Kemal Metin Kir • Elgin Ozkan
Gastric carcinoma is one of the fourth most common cancer worldwide, with 988,000 reported cases in 2008.1 It is seen more commonly in men and in several countries of the Middle East and Asia.1–3 Over the previous few decades, the incidence of gastric cancer has decreased, although it is the second most common cause of cancer death after lung cancer (736,000 deaths worldwide in 2008).1
Gastric cancer is generally asymptomatic in the early stages. It is difficult to diagnose at an early stage unless there is a screening program as in countries such as Japan in which the disease is endemic. When typical symptoms occur, especially in western countries, more than 80% of patients have advanced stage disease with a poor prognosis.4 The cumulative 5-year survival rate of gastric cancer remains under 20%.5–8 Early diagnosis and accurate staging of the disease can improve survival.
Complete resection of a gastric tumor with lymph node dissection is an effective curative treatment for gastric cancer. However, accurate preoperative staging is critical in determining the most suitable therapy and in selecting curable patients for surgery. Currently, computed tomography (CT) is the most common imaging method used for staging. Its sensitivity is limited, however, particularly in detection of lymph node metastasis, small hematogenous metastasis, or peritoneal carcinomatosis.9,10 Endoscopic ultrasonography (EUS), magnetic resonance imaging (MRI), and laparoscopic diagnosis can also be used for staging.11–13 There are some limitations to these methods. Accurate detection of extent of disease and hence identification of potentially curable versus incurable patients by a single conventional imaging method is unlikely.
Currently, radionuclide imaging with positron emission tomography (PET) using 2-[fluorine-18]fluoro-2-deoxy-D-glucose (18F-FDG) has been recognized as a useful diagnostic modality in clinical oncology. In this chapter, the applications of 18F-FDG PET and PET/CT scan as a radionuclide imaging method in the diagnostic workup of gastric carcinomas are reviewed. In addition, the clinical use of bone scintigraphy in gastric carcinomas is reevaluated.
POSITRON EMISSION TOMOGRAPHY
Preoperative Staging of Gastric Cancer
Most studies show that 18F-FDG PET is not an accurate imaging technique for the primary diagnosis of a gastric tumor because of its low sensitivity despite its high specificity.14–21 Primary tumors are not detected by 18F-FDG PET in about 20% of patients with gastric cancer (Fig. 7.1). The sensitivity and specificity for detecting primary tumors range from 21% to 100% and from 78% to 100%, respectively.15,17–19,22–27
In 18F-FDG PET imaging, the low detection rate in primary gastric tumor is a consequence of different histologic subtypes, tumor location, tumor size, depth of tumor invasion, and background activity in the normal gastric wall.
About 95% of all gastric malignancies are adenocarcinoma. The remaining 5% include lymphomas, nonepithelial tumors such as gastrointestinal stromal tumors (leiomyomas or leiomyosarcomas), and others.28 Gastric adenocarcinoma is a malignant epithelial tumor, originating from the glandular epithelium of the gastric mucosa. According to the latest Japanese classification,29 the common malignant epithelial tumors can be subclassified according to histologic components such as tubular adenocarcinoma (TC), papillary adenocarcinoma (PC), poorly differentiated adenocarcinoma (solid and nonsolid type), signet-ring cell carcinoma (SRC), and mucinous adenocarcinoma (MC). Yamada et al.30 showed that cohesive carcinomas (TC, PC, and solid type poorly differentiated adenocarcinoma) are more detectable than noncohesive carcinomas (SRC, MC, and nonsolid type poorly differentiated carcinoma) (65% versus 14%, respectively). This is a consequence of a higher expression of GLUT-1 on the cell membrane of cohesive carcinomas.31,32 Alakus et al.33 reported that the 18F-FDG uptake in gastric cancer depended on GLUT-1 expression. SRC and MC typically have less prominent 18F-FDG uptake because of high mucus content. However, GLUT-1 positive SRC has a higher degree of 18F-FDG uptake than GLUT-1 negative tumors. Furthermore, according to the most commonly used histologic classification, the Lauren classification, which describes the pattern of spread of the primary tumor, there are two major types of gastric tumor: Intestinal or nonintestinal (diffuse). Stahl et al.18 reported that nonintestinal and intestinal tumors contain intracellular or extracellular mucus approximately 81% and 11%, respectively. Increased 18F-FDG uptake is more frequently seen in the intestinal type of gastric cancer than in the nonintestinal type (83% versus 41%). The cause of low 18F-FDG uptake in the nonintestinal type is explained by low GLUT-1 expression on the cell membrane and the abundance of mucus content.
