Nuclear Medicine PET/CT Gastrointestinal Assessment, Protocols, and Interpretation

Anatomy and Physiology

Esophagus and Gastroesophageal Junction

Optimum treatment planning of esophageal cancers requires an accurate description of cancer location in upper gastrointestinal tumors, which is impossible without a clear understanding of the segmental esophageal anatomy. Anatomical levels for these cancers are reported relative to anatomical landmarks set by the American Joint Committee on Cancer (AJCC) staging system.

The esophagus is divided into 4 segments. This delineation is vital to ensure that the tumor is covered in its entirety in the radiotherapy field. If surgical resection is planned, the choice of approach is appropriate for the tumor's location. The Siewert-Stein classification categorizes gastroesophageal junction (GEJ) tumors into 3 groups based on their epicenter's location relative to the gastroesophageal junction. Regional lymph nodes for the esophagus include the supraclavicular, periesophageal, and celiac nodes.[4]

Large Intestine

The large intestine extends from the cecum to the anal verge, where the stratified squamous epithelium of the anal canal meets the anal skin. For colorectal cancers, the tumor's relationship with the peritoneal reflection carries significant prognostic value. Peritoneal involvement classifies the disease as T4a and increases the likelihood of peritoneal metastases.[5]

The parietal peritoneum covering the abdominal wall reflects anteriorly onto the cecum and the ascending and descending colon, becoming the visceral peritoneum while leaving their posterior circumference uncovered. The transverse and sigmoid colon are almost entirely intraperitoneal, except for the areas along the mesenteric vessels. The peritoneal reflection on the pelvic structures forms the rectouterine pouch in the female body and the rectovesical pouch in the male body, partially covering the pelvic sidewall on both sides. The rectum is covered by the peritoneum anteriorly and laterally in the upper part, only anteriorly in the middle part, and is entirely free of the peritoneum in the lower part.

The anal canal is the terminal segment of the GIT and extends from the anorectal junction superiorly, where the rectum passes through the pelvic diaphragm to the anal verge inferiorly. This segment measures approximately 4 cm and has 2 crucial muscle layers. The inner layer, which is the continuation of the GIT's circular muscle, forms the internal sphincter. The outer layer, derived from the downward continuation of the levator ani and puborectalis, forms the external sphincter, with a small intersphincteric space separating the internal and external sphincters.

Nodal metastases from colon cancer spread along the mesenteric vessels to the origin of the superior mesenteric artery (SMA) in right-sided tumors or the inferior mesenteric artery (IMA) in left-sided tumors, potentially involving the paraaortic nodes. Rectal tumors drain into the mesorectal nodes, then to the superior rectal artery nodes. From there, metastases can travel along the sigmoid mesentery root to the paraaortic nodes or drain into the internal iliac nodes.

Anal cancer has a greater predilection for spreading through the lymphatic system rather than the bloodstream.[6] Tumors superior to the dentate line follow the drainage pathway of rectal tumors, while those inferior to the dentate line have a predilection for draining into the external iliac system via the inguinal and femoral nodes.

Neuroendocrine Tumors

Gastroenteropancreatic NETs (GEP-NETs) are a diverse group of neoplasms originating from embryonal neural crest cells. These tumors can develop in virtually any part of the GIT, with the small intestine being the most common location. Gastroenteropancreatic NETs exhibit a wide range of clinical behaviors, from indolent, slow-growing forms to highly aggressive variants. This variability in clinical behavior correlates with the tumors' cellular proliferation rate, which is measured using immunohistochemical staining for the Ki67 protein.

According to the European Neuroendocrine Tumour Society and World Health Organization 2010 Classification Systems for NETs, these tumors are categorized into 3 grades based on the Ki67 index. Grade 1 tumors are well-differentiated with a Ki67 index below 2% and demonstrate indolent behavior. Grade 3 tumors are poorly differentiated, with a Ki67 index above 20%, and exhibit aggressive clinical behavior. Grade 2 tumors, which are moderately differentiated, display a behavior and proliferation profile between these 2 extremes.[7][8]

Radiotracers for Positron Emission Tomography/Computed Tomography Imaging

The most commonly used radiotracer in PET/CT imaging is 18F-FDG. Activity detection occurs through multiple collisions between the positron emitted from the radioactive material and surrounding electrons in the biological environment. This process continues until the positron loses its kinetic energy and combines with an electron to form a short-lived positronium molecule. The positronium then undergoes annihilation, converting its mass into 2 γ-ray photons, each having an energy of 511 keV and traveling in opposite directions 180° apart.

