Incidental Uptake in Gastrointestinal Tract on 18F-FDG-PET/CT: Is It Worth to Investigate? A Study with 371 Patients Open Access

Positron emission tomography (PET) employing fluorodeoxyglucose (FDG) has become an increasingly used diagnostic tool in oncology for tumor staging or posttreatment patient monitoring. Additionally, PET-FDG has also expanded beyond oncological applications into non-oncological contexts [1‒4]. Among PET radiolabeled tracers, 18 Fluorine-fluorodeoxyglucose (18F-FDG-PET/CT) stands out as the most frequently employed. Operating as a glucose analog, 18F-FDG serves as an indicator of glucose metabolism [5]. Conditions characterized by heightened metabolic activity, such as cancer or inflammation, exhibit increased FDG uptake, resulting in anomalous accumulation [2, 6]. However, the nonspecific nature of 18F‐FDG‐PET/CT uptake poses challenges, as physiological or benign conditions may manifest with patterns resembling pathological accumulation, potentially leading to misinterpretations and resource utilization [7, 8]. Specifically concerning lesions within the gastrointestinal tract (GIT), 18F-FDG-PET/CT demonstrates high sensitivity but lacks specificity [9]. The uptake of 18F-FDG within the GIT exhibits considerable variability, ranging from mild to intense, and may manifest with either focal or diffuse distribution patterns. While diffuse uptake is often attributed to physiological or inflammatory origins, focal uptake more commonly indicates a pathological condition [10, 11]. Incidental or unexpected 18F-FDG uptake is relatively prevalent [12], yet the clinical significance of such occurrences in patients with malignancies remains incompletely defined [9]. Previous investigations have addressed this topic; however, many were constrained by small sample sizes [1, 9] or focused solely on colorectal uptake [13, 14]. This study aimed to conduct a retrospective evaluation of the nature and clinical significance of unexpected 18F-FDG-PET/CT findings within the GIT among patients subsequently referred for endoscopic examination.

This retrospective study was conducted from June 2016 to October 2021 and included all patients who underwent 18F-FDG-PET/CT at our facility and exhibited incidental uptake within the GIT leading to endoscopic examination within a 12-month period. Lesions identified as physiological by nuclear physicians were also included in the analysis. When applicable, endoscopic reports were supplemented with histological examination findings.

The clinical indications for 18F-FDG-PET/CT were established by the assistant physicians overseeing patient care. These indications encompassed both diagnostic evaluations and follow-up assessments for a spectrum of malignancies, such as Hodgkin and Non-Hodgkin lymphoma, breast carcinoma, lung carcinoma, uterine and cervical carcinoma, esophageal adenocarcinoma, head and neck malignancies, melanomas, multiple myelomas, colon carcinoma, among others.

We defined incidental uptake as an unexpected detection of FDG accumulation in the GIT, when the ¹⁸F-FDG-PET/CT scan was not the intended to target any pathology of the GIT. We defined the right colon as cecum/ascending colon/transverse colon and left colon as descending and sigmoid colon.

Patients with incomplete endoscopic examinations (that did not reach the location of the uptake – 3 patients) or that were not submitted to endoscopic examination in the 12 month-period (12 patients) were excluded from this analysis. All the data were collected through assessment of clinical records, which included nuclear medicine report regarding 18F-FDG-PET/CT scans, gastroenterologist endoscopic examinations, and histopathological reports. The studied was carried out in accordance with Declaration of Helsinki and was approved by the Ethics Committee of our institution.

Patients were asked to fast for a minimum of 4 h prior to ¹⁸F-FDG injection, and not to ingest any food with sugar in the day before. They were also asked to avoid physical exercise in the day prior to the exam.

On the day of the examination, each patient received an intravenous injection of 3.7 MBq/kg of 18F-FDG. Blood glucose levels were required to be <200 mg/dL, and diabetic patients were instructed to abstain from insulin usage. Patients were advised to rest for 1 h prior to the examination to minimize muscular activity and were encouraged to void to reduce bladder activity.

Imaging was performed 60 min after injection of ¹⁸F-FDG. Patients were in supine position, with both arms crossed above the head. A topogram was acquired to ensure body coverage from the apex of the skull to the mid-thigh, followed by the acquisition of low-dose CT attenuation correction maps (3–5 mSv). PET acquisition entailed 3 min of data acquisition for each bed position. Image fusion was executed utilizing an iterative algorithm.