Tumor location also influences the sensitivity of 18F-FDG PET.17,18,24 The detection rates of proximal and distal parts of gastric cancer have been found to be 74% and 41%, respectively.18 This difference is explained by the higher incidence of the intestinal type in the proximal part of stomach.
Tumor size and depth of tumor invasion are additional factors that affect the detection rate of primary gastric cancer. The detection rate for early and advanced primary tumors ranges from 0% to 44% and from 34% to 94%, respectively.17,19,34–37 In a recent study, the sensitivity of 18F-FDG PET/CT for detection of early and advanced gastric cancer was found to be 21% and 74%, respectively.38 Although tumor depth is an important factor for the selection of curable patients for surgery, it cannot be accurately evaluated by PET, because of the limitations of resolution and physiologic 18F-FDG uptake. Therefore, PET imaging is not especially useful in determining the T stage. There is a positive correlation, however, between T stage and PET sensitivity (Fig. 7.2).20,24,38,39
Variable and sometimes intense physiologic 18F-FDG uptake can be seen in the gastric wall because of its high blood flow. In addition, inflammatory mucosa secondary to gastritis is a frequent cause of nonspecific 18F-FDG accumulation. This accumulation may cause false-positive findings or, conversely false-negative findings because of weak uptake in gastric lesions.16,18,24 To prevent the low detection rate of gastric lesions, distension of the stomach by water prior to PET imaging is recommended.40,41 Milk has been used to reduce the physiologic FDG uptake in the gastric wall.42 With gastric wall distension, malignant lesions can be observed more clearly. Some small lesions with only mild uptake can also be detected at an early stage.
Lymph Node Metastasis
The presence of lymph node metastasis in gastric carcinoma has an important role in determining the most suitable therapy and achieving a good prognosis. The usefulness of PET alone, in comparison with CT scan and hybrid PET/CT in the preoperative staging of lymph node status is shown in Table 7.1. In general, PET is less sensitive for the detection of lymph nodes, ranging from 22% to 61%.15,17,19,23–26,43,44 The low sensitivity may reflect the relatively poor spatial resolution of the PET system (Fig. 7.3). Hence, perigastric lymph nodes often cannot be distinguished from a primary tumor and the normal gastric wall. CT has relatively higher sensitivity than PET for the detection of lymph nodes, ranging from 52% to 77% in same series. By contrast, 18F-FDG PET has good specificity for lymph node staging of gastric cancer, ranging from 92% to 100% for PET and 62% to 94% for CT (Fig. 7.4).17,19,23,24,26
FIGURE 7.1. Non-FDG–avid gastric carcinoma. The coronal PET images do not show abnormal FDG uptake in the gastric wall corresponding to the primary carcinoma. Histopathologic examination of surgical specimen reveals signet-ring cell carcinoma.
FIGURE 7.2. FDG-avid gastric carcinoma. The axial CT image shows eccentric wall thickening in the distal part of stomach, and the PET image shows intense FDG accumulation (SUV, 18.7) in this area. Histopathologic examination is consistent with T4a gastric adenocarcinoma.
REPORTED SENSITIVITIES AND SPECIFICITIES OF PET AND/OR PET/CT AND CT IN THE DETECTION OF LYMPH NODE METASTASES IN GASTRIC CANCER
The sensitivity and specificity of 18F-FDG PET variy with lymph node staging status. The mean sensitivity of PET and CT for N1 lymph nodes has been reported as 27.5% and 68%, respectively. In addition, PET has low sensitivity (33% to 46.2%) but high specificity (91% to 100%) for the detection of N2/N3 lymph nodes.23–25,40,43,44 The detection of distant lymph node metastases can be easier by PET because they can be distinguished from primary tumors (Fig. 7.5).25 CT detects both regional and distant metastases, but it cannot help detect cancerous involvement of normal-size nodes and cannot help distinguish between reactive hyperplasia and metastatic enlargement.21 PET seems to be an effective adjunctive method to detect anatomically small but metabolically active foci of metastatic disease.
FIGURE 7.3. Non-FDG–avid lymph node. The axial CT and axial PET images (A) as well as the axial fused PET/CT image (B) do not show FDG-avid lymph nodes. However, after surgery, histopathologic examination reveals multiple metastatic lymph nodes (17/23 in the lesser curvature and 1/18 in the greater curvature).
FIGURE 7.4. FDG-avid lymph node. The axial CT image shows diffuse wall thickening in the greater curvature of the stomach and enlarged lymph node. Intense FDG uptake is also detected in these regions (SUV, 31.5 in the stomach; SUV, 17.8 in the enlarged lymph node). However, no other lymph nodes are detected by PET.
