and the following patient or tumor characteristics were analyzed: lesion size, plasmatic o,p'DDD levels (equal to, less than, or above 14 mg/liter in patients receiving treatment), hormonal secretions (present or absent), high mitotic count (less than or above 20 mitoses per 50 high-power fields). A generalized estimating equation model for binomial data was used to take into account the patient effect. Prognostic univariate analyses studied the following variables: number of metastatic organs detected on PET/CT, SUVmax, and FDG volume uptake. The Kaplan-Meier method and the log-rank test were used for the estimation and comparison of survival curves. All reported P values are two-sided.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Twenty-eight consecutive patients (eight males, 20 females; mean age 49 yr, range 22–73 yr) were enrolled in this study. Nineteen patients were already known as metastatic and nine were considered in complete remission. Among the nine patients in complete remission, six had already undergone reoperation for distant metastasis or local relapse. ACC diagnosis was confirmed by an experienced pathologist (B.C.) in 27 patients; in the remaining patient, the diagnosis of ACC was retained because of an adrenal mass with lung metastases, high cortisol, and undetectable ACTH plasma levels. High mitotic counts (more than 20 mitoses per 50 high-power fields) and atypical mitoses, assessed in 23 patients, were present in five and eight patients, respectively. Mean time between initial surgery and PET/CT was 62 months (range 1–363; median 34 months). Overall, previous treatment modalities included surgery, systemic chemotherapy, liver chemoembolization, and external beam radiation therapy in 11, 13, three, and five patients, respectively. At the time of the study, nine patients had secreting ACC and 19 were under o,p'DDD treatment, among whom eight had o,p'DDD plasma levels above 14 mg/liter (mean 13.5, range 3.3–35.0 mg/liter).
The median follow-up after inclusion in the study was 8 months (range 0–16). Ten patients died from tumor progression and one from treatment toxicity.
Imaging results
Per-patient analysis. Twenty-two patients had evidence of disease on the PET/CT or TAP-CT. PET/CT and TAP-CT were concordant in 25 patients, being abnormal on both imaging modalities in 20 patients and both normal in five patients. PET/CT and TAP-CT were discordant in three patients. In one patient, PET/CT showed abnormal uptake in the axillary region that proved to be a fibrohistiocytoma at surgery. In one patient, PET/CT depicted a local relapse, whereas TAP-CT was normal. In the remaining patient, PET/CT was normal, whereas TAP-CT detected one liver lesion.
Per-organ analysis.
The total number of metastatic organs was 57 (Table 1
). PET/CT detected lesions in 53 organs and TAP-CT in 47 organs. The sensitivity of PET/CT for the diagnosis of a metastatic organ was 93% (95% CI 83–98%) and the sensitivity of TAP-CT was 82% (95% CI 70–91%), the difference being not statistically significant (P = 0.11). With PET/CT, 10 as-yet-unknown metastatic organs were diagnosed (two mediastinum, five local relapse, one peritoneum, one bone, and one testis), but four metastatic organs were missed (two liver, one mediastinum, and one local relapse) (Fig. 1). Organ involvement that had been detected only with PET/CT was confirmed by the evolution in seven cases and histologically in three cases. Of note, lung lesions were detected with PET/CT in two cases because lesions were seen on the correction attenuation CT scan, but they did not have FDG uptake.
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Per-lesion analysis.
The total number of lesions detected was 269 in 22 patients (Table 1
). PET/CT detected 243 lesions, and TAP-CT 237. The sensitivities of PET/CT for the diagnosis of lesions was 90% (95% CI 86–94%) and the sensitivity of TAP-CT was 88% (95% CI 84–92%), the difference being not statistically significant (P = 0.43). There were 44 non-FDG avid lesions. PET/CT and TAP/CT therefore detected more lesions than the PET alone could have (P < 0.001).
The detection of the lesions with PET/CT and TAP-CT according to the organs involved are reported in Table 2. In the 57 metastatic organs, the number of lesions detected with PET/CT was superior, identical to, or inferior to TAP-CT in 14 (25%), 33 (58%), and 10 (18%) cases, respectively. Thirty-eight percent of local relapses were seen only on PET/CT. Thirty-three, 30, and 24% of the liver, bone, and mediastinal lymph nodes lesions, respectively, were seen only on PET/CT. Among the bone lesions seen only with PET/CT, there was one vertebral metastasis recurring after surgery (not seen on BS) and two distant bone metastases, not in the field of view of the TAP-CT (but visible on BS). Mediastinal lymph nodes were detected with PET/CT in only 24% of the cases and with TAP-CT in only 29% of the cases. Finally, 8 and 16% of the lung and abdominal lymph nodes and peritoneal metastases, respectively, were seen only with TAP-CT.
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Changes in therapeutic decisions
Because of PET/CT results, treatment modalities were modified in four patients (14%), leading to surgery (two cases), radiotherapy (one case), and systemic chemotherapy (one case). In addition, an axillary FDG uptake led to an axillary lymph node dissection in one case, with a definitive diagnosis of histiocytofibroma. A control PET/CT performed 3 months later confirmed the disappearance of the uptake.
Predictive factors for FDG uptake (Table 3)
The size of the lesions (mean 19 mm, range 2–115; median 15) and the detection of FDG uptake were closely related (P < 0.001). Lesions with a size of 5 mm or less showed FDG uptake in 17% (9 of 53); lesions 5–10 mm had uptake in 61% of cases (19 of 31); lesions larger than 10 mm had uptake in 90% (132 of 146) of cases. Of note, lung lesions accounted for all lesions 5 mm or less and for 71% of the lesions measuring 5–10 mm. Neither hormonal secretion status nor plasma o,p'DDD levels correlated with FDG uptake (P = 0.47 and 0.8, respectively). In fact, FDG uptake was present in 124 of the 176 (77%) metastatic organs with plasma o,p'DDD levels above 14 mg/liter and in 73 of the 91 (80%) metastatic organs of patients with plasma OP'DDD levels less than 14 mg/liter, (P = 0.8). However, the only responding patient to o,p'DDD therapy had non-FDG avid lesions.
