Colonoscopic Findings in Patients With Incidental Colonic Focal FDG Uptake

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1 Nuclear Medicine and Molecular Imaging Original Research Keyzer et al. Colonoscopy After Focal Colonic FDG Uptake Nuclear Medicine and Molecular Imaging Original Research Caroline Keyzer 1 Benjamin Dhaene 1 Didier Blocklet 2 Viviane De Maertelaer 3 Serge Goldman 2 Pierre Alain Gevenois 1 Keyzer C, Dhaene B, Blocklet D, De Maertelaer V, Goldman S, Gevenois PA Keywords: colon, focal FDG uptake, incidental findings, PET/CT DOI: /AJR Received March 5, 2014; accepted after revision July 22, Department of Radiology, Hôpital Erasme, Université libre de Bruxelles, Rte de Lennik 808, B-1070 Brussels, Belgium. Address correspondence to C. Keyzer (caroline.keyzer@erasme.ulb.ac.be). 2 Department of Nuclear Medicine, Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium. 3 Department of Biostatistics and Medical Informatics and Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université libre de Bruxelles, Brussels, Belgium. WEB This is a web exclusive article. AJR 2015; 204:W586 W X/15/2045 W586 American Roentgen Ray Society Colonoscopic Findings in Patients With Incidental Colonic Focal FDG Uptake OBJECTIVE. The purpose of this study was to investigate the nature of FDG-avid and non FDG-avid lesions detected at colonoscopy in patients presenting with incidental focal colonic FDG uptake at PET/CT. MATERIALS AND METHODS. Among 9073 patients who underwent PET/CT over a 4-year period, 82 patients without a history of colonic disease had focal colonic FDG uptake and underwent colonoscopy. In consensus, a radiologist and a nuclear physician read images from these PET/CT examinations. They recorded the location of focal FDG uptake in the colon and associated CT abnormalities and measured maximum standardized uptake value ( ) and metabolic volume (MV). Readings were performed twice first without and second with knowledge of lesion location at colonoscopy. The final diagnosis was based on colonoscopic findings and histopathologic results categorized into benign, premalignant, or malignant. RESULTS. One hundred seven foci of colonic FDG uptake at PET/CT and 150 lesions at colonoscopy were detected. Among 107 foci of FDG uptake, 65 (61%) corresponded to a lesion at colonoscopy (true-positive findings), and 42 (39%) did not (false-positive findings). Among 150 lesions found at colonoscopy, 85 (57%) were not FDG avid (false-negative findings). The MV of true-positive findings was lower than that of false-positive findings (4.0 ± 0.4 cm 3 vs 6.2 ± 0.7 cm 3 ; p = 0.006), but did not differ (7.4 ± 0.5 vs 7.7 ± 0.5; p = 0.649). Considering the histopathologic categories of the lesions and the false-positive findings, there was no difference in (p = 0.103), but MV was lower in premalignant lesions than in false-positive findings (p = 0.005). CONCLUSION. Focal colonic FDG uptake may indicate the presence of a benign, premalignant, or malignant lesion. Subsequent colonoscopy should not be restricted to the colonic site of FDG uptake. F luorine-18-fdg PET/CT is being increasingly used, mainly in the diagnosis, staging, and follow-up of cancer but also in other conditions, such as fever of unknown origin and systemic inflammatory diseases [1 5]. Regardless of these conditions, unexpected FDG uptake that is, uptake in unusual locations relative to the common metastatic spread of the investigated cancer or unrelated to the suspected disease is regularly identified at various anatomic sites, including the colon [6, 7]. Such incidental colonic FDG uptake can be diffuse, segmental, or focal. When diffuse or segmental, it generally results from physiologic or inflammatory changes [8 10]. When focal, as in % of patients undergoing PET/CT examinations, it results from malignant or premalignant lesions in 38 92% of patients [8 20]. In attempts to discriminate be- tween malignant and benign conditions, the use of parameter measurements, such as FDG maximum standardized uptake value ( ) and metabolic volume (MV), also known as metabolic tumor volume, has been proposed [8, 10, 11, 15, 17]. Furthermore, 8% of patients without any colonic FDG uptake have premalignant or malignant colonic lesions at colonoscopy [10]. In addition, in patients with focal colonic FDG uptake, colonoscopy may reveal lesions other than the FDG-avid one [11, 12, 16]. However, the histopathologic features of non FDG-avid colonic lesions have been investigated only in small study groups, preventing us from drawing definite conclusions [11, 12, 17]. The purposes of this study were to investigate the nature of FDG-avid and non FDGavid lesions detected at colonoscopy in patients presenting with incidental areas of W586 AJR:204, May 2015