Some authors have concluded that higher 18F-FDG uptake in primary gastric tumor is associated with lymph node metastasis.19,24,45 High 18F-FDG uptake of the primary tumor is associated with larger tumor size and deeper tissue invasion.45 Consequently, hypermetabolic primary tumor and especially hypermetabolic local lymph nodes are related to incurable surgery.46 However, regional lymph node metastases from the non–18F-FDG-avid gastric carcinomas are less detectable by PET/CT.15
FIGURE 7.5. Distant metastatic lymph nodes. The coronal fused PET/CT image shows high FDG uptake in the stomach corresponding to the primary carcinoma (SUV, 30.6). The image reveals also widespread FDG accumulation in the left apical, mediastinal, and abdominal lymph nodes (SUV, 24.8) consistent with the distant lymph node metastases.
In a recent study, a statistically significant difference was found in the detection of locoregional lymph node metastasis by PET/CT alone (43.5%), EUS alone (52.4%), and the combined use of both (67.7%).47 The hybrid imaging modality of PET/CT has low sensitivity (30.3%) for N staging because of the still limited spatial resolution.38 Nonenhanced CT images of integrated PET/CT are not sufficient to resolve this issue. EUS is primarily used for the evaluation of lymph nodes around the lesions. However, it has low accuracy and sensitivity in the N staging of gastric cancer because of approximately half of the metastatic lymph nodes having a smaller size than the criteria for metastatic lymph nodes.48,49 In the current staging system, the number of pathologic nodes is important.50 However, accurate counting of pathologic lymph nodes cannot be readily made by EUS. The combined use of modalities would seem to be more effective for N staging in gastric cancer.
Distant metastases from gastric cancer include solid organs, the peritoneum, and distant lymph nodes. Solid organ metastases are rare at the time of initial diagnosis. The main pathway for solid organ metastases is hematogenous spread, and the most common sites include the liver, lungs, adrenal glands, and skeleton (Fig. 7.6). The role of 18F-FDG PET/CT to detect distant metastases is not clear, and the overall sensitivity, specificity, and accuracy ranges from 35% to 71%, 74% to 99%, and 73% to 96%, respectively.51–54 Yoshioka et al.51 found a sensitivity and specificity of 85% and 74% for the detection of liver metastasis; 67% and 88% for lung metastasis; 24% and 76% for ascites; 4% and 100% for pleural carcinomatosis; and 30% and 82% for bone metastasis, respectively.
Peritoneal carcinomatosis is one of the most common types of spread. It has a poor prognosis. The presence of peritoneal metastasis is an important factor in the decision to change treatment. About 25% of patients with locally advanced tumors on EUS have occult peritoneal disease that may only be identified with laparoscopy.55 PET is of little value in the detection of peritoneal carcinomatosis, with low sensitivity (range: 9% to 50%) and relatively high specificity (range: 63% to 99%). The cause of low sensitivity can be explained by extensive fibrosis with a few malignant cells in the disseminated lesion, and the small size of peritoneal lesions may be another reason for the low detection rate.23 Two patterns of 18F-FDG uptake indicative of peritoneal dissemination are (a) diffuse uptake spreading uniformly throughout the abdomen and pelvis and (b) discrete focal uptake located within the abdomen or pelvis and outside expected nodal stations or solid viscera.21 Although 18F-FDG PET has lower sensitivity than CT to detect peritoneal metastases (35% versus 77%), the specificity of PET is higher than that of CT (99% versus 92%).52 CT has many false-positive findings. Yang et al.54 reported the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT (88%, 74%, 93%, 81%, and 91%), which are significantly higher than that of CT (78%, 39%, 94%, 72%, and 79%). A recent systematic review showed that ultrasound, EUS, CT, and 18F-FDG PET do not have sufficient sensitivity and specificity to evaluate liver and peritoneal metastases of gastric cancer.56 The role of laparoscopy, PET/CT, MRI, and new PET tracers (such as 18F-FLT) to detect liver and peritoneal metastases of gastric cancer needs to be studied.
FIGURE 7.6. Distant organ metastasis. The coronal PET images show pathologic FDG uptake in the stomach and local lymph nodes consistent with local disease. The PET examination reveals also liver metastases corresponding to the extent of disease.
