J Gastrointest Surg (2012) 16:1847–1853 DOI 10.1007/s11605-012-1941-3

ORIGINAL ARTICLE

Clinical Significance of Incidental Colonic 18F-FDG Uptake on PET/CT Images in Patients with Gastric Adenocarcinoma Jung Ho Shim & Joo Hyun O & Seong Il Oh & Han Mo Yoo & Hae Myung Jeon & Cho Hyun Park & Sung Hoon Kim & Kyo Young Song

Received: 13 May 2012 / Accepted: 15 June 2012 / Published online: 30 June 2012 # 2012 The Society for Surgery of the Alimentary Tract

Abstract Background and Objectives We assessed the ability of positron emission tomography–computed tomography (PET/CT) to detect synchronous colonic pathology and determined the significance of 18F-fluorodeoxyglucose (18F-FDG) activity in the colon of gastric cancer patients. Methods A total of 239 gastric cancer patients who underwent PET/CT and colonoscopy preoperatively were included. FDG uptake patterns on PET/CT were classified as (1) group A, focal; (2) group B, diffuse; and (3) group C, no uptake. The PET/ CT findings were compared with the results of concurrent colonoscopy. Results In group A, a total of 123 polyps of >0 mm were observed. Of these, nine polyps were colonic adenocarcinomas and six were high-grade dysplasia. The incidence of colonic adenocarcinomas was significantly higher in group A than in the other two groups (p00.037). There was a significant correlation between SUVmax values and incidence of colonic polyps of >10 mm (r00.471, p00.04). The distribution pattern of SUVmax in polyps with adenoma (>10 mm) was less homogenous than in polyps (>10 mm) with adenocarcinoma. Conclusions The focal colonic FDG uptake in PET/CT requires colonoscopic confirmation. The suspicion of colonic malignancy increased in the presence of polyps >10 mm that showed a positive correlation with the SUVmax. Keywords 18F-FDG uptake . PET/CT . Gastric cancer . Colon uptake . Colonoscopy

Introduction Gastric cancer is the fourth most common cancer worldwide, accounting for >800,000 new cases per year, and it is still the second most common cause of cancer-related deaths.1 Multidisciplinary therapy including surgery, chemotherapy, and J. H. Shim : S. I. Oh : H. M. Yoo : H. M. Jeon : C. H. Park : K. Y. Song (*) Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong( Seocho-gu Seoul 137-701, South Korea e-mail: [email protected] J. H. O : S. H. Kim Department of Radiology, The Catholic University of Korea, Seoul, South Korea

radiation therapy is routinely applied to treat gastric cancer patients and enhance their survival.2,3 The incidence of colon cancer as a second primary malignancy in patients with gastric cancer is higher than that in normal populations. Several investigators advocate the use of colonoscopy during staging workup of gastric cancer; however, there is no consensus regarding the need for routine colonoscopy for the evaluation of second primary in gastric cancer patients. Accurate preoperative staging is critical to determine the most adequate therapeutic modality, and computed tomography (CT) scan is the standard imaging modality for preoperative staging. However, CT has been less than satisfactory in characterizing regional or distant lymph nodes and peritoneal metastases.4,5 A positron emission tomography (PET) with 18 F-fluorodeoxyglucose (18F-FDG) has been implemented successfully for the evaluation of malignant tumors. At staging, one of the major advantages of 18F-FDG-PET is the detection of unsuspected metastases, which may determine changes in the therapeutic plan for patients with various malignancies. However, FDG-PET has rarely been used as a complementary diagnostic modality for gastric cancer because