2 Colonoscopy After Focal Colonic FDG Uptake focal FDG uptake in the colon and to evaluate the performance of and MV in discriminating between benign, premalignant, and malignant conditions. Materials and Methods Patients This retrospective study was approved by our institutional ethics committee, and the requirement for written informed consent was waived. Between September 2008 and July 2012, 9073 consecutively registered patients underwent whole-body 18 F- FDG PET/CT examinations at our institution. We selected from our database those for whom the PET/CT report specifically mentioned colonic focal FDG uptake (i.e., well-localized and nodular focus) and who had no history of a colorectal disorder. Patients with a report that mentioned diffuse or segmental uptake were not considered. This resulted in selection of 232 patients (2.6%). Among these patients, we considered only those who underwent colonoscopy at our institution within 4 months after PET/CT. One patient who had right colonic focal FDG uptake but underwent only sigmoidoscopy was excluded. Thus the final study group consisted of 82 patients (35 women, 47 men; mean age, 63 ± 10 [SD] years; range, years). Figure 1 shows the process of inclusion and exclusion of the patients. The underlying disorders justifying PET/CT and corresponding numbers of patients are shown in Table 1. PET/CT reports of 9073 patients Focal colonic FDG uptake n = 232 Colonoscopy at our institution < 4 months after PET/CT n = 83 Final study group n = 82 TABLE 1: Indications for PET/CT Examinations Indication PET/CT Examinations The patients fasted for at least 6 hours before PET/CT. The blood glucose level before FDG injection had to be less than 150 mg/dl. Acquisition was performed 90 minutes after IV injection of 3.7 MBq/kg of FDG. All PET/CT studies were performed with a commercially available PET/CT scanner (Gemini-16, Philips Healthcare) in full 3D acquisition mode. PET scans were acquired with 3-minute bed position at each of 8 12 bed positions. The images were iteratively reconstructed by means of 3D Raw Action Maximum-Likelihood Algorithm software (3D-RAMLA, Philips Healthcare). Frequency (No. of Patients) Oncologic disorders Lung nodule characterization or lung cancer 20 Cancer of unknown origin (metastatic disease with undetected primary lesion) 14 Melanoma 8 Lymphoma 7 Head and neck cancer 6 Gastroesophageal cancer 4 Breast cancer 3 Urinary tract cancer 3 Gynecologic cancer 2 Hepatopancreatobiliary cancer 2 Chondrosarcoma 1 Mesothelioma 1 Nononcologic disorders Fever of unknown origin 7 Sarcoidosis 2 Systemic lupus erythematosus 1 Polymyalgia rheumatica 1 Follow-up at another institution n = 46 Delay between colonoscopy and PET/CT > 4 months n = 103 Left colonoscopy and FDG uptake in right colon n = 1 Fig. 1 Flowchart summarizes patient inclusion and exclusion criteria that resulted in final study group. Unenhanced CT scans from the base of the skull to the upper thigh were obtained for attenuation correction and anatomic localization and to aid in diagnosis. The tube voltage was 120 kvp, and the tube current ranged between 40 and 120 mas according to our standard protocol based on BMI. The patients were given no specific breathing instructions, and scanning was performed during quiet tidal breathing. Axial CT images were reconstructed with a slice thickness of 2 mm at 1.5-mm intervals. Image Analysis PET/CT studies were retrieved from the electronic archival system. Patient information was erased from all images, which were then loaded on a clinical workstation with a fusion viewer to provide multiplanar reformatted images (Extended Brilliance Workspace, version 4.5.3, Philips Healthcare). PET/CT scans were interpreted in consensus by a board-certified nuclear medicine physician with 9 years of experience and a boardcertified radiologist with 5 years of experience in reading PET/CT images. Two reading sessions were conducted. In the first session, readers were blinded to endoscopic and histopathologic results and were asked first to record whether a focal area of FDG uptake was visible in the colon and if so to localize it (rectosigmoid colon, descending colon, splenic flexure, ascending colon, hepatic flexure, transverse colon, or cecum); second, to measure and MV by using automated SUV-based AJR:204, May 2015 W587