Evaluation of Tumor Recurrence
Complete resection of the tumor with lymph node dissection is the only curative treatment for gastric cancer, and early stage gastric cancer can be cured by surgical resection. Even after complete resection of the tumor, disease recurrence occurs in 40% to 60% of patients with advanced disease,57,58 and prognosis is very poor. In fact, despite successful surgery, the 5-year survival rate is about 35%, and even with adjuvant chemoradiotherapy, the survival rate is 40%.59 The most important factors for prediction of recurrence are the stage of gastric cancer, depth of tumor invasion, and extent of lymph node metastasis.60–63
The most common sites of recurrence include the gastric bed, peritoneal dissemination, retroperitoneal lymph nodes, and hematogenous metastases (such as liver) (Fig. 7.7).64 Various methods, such as tumor markers, endoscopy, and imaging modalities (CT, PET, and ultrasound) have been used, but each has limitations. For example, tumor markers are used to detect subclinical recurrence, but they cannot localize the recurrence site, and endoscopy cannot detect extraluminal recurrence.65 CT is the most frequently used conventional imaging method to detect recurrent disease in gastric carcinoma. It has high sensitivity for solid organ metastases such as the liver but low diagnostic accuracy for peritoneal or lymphatic metastases. In particular, postoperative CT scan has limited value in differentiating postsurgical changes from local tumor recurrence. In a recent study, Shim et al.66 evaluated the clinical role of laparoscopy as an alternative to CT and PET scans in the detection of gastric cancer recurrence in 12 patients. The researchers reported that laparoscopy might be useful to detect recurrence, particularly in patients with advanced (T3 or T4) gastric cancer. Despite a severe lack of evidence for recurrence based on CT or PET, peritoneal dissemination and malignant ascites can be confirmed by laparoscopy.
FIGURE 7.7. Recurrent disease in a patient who underwent surgery for gastric carcinoma. The axial fused PET/CT images show an area of intense FDG uptake (SUV, 11.2) on the left para-aortic region consistent with recurrence.
PET, a molecular imaging modality, provides functional information about the tumor, and PET/CT adds anatomical information to the functional evaluation. There have been some studies about the role of 18F-FDG PET and PET/CT in the evaluation of gastric cancer recurrence after surgery. In these studies, the sensitivity and specificity of PET or PET/CT to detect recurrent disease ranges from 54% to 96% and 69% to 100%, respectively.41,67–74 In a recent meta-analysis (9 studies with 526 patients), overall sensitivity and specificity of 18F-FDG PET was found to be 78% and 82%, respectively.64 In studies in which both 18F-FDG PET and other diagnostic tests were compared, the sensitivity and specificity of 18F-FDG PET, contrast CT, and combined PET and CT were 72% and 84% for PET, 74% and 85% for CT, 75% and 85% for combined PET and CT, respectively.64 PET has good but limited diagnostic accuracy in the overall evaluation of recurrent gastric cancer. Kim et al.67 compared the value of 18F-FDG PET/CT and contrast-enhanced CT in 28 patients with confirmed recurrent gastric cancer. The sensitivity was 54% and 64%, the specificity was 85% and 87%, and accuracy was 78% and 82%, for PET/CT and contrast CT, respectively. In this study, PET/CT was as accurate as contrast CT in the detection of gastric cancer, except for the detection of peritoneal dissemination. However, PET/CT detected secondary malignancies. Sim et al.69 also reported similar sensitivity and specificity for PET/CT and contrast CT, with the exception of peritoneal seeding. Bilici et al.68evaluated the clinical role of PET/CT and diagnostic CT in 24 patients with confirmed recurrent gastric cancer and assessed the impact of PET/CT results on therapy management. The overall sensitivity was 96% and 63% and the overall specificity was 100% and 10%, for PET/CT and CT, respectively. These results showed that PET/CT was a highly effective modality for the detection of recurrent gastric cancer compared to diagnostic CT. In addition, in 18 (52.9%) cases, the management of the patient’s treatment was changed because of the 18F-FDG PET/CT results.
18F-FDG PET also provides additional prognostic information about recurrent gastric cancer. De Potter et al.74 found a statistically significant difference for survival between 18F-FDG PET-negative and 18F-FDG PET-positive cases (18.5 versus 6.9 months). In a recent study, 18F-FDG uptake was found to be a significant prognostic factor for recurrent disease, especially TC and poorly differentiated adenocarcinoma. The disease-free survival rate was 95% for the 18F-FDG-negative group and 74% for the 18F-FDG–positive group (p < 0.0001).75
Although it has some limitations, 18F-FDG PET is a useful imaging method for the detection of recurrent gastric cancer despite low 18F-FDG uptake in some histologic subtypes (MC and SRC); background activity in normal gastrointestinal system; and limited spatial resolution for small lesions, especially for peritoneal seeding.
