Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) has emerged as a cornerstone in cancer evaluation imaging, with a well-established history spanning several years. This imaging modality, encompassing the examination of the body from the base of the skull to the upper thighs, comprehensively covers the chest and abdominopelvic regions in a singular scan, allowing for a holistic assessment of nearly the entire body, including areas of marginal interest. The inherent advantage of this expansive scan range lies in its potential to unveil unexpected incidental abnormal hypermetabolic areas. The identification of incidental focal FDG uptake within colorectal regions during PET/CT scans is not an uncommon occurrence, albeit fraught with challenges associated with non-specific FDG uptake. The presence of benign colorectal lesions or physiological uptake poses a particular obstacle, as these may manifest with FDG uptake levels that mimic malignancy. Consequently, physicians are confronted with a diagnostic dilemma when encountering abnormal FDG uptake in unexpected colorectal areas. Existing studies have presented divergent results concerning these uptakes. Standardized uptake value and its derivatives have served as pivotal metrics in quantifying FDG uptake in PET images. In this article, we aim to succinctly explore the distinctive characteristics of FDG, delve into imaging findings, and elucidate the clinical significance of incidental focal colorectal uptake. This discussion aims to contribute valuable insights into the nuanced interpretation of such findings, fostering a comprehensive understanding.

Since the introduction of fluorine-18 fluorodeoxyglucose (F-18 FDG) for clinical imaging, it has emerged as a pivotal oncologic imaging radiopharmaceutical in the domain of nuclear medicine. F-18 FDG serves as a prominent radioactive tracer for utilization in positron emission tomography (PET) or PET/computed tomography (PET/CT). While PET alone provides functional images with limited anatomical detail, the integration of simultaneous anatomical imaging within the same machine in hybrid PET/CT enables precise localization of FDG metabolism. Given that biochemical alterations precede physical manifestations, the molecular-level insights offered by PET/CT play a crucial role in the early detection of disease states[1,2].

The initial impediment to widespread F-18 FDG use was the necessity for a cyclotron and a radiochemical laboratory for production. However, advancements over time have led to the deployment of this equipment in various regions, significantly enhancing its availability. Currently, F-18 FDG scans are globally employed for purposes ranging from diagnosis to treatment planning, evaluation, and follow-up. The practicality of F-18 FDG for everyday clinical use in hospitals is underscored by its approximate half-life of 110 min.

In contrast to other imaging modalities like CT or magnetic resonance imaging, the F-18 FDG PET/CT scan encompasses a broad range, spanning from the skull base to the upper thigh (torso), or in some instances, the entire body. This extensive scan range may encompass areas of lesser interest, potentially leading to the observation of increased FDG metabolism (hypermetabolism) at unexpected sites. This article delves into the distinctive characteristics of FDG, presenting imaging findings and exploring the clinical significance of incidental focal colorectal hypermetabolism.

The initial synthesis of FDG, credited to Pacák et al[3] in 1968, marked a significant milestone in medical imaging. F-18 FDG, developed by Ido et al in 1978, revolutionized PET imaging and found widespread application in oncology, neurology, and cardiology[3-6]. Structurally based on glucose, FDG substitutes the hydroxyl group on the 2-carbon of a glucose molecule with the fluorine-18 radionuclide[7,8]. Cellular uptake of this glucose analogue occurs primarily through glucose transporters 1 and 3, mirroring the uptake of natural glucose molecules into cells[7-9]. However, due to structural differences, FDG cannot complete the glucose metabolic pathway and becomes trapped within cells[10]. Despite this, the common initial metabolic behavior between FDG and glucose allows FDG to effectively evaluate and represent glucose metabolism in cells.

Living cells need glucose as energy source. The phenomenon known as the Warburg effect elucidates the heightened glucose uptake by cancer cells compared to normal cells for energy production[11]. Cancer cells prefer glycolysis over oxidative phosphorylation for energy production, despite its lower efficiency, as the rapid process aligns with the energy demands of cancer cells[12-15]. The increased glycolytic rate facilitates FDG uptake in cancer cells, enabling visualization through PET[16]. However, it is crucial to note that FDG is not exclusive to cancer cells. Organs with naturally high glucose metabolism, such as the brain or liver, exhibit increased FDG uptake. Moreover, benign conditions with elevated glycolysis also accumulate FDG in cells[17-21]. In essence, FDG demonstrates no discriminatory ability between malignant and benign cells.

The assessment of accumulated FDG involves both visual interpretation and quantitative measurement. The semi-quantitative index known as the standardized uptake value (SUV) serves as a representative dimensionless ratio indicating relative concentration in a region of interest[22]. SUV is calculated as follows: SUV = [tissue radioactivity concentration (decay-corrected) (mCi/mL)]/[injected tracer dose (mCi)/body weight (g)].