We defined unexpected FDG uptake as any instance where the nuclear medicine physician visually deemed the GIT uptake abnormal, based on either its pattern or quantity, with consequent documentation on the report. In some 18F-FDG-PET/CT reports, the nuclear medicine physician provided a qualitative assessment indicating whether the uptake was suggestive of inflammatory nature or suspicious for malignancy. This assessment was based on the physician’s experience, involving visual analysis of the images, correlation with the uptake on the CT component of the study as well as the nature of the uptake, focal or diffuse. These data were gathered to evaluate the physician's capability to discern whether the uptake warranted further investigation. Additionally, the uptake pattern (focal or diffuse) and maximum standardized uptake value (SUVmax) were also recorded.

All procedures were carried out by an accredited gastroenterologist. All endoscopic examinations were retrospectively reviewed via medical records. Colonoscopies adhered to institutional bowel preparation protocols. Lesions considered were those correlating with the sites of uptake as indicated in the 18F-FDG-PET/CT report; if multiple lesions were present, only the most advanced was considered. Esophagogastric and colorectal lesions were categorized by appearance into likely cancerous, premalignant, nonneoplastic, inflammatory, or showing no changes. In cases of multiple lesions, only those at the site of uptake were analyzed.

Biopsy or resection, when considered appropriate, was conducted in all patients exhibiting suspicious malignant or premalignant lesions. Histological sampling was selectively conducted solely in cases demonstrating abnormal findings; therefore, if the endoscopic examination yielded normal results, no histological samples were acquired.

Histopathological analysis of the biopsies was carried out utilizing the latest classification provided by the World Health Organization and by dedicated GI tract pathologists. Premalignant lesions were stratified based on the assessment of low- or high-grade dysplasia.

Patients who had serrated sessile lesions and adenomas with low- or high-grade dysplasia, and with malignant lesions, were labelled has having pre-malignant/malignant findings, while all other findings were considered benign. In the colon, adenomas (tubular or tubulovillous) were considered advanced if ≥1 cm and/or with high-grade dysplasia. In regard with serrated sessile lesions, only those with at least 1 cm or with dysplasia were considered advanced.

The χ² test was used to identify association between location of the uptake and pre-malignant/malignant findings, and between these and the nuclear medicine physician’s qualitative assessment. To evaluate differences between SUVmax of benign and premalignant/malignant findings, the Mann-Whitney U test was used. In addition, receiver-operating characteristic (ROC) analysis was used to identify cut-off values for SUVmax, to accurately differentiate benign from premalignant/malignant findings. Sensitivity and specificity with a 95% confidence interval were also obtained. SPSS Statistics for Windows, version 27.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.

A total of 371 consecutive patients with incidental GIT uptakes who underwent endoscopic examination within 12 months following 18F‐FDG‐PET/CT examination were included in the study. The mean interval between 18F‐FDG‐PET/CT and endoscopic examination was 61 days.

The majority of patients were referred by hematology (32.6%) and oncology (23.8%) departments, with most undergoing 18F‐FDG‐PET/CT examination for neoplasm surveillance (40.1%) or staging (22.2%), as detailed in Table 1. Analysis included 387 incidental uptakes from 371 patients, comprising 206 males and 165 females, aged 13–90 years (mean 63). Among these, 193 uptakes were located in the upper GIT, prompting investigation via upper endoscopy, while 194 were identified in the lower GIT, requiring sigmoidoscopy or colonoscopy examination.

There were 193 incidental uptakes in the upper GIT among 187 patients, comprising 101 (54.0%) males and 86 (46.0%) females, aged between 13 and 90 years, with a median age of 63. The distribution of these uptakes within the upper GIT is detailed in Table 2.

In the esophagus, 13.8% (11/80) of incidental 18F‐FDG‐PET/CT uptakes corresponded to malignancies. Of these, 2 patients presented with adenocarcinoma (both located at the distal esophagus/gastroesophageal junction [GEJ]), while nine exhibited squamous cell carcinoma, predominantly situated in the proximal and mid esophagus (four each), with one located at the distal esophagus. However, the majority of incidental uptakes corresponded to inflammatory conditions (Fig. 1), with most patients displaying reflux esophagitis or no abnormalities during endoscopy.

Regarding uptake patterns, 15 cases (18.8%) demonstrated diffuse uptake, 47 cases (58.7%) exhibited focal uptake, while in 18 cases (22.5%) uptake pattern was not specified in the report. Among the malignancies, focal uptake was observed in 6 cases (54.5%), diffuse uptake in 3 cases (27.3%), while uptake specification was lacking in 2 cases (18.2%).