A coincidence event occurs when both annihilation photons are detected within a short time interval, and the photons are assumed to have originated from positronium annihilation along the line connecting the 2 points. This process eliminates the need for a physical lead collimator, resulting in significantly better sensitivity compared to single photon emission computed tomography (SPECT) imaging, as no extrinsic collimation is required.[9] 

In gallium imaging, the conjugated version of octreotide is attached to a gallium-68 radiotracer through a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand. This conjugation allows the radiotracer to effectively bind with SSTRs found on well-differentiated NETs. However, more aggressive, poorly differentiated tumors may not show significant uptake on gallium PET and are sometimes better assessed with FDG-PET due to their lower expression of SSTRs and increased glucose metabolism.[10]

Indications

Evidence-based indications for the use of FDG-PET/CT for gastrointestinal tumors in the United Kingdom, as published by the UK Royal College of Radiologists in 2016, include the following:

• For esophageal and gastroesophageal cancers, PET/CT is indicated for staging and restaging when radical treatment is appropriate, including in patients who have received neoadjuvant therapy. PET/CT is also useful for evaluating suspected recurrence when other imaging techniques yield negative or equivocal results. Additional proposed indications include response assessment and radiotherapy planning.
• For colorectal cancers, PET/CT is indicated for staging disease with synchronous metastases at presentation, such as pulmonary and liver lesions. Other indications include restaging in patients with recurrence, assessing treatment response, detecting recurrence in the presence of rising tumor markers, and evaluating clinical suspicion of recurrence when other imaging modalities have normal or equivocal results. Posttreatment, PET/CT may also be used to evaluate indeterminate presacral masses.
• PET/CT is performed in anal cancer for staging in selected patients requiring radical treatment. Additional proposed indications include radiotherapy planning and response assessment.
• For NETs, FDG-PET/CT is indicated for staging and restaging poorly differentiated tumors that show normal or negative m-iodobenzylguanidine (MIBG) and octreotide scans. Gallium-68 DOTA-[1-Naphthylmethyl] octreotide PET/CT (68Ga-DOTANOC PET/CT) is indicated for staging well-differentiated NETs (grades 1 and 2), detecting unknown primaries, and evaluating recurrence (see Image. Gastrointestinal Neuroendocrine Tumor on Advanced Nuclear Imaging).

Contraindications

Imaging with PET/CT requires careful patient preparation. Poor glycemic control, incomplete fasting, and insulin injection immediately before the scan can affect the radiotracer's biodistribution. Elevated blood glucose competes with FDG for binding to GLUT-1 transporters, while high insulin levels can redirect a significant amount of FDG to skeletal muscles and adipose tissue via insulin-dependent glucose transporter type 4 (GLUT-4).

Ideally, PET/CT should be delayed for at least 6 weeks after radiotherapy or surgery and at least 2 weeks after stent placement to prevent inflammatory uptake at the intervention site, which may lead to overestimation of the disease.[11]

Patients with claustrophobia may require sedation. PET/CT is generally unsuitable for pregnant patients, and an alternative means of evaluating disease in this group should be arranged. Breastfeeding mothers should avoid contact with their infants after the scan. The general recommendation is to have the infants bottle-fed by a 3rd person for up to 12 hours after the scan.[12][13]

Equipment

The radiopharmaceutical is prepared in cyclotrons and brought into the department in lead-lined containers early in the morning. The handling process requires exquisite care and diligence to avoid exposure to the staff and the public. The radiotracer is injected through a tungsten syringe employed in a specialized carrier and is kept behind a lead screen.[14]

The PET/CT system comprises stand-alone PET and CT scanners housed in a single gantry. The patient bed is shared between the 2 scanners and moves smoothly from the PET to the CT component during image acquisition.