The widespread application of SUV is evident in its utility for distinguishing malignant from benign lesions. This is particularly crucial in oncological diagnostics, where determining a cutoff specific to a particular cancer facilitates reference value comparisons. Moreover, SUV plays a pivotal role in the assessment of treatment efficacy, enabling the comparison of pre- and post-therapy imaging data. Various metrics can express SUV, including the maximum SUV (SUVmax) representing the highest value in a single pixel, the mean SUV (SUVmean) derived from the average value in a freely drawn region, and the peak SUV (SUVpeak) determined as the average SUV in a small fixed-sized region centered on a high uptake portion. While SUVmax maintains consistency across different measurements, it is susceptible to noise[23,24]. SUVmean, on the other hand, is sensitive to variations induced by the delineated area[25,26]. SUVpeak, encompassing a relatively large volume, exhibits resilience against noise interference but may pose challenges in the analysis of small or tiny lesions[27-29]. Additionally, alternative SUV-related parameters such as SUV corrected for lean body mass, metabolic tumor volume, and total lesion glycolysis find application in diverse clinical scenarios. Regrettably, no singular parameter emerges as flawless in addressing all aspects of SUV assessment.

The degree of FDG uptake is subject to variation, influenced by factors such as cellularity, cell activity, tumor size, and the local microenvironment[30-33]. It is important to recognize that not all cancer cells experience glucose deprivation, and FDG accumulation may not always be pronounced within them. In colorectal cancer, SUVmax values exhibited variability based on lesion length, clinical stage, pathological tissue type, and tumor differentiation[34]. For non/low-FDG-avid cancer cells, alternative radiopharmaceuticals like radiolabeled amino acids, choline, and analogues are viable options in PET imaging for cancer detection and management[35-38].

Given the shared plasma membrane protein transport for both glucose and FDG, blood glucose concentration plays a role in FDG transport. Early studies in the 1990s highlighted that elevated blood sugar levels adversely affected image quality, as FDG competed with blood glucose for cellular membrane transport[39-42]. Current guidelines from the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging recommend conducting F-18 FDG PET/CT when blood glucose is controlled, ideally below 11 mmol/L (approximately 200 mg/dL)[16,43]. While recent literature suggests limited impact of blood glucose levels on imaging outcomes[44-48], adherence to published guidelines remains widespread.

The heightened glycolytic activity of cancer cells contributes to increased FDG uptake, resulting in prominently intense PET imaging[49-51]. SUV is a widely used metric in clinical settings, although its utility is not without limitations. An SUV of 2.5 or higher generally indicates potential malignancy, with an SUVmax of 3.5 to 4 suggested for colon lesions[52]. However, it is crucial to note that both malignant and non-malignant cells can exhibit elevated SUV due to the non-specific uptake mechanism of FDG[53-57]. It is well known that active infectious/inflammatory lesions or benign polyps may present high FDG uptake mimicking malignant lesions[58-62]. Additionally, physiological gastrointestinal FDG uptake is also common and intense colonic FDG uptake with metformin is well known[63-67]. Thus, interpreting high FDG uptake alone does not provide a definitive distinction between malignant and non-malignant lesions. FDG remains impartial in its diagnostic specificity.

When the criteria for heightened FDG uptake are satisfied, resulting in a conspicuous elevation in FDG metabolism within the image, the manifestation of uptake can assume a focal and/or diffuse nature. While not universally applicable, diffuse uptake in certain organs is more likely to be benign or physiological in origin than malignant[54,56,68-71]. In contrast, focal uptake holds greater clinical significance, necessitating careful consideration to avoid overlooking the potential presence of a malignant lesion[72-75]. The uptake pattern is of importance.

Figure 1 illustrates two cases of heightened FDG uptake in the gastrointestinal tract. In panel A, we observe diffuse intestinal FDG uptake in a 58-year-old male patient recently diagnosed with B-cell lymphoblastic lymphoma. Meanwhile, panel B presents hypermetabolism localized to the hepatic flexure area and descending colon of a 51-year-old woman with a previous history of gastric cancer. Despite the high metabolic activity, colonoscopic examinations in both cases revealed no pathological findings such as tumors or inflammation. This absence of detectable abnormalities underscores the physiological nature of the observed bowel uptake, suggesting the complexities and subtleties of interpreting such imaging findings. Figure 2 illustrates the distinct patterns of FDG uptake within the intestinal tract of an 87-year-old male patient diagnosed with non-small cell lung cancer. The image depicts both focal and diffuse FDG uptakes, which are crucial indicators in oncological imaging. Diffuse FDG uptake along the intestinal tract is commonly observed and often attributed to physiological processes. However, it is still imperative to discern between physiological and pathological uptake to guide clinical decision-making effectively. Of particular interest is the focal hypermetabolism detected in the proximal transverse colon. Such localized hypermetabolic activity raises concerns regarding the presence of a potential pathological lesion. In this case, subsequent colonoscopy was performed to elucidate the nature of the observed focal hypermetabolism. Despite the heightened suspicion, no significant abnormal lesions were identified during the procedure. These instances underscore the importance of discerning between physiological and pathological causes of increased FDG uptake in the gastrointestinal tract, particularly in the context of oncological surveillance.