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of its limited resolution as compared to CT; moreover, its sensitivity and accuracy have been a source of controversy in gastric cancer staging.6–8 Recently, FDG-PET has been integrated with CT to improve anatomic localization, and PET/CT has been reported to offer several potential advantages over the use of FDG-PET or CT alone. Therefore, PET/ CT has been used as a preoperative staging method in gastric cancer patients.9–11 The diagnosis of cancer is based on the ability of 18F-FDGPET to detect foci of tumors with increased glycolysis.11 However, although increased 18F-FDG uptake is observed in malignant lesions, it is also observed in benign, inflammatory, or granulomatous processes and in sites of normal, physiologic tracer biodistribution. 18F-FDG is excreted, in part, through the gastrointestinal tract (GIT), with uptake in the distal esophagus, stomach, small intestine, and large intestine representing normal patterns of tracer distribution.12,13 Although hybrid PET/CT has improved the landmarks for better characterization of increased 18F-FDG uptake, gastrointestinal uptake, especially colonic uptake patterns, can vary from mild to moderate to occasionally intense. The mechanism of FDG uptake in the colon is unclear, and the factors that influence the level and pattern of uptake are unknown. Moreover, interpreting such uptake patterns is often a diagnostic challenge. Therefore, the present study evaluated the frequency of incidental focal sites of 18F-FDG uptake in the colon and assessed the clinical significance of these unexpected findings.

Material and Methods Patients Between January 2009 and July 2010, a total of 370 patients diagnosed with primary gastric cancer underwent curative resection at our institution. Of these, 239 patients who had undergone preoperative PET/CT and colonoscopy were enrolled. Medical records of these patients were retrospectively reviewed for demographic characteristics and histopathological data of the primary cancer lesion. Colonoscopy was performed within 90 days after performing PET/CT, and routine preoperative colonoscopy was recommended for patients older than 65 years or patients who had undergone colonoscopy within 5 years. The PET/CT reports were reviewed to identify those that were read as having incidental FDG activity in the colon. Patients with a previous history of malignancy or disease involving the colon including prior colon resection were excluded from the analysis. Patients unable to undergo a complete colonoscopy to the cecum for any reason were also excluded. Two radiologists were assigned to assess the pattern and degree of colonic uptake without knowledge of the colonoscopic or histological findings of the patients. The patterns

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of FDG uptake on nonattenuation-corrected abdominal images were defined specifically as follows (Fig. 1): group A, focal uptake: single foci of intense uptake in the colon and focal intense uptake were measured at the most intense colonic segment within the whole colon; group B, diffuse uptake: whole colonic uptake greater than hepatic uptake with no discernable focal or nodular intense uptake within the colon; and group C, no uptake: no discernable uptake with less background hepatic uptake or uptake similar to that in the liver. The study was approved by the Institutional Review Board of our hospital. PET/CT Imaging Protocol All scans were obtained using an integrated PET/CT inline scanner (Discovery ST-8, GE Healthcare, Waukesha, WI, USA). The full-width half maximum of the scanner was 6 mm. Patients fasted for ≥6 h before undergoing PET/CT. Blood glucose was measured 1 h before 18F-FDG injection; a blood glucose level of ≥150 mg/dl resulted in deferral of PET/ CT. Approximately 1 h before PET/CT, each patient received an injection of 12–20 mCi (440–740 MBq) of 18F-FDG. Noncontrast-enhanced CT was performed from the base of the skull to the upper thighs for attenuation correction and diagnosis (150 mA s; 120 kVp; table speed, 13.5 mm/rotation; beam collimation, 8×12.5 mm). Axial CT images were reconstructed using a soft reconstruction kernel with a 3.75mm slice thickness and a 3.27-mm slice thickness to match the PET images. PET was conducted in the two- or threedimensional mode for 3 min per bed position, and images were reconstructed using standard vendor-provided reconstruction algorithms that incorporated ordered subset expectation maximization. Attenuation correction of PET images was performed using attenuation data from CT. The manufacturer's software was used to correct emission data for scatter, random events, and dead time losses. The fullwidth half maximum on the scanner was 6 mm. PET/CT parameters were uniform for all preoperative studies of gastric cancer patients at our institution. Statistical Analysis Statistical analysis was performed using Fischer's exact test. The primary aim of this statistical analysis was to determine whether there is a special 18F-FDG uptake pattern that may predict the presence of an underlying relevant pathology. For this purpose, the outcome of focally increased 18F-FDG uptake (group A) was compared with that of segmentally or diffusely increased 18F-FDG uptake patterns (groups B and C). p<0.05 was considered statistically significant. We defined a truepositive PET/CT finding as a focal uptake (group A) and a corresponding lesion on colonoscopy situated in the same segment. A false-positive finding was defined as a focal

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Fig. 1 Colonic uptake patterns. a focal, b diffuse, c none, and d colonoscopic findings of patient with image a

uptake pattern with no corresponding lesion on colonoscopy. A false-negative finding was defined as diffuse or no 18F-FDG uptake patterns (groups B and C) with relevant colonoscopic finding.