3 Keyzer et al. 3D contouring software available at the workstation (MV was defined as the volume produced by segmentation at a fixed 50% of threshold obtained with a region-growing algorithm with the maximum intensity voxel as seed [21]); and, third, to record the CT findings at the site of FDG uptake as follows: 1, colonic wall thickening, intraluminal nodule, or diverticulum; 2, ileocecal valve; or 3, no abnormality. For the second session, the readers were given the location of the lesions seen at colonoscopy but were still blinded to the corresponding histopathologic features. The location of the lesion at colonoscopy was provided either in terms of the segment of the colon that was involved or in terms of its distance from the anal margin. Readers then had to determine whether the lesion seen at colonoscopy corresponded to focal colonic FDG uptake at the same location and if it did to describe it with the same criteria used in the first reading session. When the location at colonoscopy was provided in terms of distance from the anal margin, readers assigned the corresponding colonic segment by summing consecutive colonic distances from the anal margin on the axial, coronal, and sagittal images. Final Diagnosis The final diagnosis was based on colonoscopic and histopathologic results. Colonoscopic results included identifying the colonic segment with the lesion and its distance from the anal margin. The size of the lesion, when available at colonoscopy, was categorized as smaller than 5 mm, between 5 and 20 mm, or larger than 20 mm. The histopathologic features of the lesions were grouped into three categories: hyperplastic polyps, unspecific ulcerations, and benign tumors (i.e., lipoma, angiolipoma) considered benign; adenomas with low- to high-grade dysplasia considered premalignant; and adenocarcinomas considered malignant. The location of FDG uptake at PET/CT and the lesion at colonoscopy was finally defined as within the rectosigmoid colon; the left colon, including the descending colon and splenic flexure; the right colon, including the ascending colon, hepatic flexure, and transverse colon; or the cecum. Statistical Analyses We analyzed only the results of the second reading session because our main purpose was to compare PET/CT findings with the histopathologic results. Still, to gain some insight into the influence of a priori knowledge on PET/CT data evaluation, we also analyzed the discordant results between sessions. Continuous quantitative variables were summarized by mean and standard error of the mean (SEM). Discrete variables were summarized by their proportions. Per-lesion analyses were performed. Proportions were compared by use of the Pearson chisquare test. The Student t test and ANOVA followed by Tukey multiple comparisons tests, if appropriate, were used to compare the means of the quantitative continuous variables. There was no homogeneity of variance for the results of MV. Therefore, we used the Welch t test and ANOVA followed by the T3 Dunnett comparison test to compare the means of MV. Logistic regression using the Enter procedure was performed to evaluate the influence of, MV, CT findings, and location of FDG uptake in the colon on the probability of having a corresponding lesion (regardless of histopathologic result) at colonoscopy. Statistical significance for all tests was set at p < The statistical software used was SPSS Statistics 20 (IBM SPSS). Results PET/CT Results and Lesion Detection at Colonoscopy At the first reading session, readers detected one, two, three, or four focal areas of FDG uptake in the colon in 66, 13, two, and one patients, for a total of 102 focal areas of FDG uptake. At the second reading session, readers detected one, two, three, or four focal