There was a significant association between the location of the incidental ¹⁸F-FDG-PET/CT uptake and malignant findings. Specifically, uptakes detected in the mid-esophagus exhibited a higher propensity for malignancy, whereas those located in the distal esophagus/GEJ were more frequently benign (likelihood ratio = 8.619, p = 0.012).

The nuclear medicine physician provided a qualitative assessment in 40 patients, suggesting a benign nature in 26 cases (65.0%) and suspicion for malignancy in 14 cases (35.0%). There was an association between the qualitative analysis by the nuclear medicine specialist and the lesion’s nature. The physician’s suspicion or prediction of malignancy in the esophagus demonstrated a sensitivity of 87.5% and specificity of 78.1% (p = 0.001). However, no correlation was observed between the uptake pattern and the type of findings in the esophagus.

The Mann-Whitney U test unveiled substantial disparities between the SUVmax values of uptake sites exhibiting either normal endoscopic findings or solely inflammatory changes (median = 5.6, n = 69) and those with malignant conditions (median = 7.6, n = 11), with U = 198.5, z = −2.53, p = 0.011, r = 0.28. Nonetheless, despite the statistical significance of the difference and acceptable sensitivity, ROC curve analysis indicates low specificity in determining a cut-off value for SUVmax.

As illustrated in Table 3, most incidental FDG uptakes in the stomach were inflammatory – chronic gastritis comprised 43.3% (42/97) and no abnormalities were found in 42.3% (41/97). There were 6 cases of adenocarcinomas (1 diffuse type and 5 intestinal type), 5 lymphomas, 1 high-grade dysplasia, and 2 melanoma metastases. Regarding uptake patterns, 38 cases (39.2%) exhibited diffuse uptake, 42 cases (43.3%) displayed focal uptake, and 17 cases (17.5%) were not specified in the report. Among the malignancies, 4 out of 6 adenocarcinomas exhibited focal uptake, while in 2 pattern uptake was not specified; 2 out of 5 lymphomas showed focal uptake, with 3 unspecified; both metastases displayed focal uptake, and the high-grade dysplasia exhibited focal uptake as well. Hence, 64.3% of malignancies demonstrated focal uptake, while 35.7% were unspecified in the report.

There was a significant association between the location of incidental FDG PET/CT uptake and malignant findings. Fourteen incidental uptakes corresponded to a malignant finding in the stomach, and they were significantly more frequent in the body of the stomach (likelihood ratio = 10.095, p = 0.018).

Qualitative analysis by the nuclear medicine specialist was available in 44 patients, indicating a benign nature in 32 cases (72.7%) and suspicion for malignancy in 12 cases (27.3%). A significant association was observed between the qualitative assessment provided in the 18F-FDG-PET/CT report and the nuclear medicine physician’s interpretation (LR = 9.850, p = 0.002). The physician demonstrated the ability to discern the presence of malignancy with a sensitivity of 83.3% and specificity of 81.6%.

Regarding pattern uptake in the stomach, 44 uptakes (45.4%) exhibited a focal pattern, while 38 uptakes (39.2%) displayed a diffuse pattern. The uptake pattern was not specified in the remaining 15 cases (15.5%). The pattern of uptake was significantly different according to the nature of the lesion, with focal uptake more commonly associated with malignant findings, while diffuse uptake was more frequently linked to inflammatory conditions or no findings during endoscopy (LR = 5.772, p = 0.016).

The SUVmax in the stomach varied significantly according to the nature of the lesion, being higher in malignant lesions (median SUV = 6.7 in benign lesions vs. median SUV 9.65 in malignant lesions, p = 0.001, r = 0.34). Additionally, ROC analysis revealed a statistically significant association between increases in SUVmax and malignant findings, with an AUC of 0.78 (p = 0.001). An optimal SUVmax cut-off of 8.2 was considered adequate to distinguish between benign and malignant findings, with 79% sensitivity and 76% specificity.

All 15 findings in the duodenum were benign in nature, 9 revealing normal mucosa, 2 bulbitis, 3 ulcers, and 1 Brunner’s gland hyperplasia. The uptake was focal in 8 and diffuse in 2, not being specified in the remnant. The SUVmax of all incidental findings in duodenum was between 4.7 and 12.3.

The distribution of the uptake in the lower GIT is summarized in Table 4. The nature of the lesion, revealed by the endoscopic study complemented with the histological examination, is detailed in Table 5.