A scintillator absorbs ionizing radiation and converts a fraction of the absorbed energy into photons of visible or ultraviolet light, which are then transformed into electrical signals by photodetectors. A typical PET scanner consists of thousands of inorganic scintillation crystals organized into blocks, which form detector modules arranged in a ring configuration. Traditionally, bismuth germanate (BGO) detectors were used, but they have now been replaced by lutetium oxyorthosilicate (LSO) detectors.[15]

These crystals absorb energy from annihilation events in the body (511 keV energy) and generate tens of thousands of visible wavelength photons, proportional to the energy deposited by the annihilation photons. "Random coincidence" occurs when 2 detected photons originate from separate annihilation events. "Scatter coincidence" happens when both photons are from the same event, but 1 or both have scattered. "True coincidence" refers to the detection of both photons from the same annihilation event.[16] 

The light photons are channeled toward the coupled photodetectors. The most common photodetectors used in PET are photomultiplier tubes (PMTs), which consist of vacuum tubes with photocathodes. The light photons interact with the cathode, producing electrons that are then amplified to generate an electric signal proportional to the energy deposited by the PET photons.

The initial image is far from perfect and is significantly influenced by PET photon attenuation in the body, variations in detector efficiency, and the recording of scattering and random events alongside true coincidences. Consequently, attenuation correction is performed using a CT scan conducted simultaneously. The CT component also provides additional anatomical information that is absent in the initial PET images.

The images are then represented quantitatively in terms of radioactivity concentration (in kBq/ml), which is converted into a standardized uptake value (SUV) by normalizing to the patient's weight and the injected radioactivity.[17] This SUV measurement quantifies glucose metabolism in a specific tissue of the body and is calculated as follows:

SUV (g/ml) = [(tracer uptake in kBq/ml) / (activity in MBq / patient's weight in kg)]

Preparation

Patient preparation for FDG-PET is complex because FDG, a glucose analog, is absorbed by tissues that normally transport glucose. As PET imaging assesses cellular-level function, it is susceptible to artifacts caused by physiological increases in cellular activity. Managing glycemic levels and minimizing activity in nontarget areas are crucial to maximizing diagnostic accuracy. 

Glycemic Control

Patients must fast for 4 to 6 hours prior to the scan to reduce competition between glucose and deoxyglucose at GLUT-1 transporters. Eating induces an insulin spike, which can divert glucose/FDG to peripheral muscles via insulin-dependent GLUT-4 receptors. In patients with diabetes mellitus, imaging is best performed in the early morning, utilizing the benefits of overnight fasting. For these reasons, insulin should not be injected before the scan. Blood glucose levels are checked beforehand to ensure they are below 200 mg/dl.[18]

Muscular Activity

Patients should refrain from exercise the day before and the day of the procedure. During the scan, patients must remain relaxed and avoid swallowing or speaking to prevent radiotracer uptake in the muscles involved in phonation.

Brown Fat Uptake

Brown fat, which produces nonshivering thermogenesis, can take up FDG in cold environments, potentially leading to false-positive PET results. A warm environment must be maintained for the patient to control brown fat activity.

Hydration

Patients should be well-hydrated to promote renal excretion of FDG. Patients are also instructed to empty their bladder just before the scan to reduce activity in the pelvic area caused by a full bladder. After the scan, patients are advised to drink water to help facilitate the excretion of radioactive material from the body. Caffeinated drinks are not recommended.

Cannulation

The procedure is thoroughly explained to patients, and any questions are addressed to minimize anxiety. Patients are then seated in a lead-lined room, where cannulation should be performed to minimize radiation exposure to staff members. A butterfly infusion set is used.

The patient's vaccine status and injection sites are documented to prevent false-positive results. Local inflammation at the injection site can cause FDG-avid reactive changes in the draining lymph nodes, commonly observed in the axilla following arm vaccinations.[19]

Technique or Treatment

The recommended intravenous dose of 18F-FDG for adults ranges from 370 to 740 MBq, while for children, it is 4 to 5 MBq/kg.[20] After injection, patients are seated comfortably in a warm environment for 1 hour to allow proper FDG distribution. Any radiotracer extravasation is documented, and patients are instructed to empty their bladder just before scanning.

Imaging is typically conducted without the use of oral or intravenous contrast. Patients are routinely encouraged to drink water, which can serve as a negative contrast agent for the GIT.