areas of FDG uptake in 63, 14, four, and one patients, for a total of 107 focal areas of FDG uptake. We did not observe any statistically significant difference between sessions (p = 0.864). The five focal areas missed at the first reading session but detected at the second session corresponded to an adenoma with low-grade dysplasia in four patients and a hyperplastic polyp in one patient all smaller than 20 mm. Mean was 7.5 ± 0.4 (range, ), and mean MV was 4.8 ± 0.4 cm 3 (range, cm 3 ). At colonoscopy, 150 lesions were detected. Eighty-five (57%) lesions were not FDG avid, and the corresponding PET/CT results were considered false-negative. Among the 107 colonic focal areas of FDG uptake, 65 (61%) corresponded to a lesion seen at colonoscopy and were considered true-positive PET/CT results. The 42 (39%) areas not corresponding to a lesion seen at colonoscopy were considered false-positive PET/CT results. The mean time between PET/CT and colonoscopy was 41 ± 3 days; 50% of our patients underwent colonoscopy within 1 month of PET/CT. The times between PET/CT and colonoscopy were not significantly different between false-positive (36 ± 5 days) and true-positive (40 ± 3 days) PET/CT results (p = 0.523). Among the 107 focal areas of FDG uptake, 55 (51%) were in the rectosigmoid, 14 (13%) in the left colon, 17 (16%) in the right colon, and 21 (20%) in the cecum. The proportions of true-positive and false-positive PET/CT results according to the CT findings and the colon segment containing the FDG uptake are listed in Table 2. There was no statistically significant association between the presence of a lesion at colonoscopy at the site of the FDG uptake and either the CT finding at the site (p = 0.182) or the colon segment containing the uptake (p = 0.181). Among the 150 lesions detected at colonoscopy, the proportion of false-negative PET/CT results was 81% (26/32) for lesions smaller than 5 mm, 53% (26/49) for lesions measuring 5 20 mm, and 13% (2/15) for lesions larger than 20 mm (p < 0.001). The mean was 7.4 ± 0.5 for truepositive and 7.7 ± 0.5 for false-positive PET/CT results (p = 0.649). The mean MV was 4.0 ± 0.4 cm 3 for true-positive and 6.2 ± 0.7 cm 3 for false-positive PET/CT results (p = 0.006). Logistic regression showed that MV was the only parameter related to the probability that a le- TABLE 2: Proportions of True- and False-Positive PET Results According to CT Finding and Location in Colon Result True- Positive False- Positive CT finding No abnormality 29/53 24/53 Abnormality 33/47 14/47 Ileocecal valve 3/7 4/7 Location in colon Rectosigmoid 38/55 17/55 Left 9/14 5/14 Right 9/17 8/17 Cecum 9/21 12/21 TABLE 3: Proportions of FDG-Avid and Non FDG-Avid Lesions According to Histopathologic Finding Histopathologic Finding FDG Avid Not FDG Avid Benign 11/36 25/36 Ulceration or benign tumor 2/10 8/10 Hyperplastic polyps 9/26 17/26 Adenoma (premalignant) 48/107 59/107 Low-grade dysplasia 31/76 45/76 High-grade dysplasia 17/31 14/31 Malignant 6/7 1/7 Total 65/150 85/150 W588 AJR:204, May 2015

4 Colonoscopy After Focal Colonic FDG Uptake False-positive Benign Premalignant Malignant Fig. 2 Graph shows mean maximum standardized uptake value ( ) according to histopathologic category (p = 0.103). Error bars indicate 95% CI. sion could be detected with colonoscopy (i.e., a true-positive PET/CT result) (p = 0.018)., CT finding, and the colonic segment containing FDG uptake (p = ) were not related to that probability. PET/CT Results and Histopathologic Features of Detected Lesions The proportions of FDG-avid and non FDG-avid lesions according to histopathologic result are shown in Table 3. The proportions of false-negative and true-positive PET/CT results were significantly different between benign, premalignant, and malignant lesions (p = 0.019). Considering true-positive PET/CT results and the corresponding histopathologic category (i.e., benign, premalignant, and malignant) and the false-positive PET/CT results, mean was not significantly different between benign (5.8 ± 0.6), premalignant Metabolic Volume (cm 3 ) (7.3 ± 0.6), and malignant (10.5 ± 1.3) lesions and false-positive PET/CT results (7.7 ± 0.5) (p = 0.103). The same computation for MV showed a significant difference between benign (4.1 ± 0.6 cm 3 ), premalignant (3.4 ± 0.4 cm 3 ), and malignant (8.5 ± 2.6 cm 3 ) lesions and false-positive PET/CT results (6.2 ± 0.7 cm 3 ) (p = 0.001) due to a significant difference (p = 0.005) between premalignant lesions and false-positive PET/CT results as revealed by the multiple comparison test (T3 Dunnett test). Mean and MV for each histopathologic category and false-positive PET/CT results are shown in Figures 2 and 3 along with the corresponding 95% CIs. Figure 4 shows a patient with two true-positive PET/CT results. Discussion With the incidental finding of focal areas of colonic FDG uptake in 2.6% of our 0 p = False-positive Benign Premalignant Malignant Fig. 3 Graph shows mean metabolic volume according to histopathologic category (p = 0.001). Error bars indicate 95% CI. Multiple comparison test revealed significant difference between false-positive finding and premalignant category of lesion (p = 0.005). patients a proportion similar to that previously reported [8, 9, 11 17] our study shows that 50% of these sites of FDG uptake correspond to premalignant or malignant lesions, that approximately 60% of all lesions seen at colonoscopy in patients with focal colonic FDG uptake are not detectable at PET/CT (whereas 70% are premalignant), and that the MV of FDG colonic uptake, but not, is lower when it corresponds to a lesion at colonoscopy, particularly if premalignant. Even if PET/CT is not used for screening for colorectal cancer, a focal area of colonic FDG uptake incidentally found at PET/CT may reveal a premalignant or malignant lesion. Most important, this study shows that when colonoscopy is performed for a patient with incidental focal colonic FDG uptake, the entire colon should be investigated. For detection of simultaneous non FDG-av- A B Fig year-old man with two foci of FDG uptake in sigmoid colon corresponding to adenoma with high-grade dysplasia. Indication for PET/CT was Horton disease. A, Axial PET image shows maximum standardized uptake value ( ) and metabolic volume for each area of focal uptake. B, Fused PET/CT image shows areas of focal uptake color coordinated to A. AJR:204, May 2015 W589

5 Keyzer et al. id premalignant lesions, the colonoscopic examination should not be restricted to the segment containing the FDG uptake. Weston et al. [10] investigated the incidence and nature of non FDG-avid lesions detected with colonoscopy. They found that colonoscopy reveals premalignant or malignant lesions in 8% of patients without any colonic FDG uptake. Our higher false-negative rate could be explained by differences in study design, including the fact that we included polyps smaller than 5 mm (two adenomas with low-grade dysplasia and four hyperplastic polyps) whereas Weston et al. included only polyps larger than 10 mm. Lee et al. [22] found that 6% of advanced adenomas in patients without focal colonic FDG uptake and 31% of advanced adenomas or neoplasms in patients with focal colonic FDG uptake including 8% in the right colon were not FDG avid. Those authors recommended a complete colonoscopic examination of all patients with focal colonic FDG uptake even if confined to the left colon, which is in line with our results. In accordance with results showing that the sensitivity of PET depends on tumor size and grade of dysplasia [10, 20, 23, 24], we observed a high proportion of lesions undetectable at PET/CT when they were either benign or smaller than 5 mm. The relation between and the histopathologic features of colonic lesions is controversial. Several studies have shown differences in depending on histopathologic features in particular, differences between malignant and benign lesions and between malignant lesions and the absence of any lesion [10, 11, 15, 17] whereas others have not [14, 25]. Weston et al. [10] reported a higher in patients with colonic cancers than in those with adenomas or without colonoscopic abnormality. In addition, they found, also in accordance with our results, that does not discriminate false- from true-positive PET findings. In contrast, Luboldt et al. [17] found a difference in between false-positive PET results and carcinomas or highgrade dysplasias. Those authors proposed an cutoff value of 5 to select all adenomas with high-grade dysplasia and carcinomas. However, we observed two lesions