Diagnostic Applications of Nuclear Medicine: Gastric Cancers
Gastric cancer is the fifth most common cancer worldwide. For the purposes of this chapter, gastric cancer will refer to gastric adenocarcinoma. The epidemiology, environmental factors, genetic predisposition, and underlying biomolecular changes of the disease will be reviewed. The staging of gastric cancer as well as the roles of conventional diagnostic imaging and nuclear imaging in this staging will be reviewed.
Finally, the efficacy of these modalities in assessing response to the various treatments described in the chapter and in the long-term surveillance for disease recurrence will be addressed.
KeywordsGastric cancer Gastric adenocarcinoma Conventional diagnostic imaging [18F]FDG-PET/CT 18F-FLT-PET/CT Staging Assessment of therapeutic response Surveillance
American Joint Committee on Cancer
Gene encoding for adenomatous polyposis coli
Gene encoding for tyrosine-protein kinase Met, also known as hepatocyte growth factor receptor (HGFR)
- CA 19–9
Carbohydrate antigen 19–9, a tumor-associated serum marker
- CA 72–4
Tumor-associated glycoprotein 72 (TAG-72), a tumor-associated marker
Gene encoding for cadherin, an adhesion molecule
Carcinoembryonic antigen, a tumor-associated marker
X-ray computed tomography
United States Food and Drug Administration
Familial interstitial gastric cancer
Gastric adenocarcinoma and proximal polyposis of the stomach
Glucose transporter 1
Hereditary diffuse gastric cancer
Human epidermal growth factor receptor 2
Oncogene regulating signaling intracellular cascades
Metastasis status according to the AJCC/UICC TNM staging system
Maximum intensity projection
Magnetic resonance imaging
Lymph node status according to the AJCC/UICC TNM staging system
Tumor protein p53, also known as cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53)
Tumor-suppressor oncogene belonging to the p53 family of transcription factors
PET response criteria in solid tumors
Positron emission tomography
Positron emission tomography/Computed tomography
Response evaluation criteria in solid tumors
Tumor status according to the AJCC/UICC TNM staging system
AJCC staging system based on parameters “T” (tumor status), “N” (lymph node status), and “M” (distant metastasis status)
International Union Against Cancer (Union Internationale Contre le Cancer)
Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer deaths . For the purposes of this chapter, gastric cancer will refer to gastric adenocarcinoma and not the lymphomas, sarcomas, and carcinoid tumors that can also primarily arise in the stomach. Gastric cancer rates are highest in Eastern Asia, Latin America, and Eastern Europe. The American Cancer Society estimates about 26,000 new cases and about 11,000 deaths from the disease in the United States in 2016. Overall, gastric cancer affects older people (average age of diagnosis is 69), men more than women, and the average person has about a 1 in 111 risk of developing the disease in their lifetime .
The worldwide incidence of gastric cancer has declined over the past few decades, and this is thought to be related to several factors including increased use of refrigeration for food and increased use of antibiotics to treat infections.
The incidence of gastric cancer varies throughout different geographic regions and can even vary in incidence among different ethnic groups in the same region. Over 70% of gastric cancers arise in developing countries, and overall there is a higher gastric cancer risk associated with living at higher geographic latitudes .
There are two main histologic types of gastric adenocarcinoma which have different epidemiologies, pathogenesis, morphology, and genetics. The most common is called the “intestinal type” because it has morphology similar to adenocarcinomas arising elsewhere throughout the gastrointestinal tract. The other “diffuse” or infiltrative type is less differentiated than the intestinal type. Intestinal-type gastric cancer is more common in males and older age groups and is likely related to environmental factors, as it is more prevalent in higher-risk areas. The diffuse type affects men and women equally, is more common in younger age groups, and has a worse prognosis . While there has been a worldwide decrease in the incidence of intestinal-type cancers that parallels the overall decrease in gastric cancers, the decrease in the diffuse type has been slower, and it now accounts for approximately 30% of gastric cancers .
Geographic and ethnic differences in the incidence of gastric cancer around the world as well as trends in gastric cancer in certain populations over time suggest that environmental factors play a key role in its development. The fact that the generations born to people migrating from high-risk to low-risk countries subsequently develop a lower incidence of gastric cancer suggests that exposures to these environmental risk factors occur early in life .