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Prognostic value of PET/CT
The prognostic factors for survival of 21 patients with at least one lesion are shown in Table 4 (one patient with a follow-up of less than 2 months was not included in the analysis). Univariate analysis showed the intensity of FDG uptake (SUVmax), and the FDG uptake volume was significantly associated with survival (P = 0.03) (Fig. 2). The number of metastatic organs diagnosed on PET/CT was not prognostic for survival (P = 0.47). Given the number of patients in the analysis, no multivariate analysis was performed. There was, however, a statistically significant correlation between FDG uptake and FDG uptake volume (P = 0.009) and a trend in correlation of an FDG volume uptake of more than 150 ml and an SUVmax of more than 10 (P = 0.08).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We showed that PET/CT and TAP-CT have a similar sensitivity for the diagnosis of ACC metastases (90 and 88%, respectively). But they are complementary imaging modalities because 12 and 10% of the lesions were seen only by PET/CT or TAP-CT, respectively. The limitations of this study are the relatively low number of patients included and the absence of systematic pathologic characterization of all FDG uptake foci. This is because it was not possible to submit patients to multiple biopsies, except for those who underwent surgery for therapeutic reasons. Our study highlights the role of PET/CT for the diagnosis of local relapses. In fact, 38% (five of 13) of the local relapses were detected with PET/CT and not with TAP-CT. Furthermore, the diagnosis of five local relapses led to therapeutic changes in three of these five patients. FDG is, however, not a tumor-specific tracer, and an increased accumulation may be seen in a variety of benign entities, and notably in postoperative changes, yielding false-positive results. In fact, three patients had false-positive foci of FDG uptake in our study, one of which was due to postoperative changes and one to a benign entity; in the remaining patient, the cause could not be reliably determined, but because of the high FDG uptake level and its persistence on a consecutive PET performed after 3 months, the lesion was most likely to be a relapse.
PET is limited by its spatial resolution. Its sensitivity for the diagnosis of lung cancer is known to be dependent on the tumor size (30). We found similar results in our study in that only 15% of the lesions with a size of 5 mm or less and 58% of the lesions with a size of 5–10 mm showed abnormal FDG uptake. However, because most small lesions are located in the lungs because of the miliary pattern of lung involvement, most of them can be detected with the CT correction attenuation scan. PET/CT did not miss any diagnoses of metastatic lung; however, in three patients it detected fewer lung lesions than TAP-CT. CT parameters or the absence of specific breathing instructions during attenuation correction CT may explain this difference. The other organs for which PET/CT detected fewer lesions than TAP-CT because of lesion size included liver (3), mediastinal lymph nodes (1), and peritoneal carcinomatosis (1). The above-cited technical reasons but also the absence of iodine contrast medium injection for the attenuation corrected CT acquisition can explain this discrepancy. Injection of iodine contrast medium is not yet routinely used because it may modify the attenuation correction coefficients (31, 32, 33). Therefore, given the low sensitivity of PET for the diagnosis of small lesions and the high frequency of lung lesions in ACC, patients with ACC should not be followed up by PET only. We believe that PET/CT cannot replace a diagnostic TAP-CT, as long as CT with attenuation correction is not as sensitive as a diagnostic TAP-CT with contrast medium injection and CT diagnostic parameters. The use of PET/CT for treatment response evaluation was not addressed in this study.
We showed that the intensity of FDG uptake is in ACC, as in other cancer types, related to the prognosis: 54% of the patients with a SUVmax above 10 died within 6 months after PET/CT examination, whereas none of the patients with a SUVmax lower than 10 died (14, 15, 16, 17, 18, 19). Furthermore, we found a close relationship between FDG uptake and a high mitotic count on initial pathological specimens, which is a well-recognized independent prognostic factor for survival (4, 9, 10, 11). Not surprisingly, we also found that the FDG uptake volume, which is representative of tumor burden was related to survival, as has been shown for thyroid cancer (19). Fifty-five percent of the patients with an FDG uptake volume of more than 150 ml but only 14% of the patients with an FDG uptake volume of less than 150 ml died within 6 months after PET/CT examination. Ultimately, whether the intensity of FDG uptake and FDG uptake volume are independent prognostic factors for survival in patients with ACC has to be determined using multivariate analysis with a larger group of patients.
In conclusion, we have shown that PET/CT is complementary to TAP-CT, and we have shown the importance of PET/CT in patients with ACC for the diagnosis of local relapse. Because of the high rate of small lesions without FDG uptake, patients with ACC should not be followed up by PET only. The intensity of FDG uptake in patients with ACC is related to survival. Whether it is an independent prognostic factor and whether it can be used for therapeutic management needs to be further studied.
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Footnotes |
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Abbreviations: ACC, Adrenocortical cancer; BS, bone scintigraphy; 95% CI, 95% confidence interval; CT, computed tomography; FDG, F-18 fluorodeoxyglucose; PET, positron emission tomography; SUVmax, maximum standardized uptake value; TAP, thoracoabdominopelvic.
This work was supported by Programme Hospitalier de Recherche Clinique AOM 02-118.
The authors have no conflict of interest.
Received July 12, 2005.
Accepted December 9, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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