1. Introduction
Positron emission tomography/computed tomography (PET/CT) is a widely used nuclear imaging technique in oncology for the detection of neoplasia [
1]. [
18F]-Fluorodeoxyglucose (FDG), the most commonly used radiolabeled tracer in PET scans, is taken up by various tissues in the human body through glucose metabolism.
The concept behind FDG PET/CT scans in the detection of malignancy is based on the observation that cancer cells metabolize glucose at a higher rate than non-cancerous cells. Hypermetabolic conditions such as infection, inflammation, and hyperplasia, as seen in colorectal polyps, may lead to increased FDG uptake [
2,
3]. Other physiologic reasons include uptake by microbiome or normal lymphoid tissue and swallowing of secretions [
2]. Accordingly, it may be difficult to differentiate between physiologic activity and malignancy on PET/CT, and certain techniques, such as dual time point imaging, have been suggested to improve the detection of malignancy [
4].
In the last two decades, the indications for PET/CT have widely developed in the realm of gastrointestinal cancers. Esophageal, gastric, and colorectal cancer patients can benefit greatly from the added value of PET/CT in management, prognosis, assessment of treatment response, planning of therapy, and re-staging [
5]. As a result of increased PET/CT utilization in the management of cancer patients and the rising proportion of the elderly population, the incidental detection of clinically significant findings such as unexpected tumor sites has increased [
6,
7]. Such findings usually present a diagnostic and therapeutic challenge for clinicians.
Multiple studies have examined incidental FDG uptake in the gastrointestinal tract (GIT) and have found variable incidence rates ranging from 0.5% to 2.6% [
8,
9,
10,
11,
12,
13]. A focal pattern of incidental FDG uptake in the GIT is reported to be associated with a higher likelihood of malignancy than a non-focal pattern [
12,
14,
15]. However, these could vary depending on the indication, examined population, and the definition of abnormal uptake. The main objective of this study was to characterize the pattern and degree of incidental GIT uptake most likely to be associated with cancerous or pre-cancerous lesions in patients who underwent whole-body PET for other purposes.
4. Discussion
Fused PET/CT has been widely used for the staging and follow-up of several types of malignancies, and this has accordingly increased the rate of incidental findings in the GIT [
17]. A recent study by Byung et al. (2016) showed that FDG PET/CT had a high diagnostic accuracy for detecting synchronous colorectal cancer in patients with gastric cancer [
18]. Several studies have shown that FDG uptake in the gastric mucosa could be focal or diffuse in a variety of benign conditions (normal mucosa, gastritis, H. pylori infection) [
19]. Similarly, in colorectal carcinoma (CRC), a meta-analysis showed the sensitivity and specificity for PET in the detection of CRC recurrence in patients with elevated CEA to be 90% and 80%, respectively [
20].
Several studies have assessed incidental FDG uptake in the GIT, but only a few included those with diffuse uptake or with upper GIT uptake. Our study is one of the largest to include any incidental GIT uptake (including upper and diffuse uptake) that was followed-up endoscopically. The rate of incidental GIT uptake in our study population was 5.6%, with 80 patients (18.2%) undergoing further investigation. Prior studies reported the incidental GIT uptake to range from 0.7 to 2.6%, with more than 50% of the patients not undergoing further endoscopic evaluation [
9,
10,
15]. However, these studies only included focal uptake and excluded uptake in the upper GIT. In our study, 29% of all patients with an abnormal lesion on endoscopy had diffuse FDG uptake on PET, which was comparably higher than the 1–17% detected in similar studies [
15,
21].
Although an incidental uptake in the lower GIT has more likelihood of being a cancer/pre-cancer lesion, 50% of the malignant lesions in our study were found in the upper GIT (
n = 8). Patients with incidental upper GIT malignancy were younger than the studied population. A study conducted by Buel et al. (2002) identified 34 solid organ recipients who were on immunosuppressive therapy and developed gastric cancer [
22]. Patients had a mean age of 58 ± 11, and 22 out of the 34 detected gastric cancers were found incidentally [
22]. Another study performed by Isobe et al. (2010) showed that among twenty-six cases of incidental GIT uptake on PET/CT for patients with lung cancer, four malignant lesions were found in the upper GIT [
23]. In our study, 37.5% of all biopsy-proven malignancies in the upper GIT were visualized as a diffuse FDG uptake. This percentage was higher than the 23% reported in one recent study also examining diffuse uptake in the upper GIT [
21].