Substantial evidence exists that the risk of gastric cancer increases with a high intake of salt and salt-preserved foods such as salted fish and cured meat. The declining incidence of gastric cancer over the past century has at least in part been attributed to the increase in availability of refrigeration, which precludes the use of salting to preserve foods. Refrigeration has also allowed for fresh fruits and vegetables to be more readily available to the public at large, providing an increased source of antioxidants which aid in cancer prevention. Dietary nitrates, obesity, low socioeconomic status, prior gastric surgery, and smoking are also associated with increased risk of gastric cancer.
Helicobacter pylori (H. pylori) has been characterized by the World Health Organization as a Group 1, or definite, carcinogen. If left untreated, H. pylori infection leads to chronic active gastritis, which is a risk factor for both the intestinal and diffuse types of gastric adenocarcinoma. In the development of intestinal-type tumors, it is thought that a cascade of histopathologic events occurs over the course of four or more decades from chronic active gastritis to atrophic gastritis to intestinal metaplasia to dysplasia and finally to invasive carcinoma .
Epstein-Barr virus (EBV) is also detected in 2–16% of gastric adenocarcinomas worldwide, but in contrast to H. pylori infection, its role in carcinogenesis is not understood .
The majority of genetic changes associated with gastric cancer are acquired, some of which are linked to H. pylori infection. Aggregation of gastric cancer within families occurs in approximately 10% of cases. However, true hereditary gastric cancer only accounts for 1–3% of total cases and is comprised of at least three syndromes: hereditary diffuse gastric cancer (HDGC) , gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial interstitial gastric cancer (FIGC) . At this time, only HDGC is understood genetically. HDGC is associated with truncating mutations in the CDH1 gene which codes for the cell adhesion protein E-cadherin. These mutations have a high penetrance and are inherited in an autosomal dominant pattern .
Underlying Biomolecular Changes
With regard to the development of intestinal-type gastric carcinomas, many studies have implicated H. pylori in the multistage carcinogenic cascade from chronic active gastritis to adenocarcinoma. Initiation of this carcinogenesis process has been linked to mutagenic nitric oxides produced by inflammatory cells responding to the H. pylori infection which in turn induce abnormalities in the DNA of gastric epithelial cells . In the various stages of gastric carcinogenesis, studies have described overexpression of oncogenes such as K-ras and c-met, as well as loss of tumor suppressor genes such as p53, p73, and APC .
The human epidermal growth factor receptor 2 gene (HER2) codes for a transmembrane tyrosine kinase receptor protein. Mutations which result in overexpression of HER2 have been linked with gastric cancer. HER2 overexpression has been found in approximately 20–30% of gastric cancers [13, 14].
Unlike the complex and poorly understood molecular pathways leading to the development of intestinal-type gastric cancers, diffuse-type carcinomas have the characteristic molecular abnormality of defective intracellular adhesions. In most cases, these result from loss of expression of the cell adhesion protein E-cadherin, which is coded by the same gene (CDH1) which is mutated in the HDGC syndrome described above .
Staging and Prognostic Classification
The TNM staging system of the American Joint Committee on Cancer (AJCC and the International Union Against Cancer (UICC) is the staging system for gastric cancer most often used in the Western hemisphere and now commonly in Asia as well.
Tumors arising in the proximal 5 cm of the stomach (gastric cardia) that extend to the gastroesophageal junction or esophagus are staged by the AJCC TNM system for esophageal adenocarcinoma. All other gastric cancers with a midpoint lying more than 5 cm distal to the gastroesophageal junction or within the gastric cardia but which do not extend into the gastroesophageal junction or esophagus are staged using the gastric staging system.
Tumor (T) staging is dependent on depth of tumor invasion and not its size. The T1 designation is divided into T1a (invasion of the lamina propria or muscularis mucosae) and T1b (invasion of the submucosa). T2 denotes invasion of the muscularis propria. T3 denotes invasion of the subserosal tissue without invasion of adjacent structures. T4 stage tumors are divided into those that extend beyond the serosa into the peritoneum (T4a) and those that extend into the peritoneum and invade adjacent structures (T4b). The adjacent structures of the stomach which can be involved in local extension include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. Extensive T4b invasion of adjacent structures can make surgical resection of the tumor difficult and thus significantly decreases prognosis.