Results Patient Demographics The patients' ages, gender distribution, preoperative levels of tumor markers (CEA, CA 19-9), and pathological characteristics of primary gastric lesion are shown in Table 1. Thirty-nine patients were classified under group A, 148 patients under group B, and 52 patients under group C. No significant differences in gender, histological grades, Lauren's classification, or pathological stages were observed. The mean age of patients in group A was 64 years (range, 37–84 years), which was higher than that of the other two groups (p00.044). The mean SUV in the primary gastric lesion was not different between the groups (p00.450).

Colonoscopic Findings and Pathology Table 2 shows the histological characteristics of colonic polyps in each group. A total of 473 polyps of >0 mm in size were detected during the perioperative colonoscopic evaluation. In group A, 123 polyps of >0 mm were detected. Of these, 9 were diagnosed as colonic adenocarcinomas, 38 were tubular adenoma with low-grade dysplasia, 30 were tubular adenoma with moderate dysplasia, and 6 were highgrade dysplasia. In group B, a total of 272 polyps were detected. Of these, 4 were diagnosed as colonic adenocarcinomas, 121 were tubular adenoma with low-grade dysplasia, and 40 were tubular adenoma with moderate dysplasia. The incidence of colonic adenocarcinomas was significantly higher in group A than in the other two groups (p00.037). The number of colonic adenomas in each group with a size >10 mm is shown in Table 3. In group A, 29 (22.6 %) polyps with a size >10 mm were detected; of these, nine were colonic adenocarcinomas, six were tubular adenoma with low-grade dysplasia, and six were tubular adenoma with moderate grade dysplasia. In group B, 29 (10.6 %) polyps were >10 mm in size, and 2 polyps were

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Table 1 Clinical characteristics of patients Group A (n039) Age Sex (male/female) Stage (6th AJCC) IA IB II IIIA IIIB IV Histologic type Well Moderate Poorly Signet ring cell Others Lauren's classification Intestinal Diffuse Mixed Unclassified Primary gastric cancer SUV uptake value Preoperative CEA CA 19-9

Table 3 Incidence of colonic adenoma (>10 mm) in each group

Group B (n0148)

Group C (n052)

p value

64 (37–84) 61 (32–80) 58 (34–79) 25/14 112/36 34/18 15 5 8 4 1 6

69 26 19 15 8 11

0.044 0.197 0.316

28 8 3 6 4 3 0.271

5 20 7

24 48 56

4 18 18

7 0

18 2

9 3

Group B (n0148)

Group C (n052)

29 (15) 9 (7)

29 (17) 2 (1)

5 (3) 0

6 (2) 6 (3) 3 (2)

14 (11) 4 (3) 4 (2)

1 (1) 1 (1) 0 (0)

0 (0) 0 (0) 2 (1)

0 (0) 0 (0) 0 (0)

0 (0) 0 (0) 1 (0)

Numbers within parenthesis are patients' numbers with colonic polyps (size > 10 mm). There was one patient with two inflammatory polyps (size > 10 mm) in group C

0.271 18 11 6 4

70 43 29 6

24 15 11 2

4.97

6.45

4.22

0.450

6.79

2.16

3.07

0.091

38.54

21.03

32.17

0.454

adenocarcinoma, 14 were tubular adenoma with low-grade dysplasia, and 4 were high-grade dysplasia. In group C, five polyps (5/78; 6.4 %) were >10 mm in size, but none of these polyps were adenocarcinomas. Table 2 Incidence of high risk adenoma or adenocarcinoma in each group (p0NS)