In clinical practice, it would be of benefit for the clinician to have a general idea of the probability of malignancy based on uptake pattern and location. When the results were examined based on the percentage of disease found in focal and diffuse uptake, the following became apparent: 46% of focal uptake was due to abnormal lesions, compared to only 30% of diffuse uptake cases. Upon further classification based on location, 5/57 of all focal uptake cases were upper GIT malignancies and 8/57 were lower GIT malignancies. As for diffuse uptake, 2/20 of all diffuse uptake represented upper GIT malignancies.
Upper GIT uptake was most frequent in the stomach. One retrospective cohort by Gilhotra et al. (2022) showed the most common upper GIT uptake in the esophagus (58.4%); however, this can be explained by inflammatory changes detected in 57% of these patients [
21]. As for the lower GIT uptake, it was most commonly observed in the sigmoid colon. This finding is in concordance with Gilhotra et al. (2022) on patients with incidental lower GIT uptake, where 67% of all patients had uptake in the left colon [
21]. It is worth noting that this uptake is not an absolute reflection of CRC incidence because the uptake may be explained by physiologic processes; moreover, the site of the highest frequency of colorectal cancer is highly variable among different population groups [
24].
Our study showed that patients who were older in age or had lower GIT uptake were more likely to have a cancer/pre-cancer lesion on further endoscopic evaluation regardless of uptake pattern. However, in patients with focal uptake, the intensity of the uptake was shown to be an independent predictor of finding a cancer/pre-cancer lesion. In our study, an SUVmax greater than 9.2 had the highest sensitivity (0.76) and specificity (0.885). In the literature, one study by Lee et al. (2022) showed a sensitivity of 0.686 and a specificity of 0.688 at an SUVmax cut-off of 7.6 for the differentiation between benign and cancer/pre-cancerous lesions, without having any significant difference in parameters when distinguishing between cancer and pre-cancerous lesions [
25]. Another retrospective study by Ozaslan et al. (2021) found a significantly higher mean SUVmax in patients with malignancy (15.0) in comparison to adenomas (10.2); however, they detected a mean SUVmax of 9.8 in normal endoscopic groups [
26]. This would mean that an SUVmax cut off of 9.2, shown to have a specificity of 0.885 in this study, would lead to a high number of false positives when used in their study. Accordingly, a 9.2 SUVmax cut off may not be of value when applied to other populations. In contrast to these findings, one large retrospective study by Gokden et al. (2022) showed no significant difference between the SUVmax of malignant and benign cases; however, they detected significantly higher mean SUVmax in malignant cases in comparison to positive cases that were less high-grade [
27].
Although incidental FDG uptake in the GIT has a low positive predictive value (0.387), several studies have concluded that it warrants a follow-up endoscopy (esophagogastroduodenoscopy or colonoscopy) [
28,
29]. Many studies have assessed colonic uptake, but very few investigated diffuse or upper GIT uptake. In our study, a cancer/pre-cancer lesion was found in eight out of the thirty-seven incidental upper GIT findings (21.6%) as well as in five out of twenty diffuse uptake cases in the GIT (25.0%).
One consideration that may explain the higher incidence of lower GIT uptake may be the use of metformin-containing anti-diabetics in patients. Metformin is previously known to increase the FDG uptake in the GIT [
30]. Accordingly, the EANM advises on the discontinuation of metformin two to three days before imaging [
16]. In our study, patients were advised to discontinue any metformin-containing anti-diabetic medication at least 48 h before the imaging. It was not documented if the patients actually withheld from taking the medication, and this may have led to a falsely elevated incidental uptake in the lower GIT. Moreover, documentation of patient diabetic status was not included in the baseline characteristics, which may be a confounder revealing elevated rates of lower GIT uptake in diabetic patients if a subgroup analysis was performed.
One major consideration to the further investigation of all incidental FDG GIT uptake on PET would be the financial burden and time consumption in a clinic or hospital setting. One study by Hadad et al. (2020), which was performed in a European country, has shown that the estimated additional cost to investigating each focus of FDG uptake in the GIT is approximately USD 1984 [
31]. The price of further investigations is highly variable, where another study by Adams et al. (2018) conducted in Canada showed an average cost of USD 127 [
6].
A subgroup analysis on other patient characteristics such as BMI and co-morbidities is needed. One other limitation in this study is the single-center study design, which reduces the external validity of the findings. A prospective, multi-center study with standardized imaging parameters is needed to reduce possible confounders that may elicit heterogeneity among studies. A holistic view of the patient’s history and clinical picture is required to optimize management. The clinician’s better judgment is needed, while maintaining a low threshold for further investigation.