Nodal (N) staging is based on the number of regional lymph nodes containing metastatic disease (positive nodes). N0 refers to no regional positive nodes, N1 refers to one to two positive nodes, N2 refers to three to six positive nodes, and N3 refers to seven or more positive nodes. The more regional lymph nodes involved with metastatic disease, the worse the prognosis. The groups of lymph nodes which drain the wall of the stomach consist of stations along the greater curvature of the stomach, in the peripancreatic and splenic area, and along the lesser curvature of the stomach. These constitute the array of regional lymph nodes related to primary gastric cancers.
Tumor location, though not a part of the TNM staging, does influence prognosis, with more favorable outcomes for tumors located more distally in the stomach .
Conventional Diagnostic Imaging Staging
Gastric cancers most commonly present clinically with weight loss and persistent abdominal pain. In tumors arising in the proximal stomach, dysphagia is a common presenting symptom. Occult gastrointestinal bleeding with or without iron deficiency anemia is also observed.
The initial workup of patients suspected of having gastric disease is usually an upper gastrointestinal endoscopy, which can best obtain anatomic location and tissue diagnosis of a gastric malignancy. Fluoroscopic barium studies are less often used due to false-negative results in up to 50% of cases and a low sensitivity for detection of early gastric cancers [17, 18]. However, barium studies may be more sensitive in detecting diffuse-type adenocarcinomas, which may present with widespread decreased distensibility of a “leather-flask” appearing stomach, termed linitis plastica, which is infiltrated by tumor. This appearance may be obvious radiographically but may look relatively normal on endoscopy.
Determination of the invasiveness of a gastric cancer is crucial to determine the ease of surgical resectability or if surgery is even feasible. Endoscopic ultrasound (EUS) is usually performed early in the preoperative evaluation after the diagnosis of gastric cancer is made. In a recent systemic review of studies comparing EUS staging with pathology, the sensitivity and specificity for EUS distinguishing T1 from T2 tumors were 85% and 90% respectively, while the sensitivity and specificity for EUS distinguishing T1/2 tumors from T3/4 tumors were 86% and 90%. For metastatic involvement of regional lymph nodes, the sensitivity and specificity were 83% and 67% respectively, findings which neither exclude nor confirm nodal positivity . However, the ability to perform EUS-guided fine needle aspiration of suspicious nodes adds to the accuracy of nodal staging. Due to the limited field of view of the ultrasound transducer, the utility of EUS in detecting metastatic disease is relatively poor.
Diagnostic contrast-enhanced CT scan of the chest, abdomen, and pelvis is usually also performed after diagnosis of a gastric cancer. CT is limited in assessing the depth of invasion, particularly with less invasive tumors (T1–T3). CT has been found to accurately assess T stage in only 50–70% of cases . However, diagnostic CT is helpful in determining the extent of invasion of T4 lesions. A gastric mass that abuts an adjacent organ without evidence of an intervening fat plane is suggestive of parenchymal invasion. Coronal and sagittal reformatted CT images may help identify clear organ invasion that is equivocal when viewed in other imaging planes. On CT, positive nodes tend to be larger than 8–10 mm in short axis, have a round shape, are centrally necrotic, and have marked or heterogeneous enhancement. In addition, CT is helpful in identifying distant M1 nodes. However, CT is limited in that it has a low sensitivity in detecting normal-sized nodal metastases and distinguishing positive nodes from inflammatory lymphadenopathy. That being said, nodal staging is only slightly more accurate with EUS compared to CT .
MRI, though not routinely used in initial staging of gastric cancers, has demonstrated similar T staging accuracy as EUS .
Nuclear Imaging Staging
2-deoxy-2-[18F]fluoro-D-glucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) scans have been shown to be of some value in primary staging of gastric cancers. The [18F]FDG-PET portion of the examination evaluates the metabolic activity of the primary malignancy and sites of metastasis, while the CT portion provides anatomic data.