As specified in Table 5, 92 of incidental uptakes (47.4%) were inflammatory or exhibited no changes at endoscopic examination, while 102 (52.6%) were premalignant or malignant – 46 adenomas with low-grade dysplasia, 5 sessile serrated lesions with no dysplasia, 23 adenomas with high-grade dysplasia (11.9%) (Fig. 2) and 23 incidental adenocarcinomas (11.9%) (Fig. 3). According to the above criterion, 57 (29.4%) incidental uptakes were advanced adenomas. Additionally, other notable findings comprised 3 lymphomas (2 diffuse large B-cell and 1 follicular), with 2 of them located at the terminal ileum, and the other one at the cecum. There were found 2 metastatic lesions (1 melanoma and 1 Meckel cell carcinoma).

Based on the pattern of uptake, 26 (13.4%) displayed diffuse uptake, 133 (68.6%) exhibited focal uptake, and 35 (18.0%) lacked specification in the report. Among the premalignant/malignant conditions, 72 (72.7%) demonstrated focal uptake, 10 (10.1%) showed diffuse uptake, and 17 (17.2%) were unspecified according to the report. 60 patients with no alterations had focal uptake. There was no significant difference observed between the uptake pattern and the nature of the lesion.

However, we found a significant association between the location of the uptake and the nature of the lesion, with the left colon revealing significantly more premalignant/malignant findings, while the rectum exhibited significantly more benign findings (LR = 19.039, p = 0.001). The nuclear medicine physician conducted a qualitative analysis in 73 patients, indicating a benign nature in 22 cases (30.1%) and suspicion for malignancy in 51 cases (69.9%). A significant association was observed between the qualitative analysis and the nature of the lesion (x² = 11.926, p = 0.001), with the nuclear medicine physician demonstrating 87.2% sensitivity in identifying premalignant/malignant findings, albeit with 50% specificity.

There were significant differences between median SUVmax in benign versus premalignant/malignant lesions (7.9 vs. 9.4, p = 0.004, r = 0.21). However, no optimal cut-off was found due to low specificity.

There was a dichotomy in patient management based on the location of the findings. Among the 11 patients diagnosed incidentally with malignancy in the esophagus, only two underwent intended curative treatment, both for squamous cell carcinoma. The remaining patients were referred to palliative care due to either metastatic lesions or low performance status. Similar results were observed in the stomach, where the majority of patients diagnosed incidentally with adenocarcinoma (5 out of 6) were referred to palliative care, with only one undergoing curative treatment through surgery. The patient with adenoma with high-grade dysplasia underwent endoscopic submucosal dissection. As for lymphomas, all patients underwent curative-intent treatment, while both patients with metastatic lesions were referred to palliative care. In contrast to the upper GIT, among the 23 patients diagnosed incidentally with cancer in the colon/rectum, 15 (65.2%) underwent intended curative treatment (surgery with or without radiotherapy and/or chemotherapy). Eight patients (34.8%) received palliative treatment due to the primary cancer stage or comorbidities.

The objective of this study was to characterize the unexpected 18F‐FDG‐PET/CT findings in the upper and lower GIT, correlate them with endoscopic findings, analyze their significance, and determine whether the incidental diagnosis of GIT malignancy alters patient management. Many studies focusing on FDG-avid lesions in the GIT, both upper and lower, have involved a limited number of patients [5, 9, 15]. To the best of our knowledge, this study represents the largest investigation to date concerning the upper GIT.

The utilization of 18F-FDG-PET/CT has been on the rise due to its efficacy in staging or monitoring malignancies. Approximately 1 to 3 percent of patients undergoing 18F-FDG-PET/CT exhibit gastrointestinal uptake [16, 17]. At our institution, given the scarcity of data regarding the management of these patients, all individuals with incidental GIT uptake are referred for endoscopic examination. However, this practice burdens the endoscopy unit and presents challenges for clinicians triaging the examinations.