Once the patient is positioned on the scanner bed, image acquisition begins with a topogram to plan the scanning area. For gastrointestinal cancers, imaging is typically performed from the base of the skull to the midthigh. The next step involves a nonbreath-hold CT scan. Afterward, the patient bed moves to the PET component of the scanner to complete the combined imaging process. The 1st set of data consists of nonattenuation-corrected images, which are then corrected using the CT scan images. The attenuation-corrected (AC) PET data can generate maximum intensity projection (MIP) images or be fused with CT images to provide both anatomical and functional assessments in all 3 dimensions.

The interpretation of PET/CT images primarily relies on maximum SUV (SUV max) measurements. The individual's general metabolic status influences this semiquantitative assessment. Therefore, the SUV max of the background mediastinal blood pool and liver is recorded as a reference.

No single SUV value can reliably distinguish between benign and malignant processes. As a general guideline, metabolic activity is typically categorized into 4 levels:

• Low uptake: SUV max less than 2.5
• Intermediate uptake: SUV max between 2.5 and 5
• High uptake: SUV max greater than 5
• Intense uptake: SUV max greater than 10

Complications

PET/CT is a safe procedure. The radiation dose from a routine diagnostic 18F-FDG at 350 MBq is 6 to 7 mSv. The CT component of the study has a reasonably low dose, ranging from 2 to 4 mSv if used only for attenuation correction and 3 to 10 mSv if used for both attenuation correction and localization. These values are lower than those from contrast-enhanced diagnostic CT scans, which have a dose of 15 to 25 mSv.[21]

Awareness of various false-negative and false-positive findings is crucial, as they can lead to misinterpretation. Some examples are discussed below.

False-Positive Positron Emission Tomography/Computed Tomography

Respiration or patient movement can cause a mismatch between the CT and PET data in fused images, leading to misinterpretation. This issue is especially problematic in abdominal imaging, where bowel movement can create a false impression of peritoneal disease due to misregistration of physiological bowel activity outside the bowel lumen. Nonattenuation correction (NAC) imaging can be reviewed in such situations to prevent misinterpretation.

Brown fat uptake in cold environments, particularly in the supraclavicular regions, can be misinterpreted as signals from lymph nodes. Correlating areas of uptake with CT images helps differentiate solid lesions from low Hounsfield unit fatty tissue.

Radiotracer extravasation and postvaccination status can lead to reactive lymph node uptake in the ipsilateral axilla. These events should be documented in the patient questionnaire for easy reference during reporting.

Inflammatory uptake at the site of radiotherapy, surgery, or biopsy may result in false-positive interpretations. Therefore, the timing of the scan postintervention is crucial to distinguish between malignant disease and inflammation. Chemotherapy can induce reactive marrow hyperplasia, leading to diffuse increased radiotracer uptake in the skeleton.[22]

False-Negative Positron Emission Tomography/Computed Tomography

Tumors with mucinous components may not show significant FDG uptake due to low cellularity, a lack of GLUT-1 transporters, and poor glucose metabolism.[23] Well-differentiated NETs may also show low FDG uptake. Gallium PET is preferred for assessment in such cases.

Artifacts from metallic and vascular stents, along with high activity from a distended urinary bladder, can obscure adjacent small tumors. Similarly, metformin use can lead to diffuse bowel activity, complicating the evaluation of colon pathologies (see Image. Esophagitis on Advanced Nuclear Imaging).[24]

Clinical Significance

Esophageal Cancer

After histological confirmation of malignancy, esophageal cancer is staged using the TNM classification. Early-stage tumors may undergo surgical resection with or without neoadjuvant therapy, while chemoradiotherapy followed by surgery is the standard treatment for locally advanced esophageal cancers.[25]

Esophageal cancers typically show focal or segmental areas of increased FDG uptake, contrasting with the diffuse uptake seen in esophagitis. T staging of early tumors is more accurately performed with endoscopic ultrasound, which can differentiate between the layers of the esophageal wall and assess the immediate periesophageal lymph nodes. Contrast-enhanced CT complements this approach. For nonlocoregional and distant lymph nodes, PET/CT is the most sensitive modality and plays a central role in the primary staging of FDG-avid esophageal tumors.