[18F]FDG-PET/CT is somewhat less sensitive than CT in the detection of regional lymph node metastases due to its relatively poor spatial resolution which makes discrimination of [18F]FDG uptake associated with regional lymph nodes from the nearby primary tumor [18F]FDG uptake difficult . However, accurate characterization of these nodes may ultimately be unimportant in clinical planning, as they would all likely be removed at the time of surgery if the patient is a surgical candidate.
Knowledge of the existence of peritoneal metastases at baseline associated with gastric cancer is important to avoid performing an unnecessary laparotomy. The ability of diagnostic CT to successfully identify peritoneal metastases can be limited by the small size of the tumor deposit(s), the presence of ascites, a paucity of intra-abdominal fat, and inadequate adjacent bowel enhancement. A few studies have reported that [18F]FDG-PET has greater sensitivity than diagnostic CT in the evaluation of peritoneal carcinomatosis . Indicators of peritoneal metastasis without definite associated CT correlates on [18F]FDG-PET/CT include a pattern of diffuse uptake spreading throughout the abdomen and pelvis along the small and large bowel walls and/or discrete foci of [18F]FDG uptake located randomly throughout the peritoneum, anteriorly in the mesentery, or dependently in the pelvis which are unrelated to solid viscera and may correlate with subtle ill-defined soft tissue density. However, the sensitivity of [18F]FDG-PET scan for detection of peritoneal carcinomatosis was only calculated at around 50%  and is likely not significantly higher using [18F]FDG-PET/CT due to the already low sensitivity for detecting small volume peritoneal carcinomatosis on CT alone as described above.
The intensity of [18F]FDG uptake of primary gastric tumors has been found to correlate with HER2 status. Specifically, gastric adenocarcinomas that overexpress HER2 demonstrate relatively decreased [18F]FDG uptake . In this regard, the baseline [18F]FDG-PET may be useful as a noninvasive means of determining HER2 status of gastric cancers and whether anti-HER2 therapies would be useful.
Surgical resection of gastric cancers with regional lymphadenectomy offers the best chance for long-term survival for patients with localized disease. Early, minimally invasive (T1) gastric cancers can be cured by complete resection. The main contraindication for surgery is the presence of distant (M1) metastatic disease. Locally invasive disease (T4b) involving a major vascular structure such as the aorta or encasement and/or occlusion of the hepatic, celiac, or proximal splenic artery is also almost always a contraindication. Distal splenic artery involvement is not an absolute contraindication as the vessel can potentially be resected en bloc with the stomach, spleen, and distal pancreas. Diffuse-type infiltrative adenocarcinoma (linitis plastica) has an extremely poor prognosis and is considered a contraindication to curative resection by many surgeons.
Patients that are not candidates for curative resection may need palliative treatment for control of local symptoms such as nausea, pain, obstruction, perforation, or bleeding from the primary tumor. Nonsurgical palliation in these cases includes stent placement, radiotherapy, and endoscopic laser therapy. In extreme cases which are highly symptomatic, palliative surgery is often performed.
Neoadjuvant chemotherapy or chemoradiotherapy is often recommended for patients with a more invasive primary tumor (T2 or higher) and/or with a high suspicion of regional nodal involvement on baseline imaging studies (N1+). Patients with bulky adenopathy suspicious for regional metastatic involvement which appears affixed to neighboring organs (such as the pancreatic head) may benefit from initial chemotherapy or chemoradiotherapy to shrink these findings and avoid a more complicated surgery (such as a Whipple procedure). The benefit of neoadjuvant therapy in patients determined to be unresectable at baseline but without distant metastatic disease (M0) is uncertain at this time.
Newer treatment options for inoperable gastric cancer include targeted therapies . In 2010, the monoclonal antibody trastuzumab (Herceptin) was approved by the FDA as a first-line treatment of HER2-overexpressing metastatic gastric cancers. Trastuzumab targets the extracellular domain of the HER2 protein and inhibits HER2 downstream cell signaling.