with an less than 5 (between 3 and 4) that had high-grade dysplasia, suggesting that should be considered with caution. MV is an index that has been evaluated in one previous study only [15]. High FDG uptake in segments of the colon is a usual finding in physiologic conditions. We postulated that an area of FDG uptake considered focal by the readers but with a high MV could in fact correspond to a small area of physiologic segmental colonic FDG uptake that was not recognized as such. A high MV could therefore be predictive of a false-positive result, in particular when is low. In the same line of reasoning, Oh et al. [15] reported that an MV less than 3.14 cm 3 is highly suggestive of dysplasia, whereas an MV greater than 3.14 cm 3 is suggestive of either a benign lesion or carcinoma. Benign lesions are then discriminated from carcinoma on the basis of, depending on whether the value is lower or higher than 9.1. In accordance with these results, we observed lower MV in association with true-positive PET results than in false-positive ones, particularly in premalignant lesions. The use of a hybrid PET/CT system rather than a dedicated PET scanner enables more accurate localization of colonic focal areas of FDG uptake [11 13]. The low-dose unenhanced CT component may also help in characterization of focal colonic FDG uptake. However, as previously reported, the absence of any CT finding does not exclude the presence of a colonic lesion, and the malignant potential of FDG-avid lesions cannot be ascertained with CT even when the reader is aware of the PET findings [11 13]. Our study had several limitations. First, because of the retrospective design, its results might have been influenced by selection bias because we included only patients with an incidental area of focal colonic FDG uptake mentioned in the PET/CT report and who had undergone colonoscopy, an examination performed on only 40% of our patients with focal colonic FDG uptake. In addition, delay before colonoscopy was longer than 1 month for 50% of our patients. However, the only, to our knowledge, prospective study addressing this question [8] had similar results in terms of true- and false-positive rates, with a very high proportion of malignancies (23% of focal FDG uptake findings). That study also revealed a large overlap in between histopathologic categories. Second, sigmoidoscopy instead of complete colonoscopy was performed on 16 of our 82 patients. However, even when considering those limited colonoscopic investigations, we observed that a high proportion of lesions were falsely negative with PET/CT. Third, we used fixed threshold based volume segmentation. Our aim, however, was not to obtain a correct estimation of polyp volume but to have an easy and reproducible measurement tool [21] to estimate the extent of FDG uptake that would be predictive of a true-positive result. In addition, MV was determined with a 50% of threshold instead of the 40% used by Oh et al. [15], because this threshold has higher accuracy and is associated with lower overestimation of the smallest sphere volumes [21, 26]. Fourth, we considered lesions smaller than 5 mm, a size close to the full width at half maximum that set the resolution of the PET system. However, PET detectability of small lesions relative to the resolution of the system depends on FDG uptake per voxel; we found that 20% of these small lesions were detectable because of their high FDG avidity. Finally, the high rate of unexpected colonic lesions could be explained, at least in part, by the fairly low participation rate in screening policies that were only recently implemented in our country. However, the proportion of patients with incidental colonic FDG uptake and the true-positive and falsenegative rates are similar to those previously reported [9 11, 13, 15, 17, 22]. Conclusion Despite a high false-positive rate, the incidental finding of focal FDG uptake in the colon at PET/CT warrants further evaluation with colonoscopy. More important, for patients with focal colonic FDG uptake, premalignant or malignant lesions are frequently found in colonic sites with no FDG uptake. Therefore, colonoscopy should not be restricted to the colonic site of FDG uptake. 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