Evaluation of Tumor Response
As stated, the prognosis of gastric cancer is poor and cancer recurrence rates are high. To improve the outcome, (neo)adjuvant chemotherapy regimens have been used.76–78 However, only about 30% to 40% of gastric cancer patients respond to chemotherapy regimens.79 To avoid unnecessary toxic treatment, an early distinction between potential responders and nonresponders is important. CT is a commonly used imaging modality to monitor tumor response. CT-based tumor response depends on tumor size reduction (Response Evaluation Criteria in Solid Tumors [RECIST] criteria). This criterion, however, is a relatively late sign of response. A metabolic response could be detected earlier by 18F-FDG PET and has been used as an early sign of response in other tumors and has potential in evaluation of the response to chemotherapy in gastric cancer. Ott et al.79 showed that a 35% reduction in 18F-FDG uptake between prechemotherapy and the PET scan taken 2 weeks after the initiation of therapy predicts the response to therapy with an 85% accuracy. Two other studies showed similar results.80,81
The use of PET in monitoring therapy response also provides a prognostic indicator. Ott et al.79 reported significantly different survival rates between the responders’ group and the nonresponders’ group (90% versus 40%). In another study, Ott et al.82 determined that survival was similar for the nonavid group and the nonresponding group and differed significantly from the responding group. In a recent study, Park et al.83 found that the maximal standardized uptake value (SUV) of the stomach is an independent predictor for progression-free survival and overall survival. In the same study, the low stomach (SUVmax) group had better disease control than the high stomach (SUVmax) group. The metabolic activity of the primary tumor evaluated by pretreatment FDG-PET can be used as the prognostic factor.83
FIGURE 7.8. Bone metastasis. A: The sagittal PET, sagittal fused PET/CT, and MIP images show multiple abnormal FDG uptake in the vertebral column and pelvic bones. B: The bone scintigraphy reveals also widespread bone metastases on the skeleton.
Future Perspectives with PET
18F-FDG PET/CT fusion images give better results in the evaluation of gastric cancer than either modality separately. Furthermore, 18F-FDG is not a perfect tracer for these assessments. 18F-FLT (3-deoxy-3–18F-fluorothymidine) has been also used as PET tracer. It is a pyrimidine analog and accumulates in proliferating tissue and malignant tumors.84 There are reports that it is more sensitive than 18F-FDG PET, especially in tumors with low 18F-FDG –uptake.85,86 It may also be useful to monitor response to therapy.87 In a recent study, 18F-FLT PET imaging has been used to assess new therapeutic agents such as dual PI3K/mTOR inhibitors.88 Further investigations are needed to evaluate the value of 18F-FLT PET in gastric cancer.
Microsatellite instability (MSI) phenotype is a marker of mutations caused by a defect in the mismatch repair (MMR) system. The MMR system is responsible for the correction of mismatches that occur during DNA replication. In gastric carcinoma, MSI phenotype has been found in approximately 15% to 25% of cases.89 The MSI phenotype of gastric cancer has an intestinal type tumor and is located in the antrum. This tumor type is seen more frequently in older women and has demonstrated good prognosis with limited lymph node metastasis.89 Very recently, a study has been published about the significance of MSI in detecting gastric carcinomas using 18F-FDG PET/CT.90 Additional studies are needed.
The incidence of bone metastasis from gastric carcinoma is very rare (range: 0.9% to 13.4%).91–95 It is usually associated with hematologic complications and has a very poor prognosis.96 An increased serum alkaline phosphatase (ALP) level is an indicator of bone metastases.95 In patients who have been diagnosed with gastric cancer, if the ALP level is high, bone metastasis need to be excluded (Fig. 7.8).
Bone scintigraphy is the most commonly used imaging modality to detect bone metastasis. It has high sensitivity, and thus it is considered the most useful screening test. Furthermore, bone scintigraphy can detect bone metastasis approximately 3 months earlier than radiography.97,98 The limitation, however, is low specificity. Therefore, a solitary hot focus needs to be evaluated to exclude trauma and/or other medical problems. Sites of bone metastases include vertebrae (66%), costa (59%), pelvic bone (43%), femur (30%), and scapula and clavicle (17%).99 When a solitary lesion is detected by bone scintigraphy, additional procedures such as 18F-FDG PET/CT, MRI, and bone marrow sampling are necessary. In conclusion, in patients with gastric cancer, bone scintigraphy is a convenient and highly useful method with high specificity to detect bone metastases.95
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