Existing literature predominantly focuses on the lower GIT [14, 18], exemplified by a study conducted by Kousgaard et al. [13], which identified a 12% risk of malignant lesions and a 72% risk of premalignant lesions. Consistent with these findings, our study revealed that 29.4% of incidental uptakes in the lower GIT corresponded to advanced polyps, and 11.9% to malignant lesions. In the upper GIT, malignancy was identified in 13.8% of esophageal and 14.4% of gastric incidental uptakes, with only one premalignant condition (adenoma with high-grade dysplasia) in the stomach. The implications of these findings on patient management are significant. Existing literature predominantly addresses changes in diagnosis and treatment in the lower GIT, with reported alterations ranging from 40% to 90% [13, 19, 20]. Similarly, our study demonstrated that 65.2% of patients with colorectal cancer underwent curative treatment. In contrast, in the upper GIT, only 22.2% (2/9) of patients with esophageal cancer and 28.6% (2/7) of those with gastric cancer or high-grade dysplasia received curative treatment. This underscores the importance of carefully selecting patients for additional diagnostic work-up, particularly those eligible for further treatment.

In similarity with other studies [5, 21‒24], we also tried to find an optimal cut-off value for SUVmax, although it significantly rises with premalignancy/malignancy, the SUVmax does not appear to be a good tool for the distinction between benign and premalignant/malignant findings in most locations, except for the stomach, were a cut-off of 8.2 can be considered, with moderate to good sensitivity (79%) and specificity (76%). Most of the available studies were not able to find an optimal cut-off of SUVmax [5]. However, more recently, Hosni et al. [22] found the value of 9.2 to be the value with the highest sensitivity (0.76) and specificity (0.88) but in opposition to our data, this value was referred to all GIT not adjusted to the location. Lee et al. [24] found a value of 7.6, with a sensitivity of 0.686 and a specificity of 0.688, to distinguish between cancer and pre-cancerous lesions but only at the colon.

In our study, the location of incidental uptake in 18F-FDG-PET/CT examinations appears to be significant. Incidental uptake tended to be benign in nature at the GEJ and in the rectum, consistent with findings reported in the literature [24]. In the GEJ, this can be attributed to inflammation caused by acid reflux from the stomach. In the rectum, although the explanation is less precise, an enlarged hemorrhoids could be a plausible cause. Conversely, incidental uptake in the mid-esophagus, body of the stomach, and descending colon were significantly more often associated with at least premalignant conditions. Regarding other characteristics of the uptake, existing literature suggests that focal uptake is predictive of at least a premalignant condition [22, 24, 25]. However, we found that focal uptake was predictive of at least a premalignant condition only in the stomach, possibly due to the fact that 18.8% of all reports did not specify the type of uptake. Our analysis of 260 uptakes in the GIT with endoscopic examinations without any changes or inflammatory findings revealed that 147 (56.5%) displayed focal uptake, 64 (24.6%) showed diffuse uptake, and 49 (18.9%) had unspecified uptake according to the report. Among 127 premalignant/malignant conditions, 87 (68.5%) exhibited focal uptake, 14 (11.0%) diffuse uptake, and 26 (20.5%) had unspecified uptake in the report. Based on these data, albeit limited by the nature of the study, we propose that upper GI uptakes with SUVmax of at least 8.2 and focal in nature should be promptly evaluated.

To the best of our knowledge, this study is the first to incorporate the qualitative analysis of the nuclear medicine physician as a metric for evaluating incidental uptake, and it has proven to be highly effective in predicting outcomes across the GIT, particularly in ruling out premalignancy/malignancy. However, further studies are required to validate this parameter as a method to assist in selecting incidental uptakes that require further evaluation.

This is a retrospective single-center study, which with the inherent limitations, could restrict the generalizability of the findings. To mitigate potential confounding factors that may contribute to heterogeneity among studies, a prospective, multicenter investigation employing standardized imaging parameters is necessary. Achieving an optimal management approach necessitates a comprehensive evaluation of the patient’s medical history and clinical presentation. However, due to the extensive analysis and considerable number of patients/uptakes and statistically significant PET parameters this study may give some valuable information about the characteristics of the uptakes at GIT and which should prompt endoscopic examination.

Our results fill an important knowledge gap in this field, providing valuable evidence to support the prioritization of certain endoscopic examinations and potentially reduce the burden of unnecessary procedures, allowing to select those who need further endoscopic examination.

This study protocol was reviewed and approved by Comissão de Ética para a Saúde of Instituto Português de Oncologia de Lisboa Francisco Gentil, Approval No. GQR.MOD.09.1. Patient consent was waived in accordance with institutional protocol, as consent is not required for cohort studies that utilize only global anonymous data without presenting any individually identifiable information.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Luís Correia Gomes and Davide Fraga were involved in manuscript drafting, data collecting and statistical analyses. Pedro Lage, Isabel Claro, and Lucília Salgado were involved in manuscript critical revision. All authors approved the final version.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.