Total number of polyps Colonic adenocarcinoma Tubular adenoma Low-grade dysplasia Moderate-grade dysplasia High-grade dysplasia Villous adenoma Low-grade dysplasia Moderate-grade dysplasia High-grade dysplasia

Number of polyps >10 mm Colonic adenocarcinoma Tubular adenoma Low-grade dysplasia Moderate-grade dysplasia High-grade dysplasia Villous adenoma Low-grade dysplasia Moderate-grade dysplasia High-grade dysplasia

Group A (n039)

Group A (n039)

Group B (n0148)

Group C (n052)

123 9

272 4

78 0

38 30 6

121 40 4

29 12 0

2 0 3

1 0 0

2 0 1

SUV and Colonoscopic Findings A true-positive lesion was defined as a lesion that was located at a matched colonic focus of FDG uptake. In group A, 49 polyps with size >0 mm and 23 polyps with size >10 mm were detected in 25 patients (Table 4). There was a significant correlation between the SUVmax value and colon polyps with size >0 mm (r 00.371, p 00.007) (Fig. 2). The SUVmax value and colon polyps with size >10 mm were also significantly correlated (r00.471, p0 0.04) (Fig. 3). The distribution pattern of SUVmax in polyps with adenoma (>10 mm) was less homogenous than in polyps (>10 mm) with adenocarcinoma. Meanwhile, 14 patients from group A showed colonic focal FDG uptake, but the colonic pathologies were not located at the matched lesion based on PET/CT. The sensitivity and specificity of FDG uptake from the PET/CT were 14.8 and 80.2 %, respectively. Moreover, the PPV and NPV were 64.1 and 28.5 %, respectively. The anatomic distributions and values of SUV focal uptake are given in Fig. 4. Table 4 Sensitivity, specificity, positive predictive value, and negative predictive value of 18F-FDG-PET based on the colonic SUV uptake patterns Colonic pathology (+)

Colonic pathology (−)

Group A (n039) True-positive rates—25 False-positive rates—14 (64.1 %) (35.9 %) Groups B and C False-negative rates—143 True-negative rates—57 (n0200) (71.5 %) (28.5 %) Sensitivity 0 14.8 %, Specificity 0 80.2 %, PPV064.1 % NPV028.5 % PPV positive predictive value, NPV negative predictive value

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Fig. 2 Significant correlation was observed between the SUVmax value and the size of colon cancers and adenomas with size >0 mm (r00.371, p00.007)

Discussion The standard imaging tools for gastric cancer staging are CT scan, endoscopic ultrasonography, and occasionally, bone scan. Of these, CT scan is the most widely used modality for determining the depth of invasion and detecting lymph node and distant metastasis. However, sensitivity and specificity of this imaging modality for the detection of lymph node metastases or early distant metastases are limited. FDG-PET is a noninvasive imaging technique based on the altered glucose metabolism of cells. This imaging tool has been shown to be superior to CT scan in the detection of several malignancies, such as evaluation of mediastinal lymph nodes in lung cancer patients or detection of lymph node metastasis in esophageal cancer. The recent integration of CT with PET has enhanced the ability to localize foci of 18F-

Fig. 3 Significant correlation was observed between the SUVmax value and the size of colon cancers and adenomas, the size of which was more than 10 mm in group A (r00.471, p00.04)