The 2 main histological subtypes of esophageal cancer are squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma primarily affects the upper and middle esophagus and is strongly associated with alcohol consumption and smoking. This tumor typically shows intense FDG uptake. In contrast, adenocarcinoma predominates in the lower esophagus, is linked to reflux and smoking, and exhibits highly variable FDG uptake. The incidence of adenocarcinoma is increasing, and it has become the most common subtype of esophageal cancer.

The PET/CT report should include details such as the location, length, and SUV max of the tumor, as tumor length serves as an independent prognostic factor for overall survival.[26] The most common sites of metastasis from esophageal cancer include the lungs, liver, bones, adrenal glands, and nonregional lymph nodes. Detection of occult metastasis through PET/CT, which may not be visible on conventional imaging, can help avoid unnecessary surgeries in patients who are unsuitable for curative resection (see Image. Occult Metastasis on Advanced Nuclear Imaging).

Assessing lung metastases with PET/CT is challenging due to the small size of individual lesions, which often fall below the threshold (1 cm) for PET characterization. Additionally, the nonbreath-hold CT component of the PET scan is suboptimal for assessing lung nodules. Sensitivity for liver metastases is also limited due to hepatic background activity, and if a metastasectomy is planned, preoperative magnetic resonance imaging (MRI) is essential for a more accurate assessment.

PET/CT is an excellent modality for ruling out new metastases or recurrence at distant sites following curative treatment for esophageal cancers. The sensitivity of PET/CT for detecting disease recurrence is high, with a pooled sensitivity estimate of around 96%. However, the specificity of this modality is lower, with a pooled specificity estimate of 78%, due to the potential for false-positive results caused by postoperative inflammatory changes and radiation pneumonitis.[27][27] PET/CT scans have a role in response assessment and radiotherapy planning, but concrete evidence for their routine use is lacking.[28]

Colonic Cancer

Colonic cancers can present with focal, intermediate- to high-intensity, eccentric, or short-segment radiotracer uptake. However, assessment is challenging due to several factors, including background physiological colonic uptake, bowel movement causing misregistration, and FDG uptake in fecal matter. Additionally, diffuse high colonic uptake, often seen with metformin intake, can obscure underlying pathology.[29]

Adenocarcinomas typically show variable uptake but generally exhibit high SUV max, except for mucinous adenocarcinomas, which demonstrate poor FDG avidity due to low cellularity and limited expression of GLUT-1 transporters. PET/CT is not routinely used to assess primary colorectal cancers or local lymph nodes due to the poor spatial resolution of PET photon detectors and the limited inherent contrast in the bowel.[30] The pericolonic nodes may also be obscured by the metabolic bloom of the primary tumor.[31] 

MRI is typically used for the local staging of rectal cancer, while contrast-enhanced CT (CECT) is employed for staging other colonic cancers. Metastatic disease is present in about 20% of colonic cancers at diagnosis.[32] PET/CT is indicated for assessing metastatic disease in advanced tumors, particularly when resection is being contemplated. The most common sites of metastases include the liver, lungs, ovaries, and peritoneum.

Metastatic disease has been traditionally treated with systemic chemotherapy. However, recognition of metastasectomy with curative intent is increasing, supported by evidence showing improved survival rates (37%–58%) in patients who undergo surgical resection, even in the presence of multiple metastases.[33][34][35] 

If surgery is considered for liver metastases, a liver MRI is essential for preoperative planning. Lung metastases require assessment with a breath-hold CT scan for precise quantification and characterization. PET/CT can detect peritoneal metastases, which may present as focal uptake or diffuse perihepatic curvilinear uptake, often corresponding with CT findings of peritoneal nodules or fat stranding. Ascites is frequently associated with peritoneal disease, although it may or may not exhibit high FDG uptake.

PET/CT plays an established role in detecting disease recurrence in patients with new clinical symptoms, abnormal examination findings, rising tumor markers, or indeterminate presacral lesions on conventional imaging. Distinguishing between recurrent disease and posttherapy changes can be challenging on PET/CT. Typically, high-intensity focal uptake persisting several months after surgery raises concern for residual or recurrent disease, while low-intensity, ill-defined uptake is expected and related to inflammatory changes.[36] PET/CT is also effective in detecting recurrence in lymph nodes and distant organs.