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Figure 1 Diffuse physiological bowel fluorine-18 fluorodeoxyglucose uptake. Images depicting fluorine-18 fluorodeoxyglucose uptake in the bowel. A: Diffuse intestinal uptake observed in a 58-year-old male patient diagnosed with B-cell lymphoblastic lymphoma; B: Regions of hypermetabolism are highlighted in the hepatic flexure area and descending colon of a 51-year-old woman with a history of gastric cancer. Colonoscopy examination yielded no evidence of abnormalities such as tumors or inflammation, confirming the physiological nature of the observed bowel uptake.

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Figure 2 Focal and diffuse intestinal fluorine-18 fluorodeoxyglucose uptake. A 87-year-old man diagnosed with non-small cell lung cancer (squamous cell carcinoma) is depicted. A: Focal (arrow) and diffuse intestinal uptakes are evident. While diffuse uptake may represent physiological activity, a focal hypermetabolic area raises suspicion for a potential pathological lesion; B: Focal uptake is specifically noted in the proximal transverse colon. Subsequent colonoscopy was performed, revealing no significant abnormal lesions.

F-18 FDG PET/CT, an integral component in the assessment of malignant diseases, often reveals suspicious focal colorectal FDG uptake. It is imperative to recognize that the technique has limitations, particularly in detecting non-FDG-avid or small malignant lesions. The likelihood of malignancy or advanced disease correlates with higher FDG uptake, underscoring the significance of diligent examination and interpretation of observed uptake.

Incidental colorectal FDG uptake occurs in approximately 5% of cases[76-78], with focal uptake presenting a higher likelihood of malignancy compared to diffuse patterns[71]. Diffuse and segmental uptake may stem from inflammation, physiological processes, or FDG excretion[79,80], generally associated with a lower risk of malignancy. Focal uptake prevalence reaches up to 16%[81], with malignant and premalignant lesions constituting around 70% of focal uptake with SUVmax exceeding approximately 5[72,81-85]. Colonoscopy is often recommended for further investigation in such cases[72,80,81,84-87], although ongoing debates surround the optimal PET parameters for distinguishing premalignant/malignant lesions from benign ones, with varying studies utilizing SUVmax[72,81,83,88,89].

Premalignant lesions are not yet malignant; however, they have more chance to develop into malignant lesions. Adenomas (tubular adenomas, villous adenomas, tubulovillous adenomas) are the most frequent premalignant lesions and others include chronic inflammatory bowel diseases, hereditary syndromes (familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis). Colorectal adenomatous polyps are known to develop in up to 40% of people over the age of 60[90]. While debates persist regarding the role of SUV in differentiating malignant/premalignant from benign lesions[76,91-95], the significance of more than 50% malignancy in focal FDG colorectal uptake is noteworthy. In terms of cancer development by the location (distal or proximal), different genetic mechanisms are suggested[96-98], however, no significant difference was observed in SUVmax depending on location[34]. Notably, the observation of mixed single/multiple focal and diffuse uptake in the colorectal region underscores the complexity of interpretation. In such cases, diffuse uptake does not conclusively exclude the need for further evaluation, including colonoscopy and histopathological confirmation.

Figure 3 illustrates focal hypermetabolism incidentally detected in the rectum of an 88-year-old man previously diagnosed with non-small cell lung cancer in his left lung. Subsequent colonoscopy and pathological analysis confirmed the presence of adenocarcinoma originating from the rectum, establishing a secondary malignancy. This case highlights the importance of vigilant surveillance in cancer patients, as the detection of secondary malignancies or metastases can significantly impact treatment strategies, overall survival rates, and quality of life for patients.

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Figure 3 Focal intestinal fluorine-18 fluorodeoxyglucose uptake. A: Maximum intensity projection depicting focal hypermetabolism superior to the urinary bladder (arrow) in an 88-year-old man diagnosed with non-small cell lung cancer; B: Axial view revealing focal hypermetabolism localized in the rectum; C: Non-contrast-enhanced computed tomography obtained from positron emission tomography/computed tomography, highlighting a space-occupying lesion within the rectum. Notably, a discernible posterior radioopaque area suggests the presence of residual contrast material from a prior contrast-enhanced examination. Subsequent colonoscopy and pathological analysis definitively identified the lesion as adenocarcinoma originating from the rectum.

The detection of unexpected focal colorectal F-18 FDG uptake is a frequent occurrence, with significant implications for clinical practice. Given the distinctive characteristics of FDG, notably its increased uptake in premalignant and malignant lesions, particularly when indicated by high SUV values, such findings warrant careful consideration. Studies have shown that a substantial proportion, approximately 70%, of focal colorectal FDG uptake corresponds to malignancies or premalignant lesions, especially when the SUVmax exceeds a threshold of approximately 5. While acknowledging the inherent limitations of F-18 FDG PET/CT, which may introduce uncertainty and hesitancy in interpretation, it is crucial to emphasize the diagnostic utility of observed FDG uptake patterns. Clinicians should be guided by these findings to pursue further proactive evaluation, thereby enhancing diagnostic precision and facilitating timely interventions. By leveraging the observed rates of malignancy and the degree of FDG uptake, clinicians can make informed decisions that optimize patient care and outcomes.