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FDG avidity. These results have stimulated investigators to conduct studies investigating the role of FDG-PET in gastric cancer staging. Although the accuracy of detecting primary lesion or lymph node status is not superior to that of other modalities, FDG-PET has the advantage of detecting unexpected distant metastasis or second primary lesions. The detection rate of unexpected additional primary lesions with PET/CT is variable, and one common site for such incidental activity is the colon. Because 18F-FDG is excreted, in part, through the GIT, its detection in the colon could represent normal patterns of tracer distribution. Physiological 18F-FDG uptake of variable intensity and localization patterns within the GIT has been described previously. Focal tracer uptake is frequently seen at the gastroesophageal junction, while moderate uptake is seen in the stomach, low-intensity uptake is detected in the small bowel, and diffuse or focal uptake in the colon.12 Incidental colonic foci of 18F-FDG uptake on PET/CT have been reported in 1.3–2.7 % of patients.14–16 Focal colonic 18F-FDG uptake has a high (70–80 %) probability of showing corresponding abnormal histopathological findings.17,18 The factors that influence the level and pattern of uptake of FDG in the colon are still unclear. High diffuse uptake hinders the detection of lesions, while intense focal uptake may result in false positives in the interpretation of malignancy by using PET. Kim et al. reported that intense colonic 18 F-FDG uptake with a focal pattern was observed more frequently in patients with constipation.19 This means that colonic contraction in association with constipation might result in high FDG uptake. To examine the relationship between colonic FDG uptake and pathological findings, we evaluated the pattern and degree of incidental colonic FDG uptake in gastric cancer patients without a known history of colorectal carcinoma who underwent both FDGPET and colonoscopy. In our study, the incidence of colonic adenocarcinoma and adenoma of >10 mm size was significantly higher in the focal uptake group than in the diffuse uptake or no uptake groups. In the focal uptake group, a total of 29 (22.6 %) polyps of >10 mm were detected; of these, 9 were colonic adenocarcinomas. In contrast, there were no polyps with adenocarcinoma in group C, and two polyps with adenocarcinoma were detected in group B. In addition, there was positive correlation between the SUVmax and colon polyps with a size of >0 or >10 mm (p00.007 and p00.04, respectively). The distribution pattern of SUVmax was less homogenous in patients with adenoma (>10 mm) than in patients with adenocarcinoma (>10 mm). However, the sensitivity and specificity of FDG uptake from the PET/CT were only 14.8 and 80.2 %, respectively. In this study, 29 and 5 polyps of >10 mm size were detected in groups B and C, respectively. This result is similar to those reported previously.20

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Fig. 4 Focal uptake patterns and distribution of SUVmax values in colon (red colon adenocarcinoma, green colon adenoma)

The anatomic distribution of focal colonic SUVmax, as illustrated in Fig. 4, shows that of the nine polyps of >10 mm size that were diagnosed as adenocarcinoma, five were in the sigmoid colon, two in the rectum, and the remaining were in the ascending colon. PET imaging is a well-accepted functional technique clinically used for cancer staging and surveillance. It relies on the uptake of the radiolabeled glucose analogue (18F-FDG) by metabolically active cells. However, there is a wide range of nonmalignant conditions characterized by an increased 18F-FDG uptake in the colon. Since the first report of an increased 18F-FDG uptake in colonic adenoma by Yasuda et al,. 21 several retrospective and prospective studies have been carried out in order to evaluate the performance of 18F-FDG-PET for detecting colorectal adenomas.22–24 Although a correlation with SUVmax on PET has not been demonstrated consistently, dysplasia grade of colon adenoma has been reported to correlate with likelihood of detection by PET.14,16 Such an association would be consistent with reported higher mitotic activity in colonic mucosa as the tissue progresses from normal to low-grade dysplasia and then to high-grade dysplasia.25

The one thing we must consider in this study is the cost effectiveness of PET/CT. In Korea, the Korean National Health Service system had launched a national campaign to conquer the common cancers since 1996. If a patient was diagnosed with cancer, including gastric, colorectal, breast, cervix, hepatobiliary, or lung cancer, then the patient could be subsidized by the Korean National Health Insurance (KNHI). Patients only have to pay 5 % of the total expenses of diagnosis and treatment for cancers. The cost of PET/CT in Korea is $850 (USD) without KNHI coverage, but for gastric cancer patients, the cost is down to $42 (USD). The KNHI accepted preoperative PET/CT as a standard staging modality. Considering that PET/CT cost $1,500 (USD) in the US, the usage of PET/CT as a diagnostic modality tends to have cost effectiveness.26 Therefore, there was no unnecessary PET/CT in this study population. In conclusion, the precise localization and characterization of focal FDG uptake in the colon, as determined by PET/CT, requires confirmation by colonoscopy and pathological diagnosis. Although no cutoff point of the SUVmax was applied, the suspicion of colonic malignancy increased in the presence of polyps of >10 mm size that showed a positive correlation with the SUVmax.

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