However, data is insufficient to definitively establish the role of PET/CT in assessing complete responders. For liver-directed therapies such as selective internal radiation therapy (SIRT), FDG-PET can be helpful, as metabolic response may be greater than morphological response.[37]

Anal Cancer

Anal cancers are rare, accounting for less than 2% of large bowel malignancies. However, their incidence has been rising in recent years, particularly in developed countries.[38] The most common cell type is squamous cell carcinoma (>70%), which is strongly associated with high-risk human papillomavirus (HPV-16) infection.[39] Combined chemoradiotherapy is curative for most patients, but those with recurrence or local failure after chemoradiotherapy may require abdominoperineal resection.

Primary anal squamous cell carcinoma exhibits very high FDG affinity, making PET/CT routinely indicated in the primary staging of anal cancer to rule out lymph nodal and hematogenous metastases (see Image. Anal Squamous Cell Carcinoma on Advanced Nuclear Imaging). Local staging is typically performed with an MRI. Additional roles of PET/CT in anal cancer management include radiotherapy planning, especially with the growing use of intensity-modulated radiation therapy (IMRT), alongside response assessment and recurrence detection.[40]

Gastrointestinal Neuroendocrine Tumors

In metastatic NETs, mixed proliferation profiles may occur at different disease sites, often becoming evident after receptor-targeted therapy. The gallium scan may show stable or regressive disease, while the CT component reveals enlargement in certain non-gallium-avid areas.[41] In such cases, FDG-PET/CT can identify increased uptake in these areas, reflecting an aggressive metabolic profile distinct from gallium-avid disease sites. This information can guide the selection of sites for tissue sampling to establish a histological correlation.

Understanding the biodistribution of 68Ga-DOTA peptides is critical for accurately interpreting pathological uptake. Normal radiotracer uptake is observed in the spleen, adrenal glands, pancreas, pituitary gland, liver, kidneys, thyroid, and salivary glands. Unlike FDG-PET/CT, 68Ga-DOTA peptide imaging shows minimal uptake in background soft tissue and muscles, enhancing the contrast of pathological findings against the background.

Enhancing Healthcare Team Outcomes

The diagnosis and management of gastrointestinal malignancies require an interprofessional approach. Upper and lower gastrointestinal endoscopies are typically the first investigations for suspected gastrointestinal malignancies. Advancements in surgery, chemotherapy, and radiotherapy have contributed to improving the overall survival rates in patients with these cancers. The judicious use of FDG-PET/CT in FDG-avid gastrointestinal malignancies plays a crucial role in reducing disease recurrence by precisely mapping disease distribution, thereby influencing treatment strategies.

Accurate stratification of patients who may benefit from curative resection has become increasingly important, as long-term survival often fails due to undetected distant metastases at the time of surgery. PET/CT's ability to detect distant disease justifies its role in the primary staging of FDG-avid gastrointestinal cancers. However, in cases where the primary tumor lacks FDG avidity, PET/CT is less reliable for assessing distant disease, as the metabolic profile of the metastases is expected to match that of the primary tumor.

PET/CT can help identify poor responders among patients undergoing neoadjuvant therapy, potentially altering management strategies for this group. However, the optimal timing for imaging and standardized response criteria for PET/CT require validation through robust evidence from randomized controlled trials.

The mechanism by which 68Ga-DOTANOC PET/CT targets SSTRs expressed by well-differentiated NETs is similarly utilized in delivering personalized molecular radiotherapy (MRT) to these tumors, a procedure known as peptide receptor radionuclide therapy (PRRT). In PRRT, gallium-68 is replaced with a therapeutic radiotracer, most commonly lutetium-177. Prior to initiating therapy, disease mapping through gallium PET or octreotide imaging determines patient suitability. Effective therapy requires that most tumor sites demonstrate radiotracer uptake above that of the liver. Following therapy, planar imaging confirms adequate radiotherapy distribution within the tumor sites.[42] This palliative therapy is being extensively studied to evaluate survival benefits in selected patient populations, offering a promising option for managing advanced neuroendocrine tumors.