Assessing Efficacy of Treatment
[18F]FDG-PET/CT may offer information on prognosis in patients with gastric cancer treated with preoperative chemotherapy. Patients responding to preoperative chemotherapy per [18F]FDG-PET/CT criteria have shown significantly improved survival compared with nonresponders . Ott et al. demonstrated that a 35% decrease in [18F]FDG uptake on PET scan performed 2 weeks after the start of preoperative chemotherapy predicted a favorable response with an accuracy of 85%. Two-year survival rate for those that responded using this criteria was 90% and was only 25% in nonresponders .
Wahl et al. delineated the [18F]FDG-PET response criteria in solid tumors (PERCIST) which represent a standardized method for evaluation of metabolic tumor response. Under these criteria, progression on [18F]FDG-PET scan is defined as an increase in [18F]FDG uptake (as measured by standardized uptake value) of greater than 20% in a region 1 cm or larger in diameter, while response to treatment is defined as a decrease in uptake of greater than or equal to 30% .
As imaging of gastric cancers with [18F]FDG-PET is somewhat limited because of the relative high number of primary tumors which are not significantly [18F]FDG-avid, early evaluation of response to treatment is difficult . Other PET radiotracers that may complement the information provided by [18F]FDG have been investigated, including 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT). 18F-FLT is phosphorylated to fluorothymidine monophosphate by thymidine kinase I, leading to intracellular trapping. Thymidine kinase I concentration increases almost tenfold during DNA synthesis. Thus, 18F-FLT uptake may accurately reflect cellular proliferation. In one such study, [18F]FDG-PET imaging of pretreatment gastric cancer was compared to 18F-FLT-PET imaging. In contrast to the standard [18F]FDG-PET, FLT-PET was able to definitively detect all locally advanced gastric cancers. Even gastric tumors with histologies that typically demonstrate little to no [18F]FDG uptake at baseline such as mucinous or signet ring adenocarcinomas demonstrated significant 18F-FLT uptake .
Because many gastric cancers are not [18F]FDG-avid on staging PET scans, repeat imaging following adjuvant treatment will likely not provide any additional useful information. Wahl et al. recommended the use of RECIST (Response Evaluation Criteria in Solid Tumors), the more widely used solid tumor response metric based on changes in morphologic size, to evaluate gastric cancers which are not significantly [18F]FDG-avid at baseline . After 18F-FLT-PET showed promise in detection of gastric tumors which are typically not significantly [18F]FDG-avid (as described above), Ott et al.  subsequently evaluated the performance of 18F-FLT-PET versus [18F]FDG-PET with regard to early response and prognosis in locally advanced gastric cancer treated with neoadjuvant chemotherapy. The only imaging parameter found to have a significant prognostic impact on survival was the 18F-FLT uptake measured 2 weeks after the start of therapy . However, caution was recommended in interpreting this result due to the small patient population and poor response rates. Further investigation is warranted at this time, but 18F-FLT, in its role as a biomarker of cellular proliferation, may prove to be a predictive parameter and provide the molecular quantitative assessment of response to treatment that [18F]FDG cannot provide in these particular gastric tumor subtypes.
As most deaths following surgical resection of gastric cancer are a result of distant recurrence, surveillance for recurrent disease is a key part of postsurgical management . Although gastric tumor recurrence following surgery has a poor prognosis, early detection may be helpful in patients with minimal lymphadenopathy or small metastatic lesions who could have a more favorable response to subsequent salvage chemotherapy or radiotherapy. To detect gastric cancer recurrence following surgery, tumor markers (CEA, CA 19–9, CA 72–4) and endoscopy are commonly utilized. However, tumor markers cannot localize or quantify the recurrent disease, while endoscopy cannot detect extraluminal recurrence.
Postoperative surveillance of asymptomatic gastric cancer patients with [18F]FDG-PET/CT has proven useful in detecting recurrent and/or metastatic disease, with a sensitivity of 84% and a specificity of 88% per a recent retrospective study conducted by Lee et al. . Finally, as another recent study has demonstrated that sensitivity for detection of recurrent gastric cancer following surgical resection is greater in patients with initially [18F]FDG-avid gastric cancers , surveillance FDG-PET/CT scans may be best utilized in patients with relatively high [18F]FDG uptake associated with the primary tumor at baseline.
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