The Role of 18F-FDG PET/CT in the Evaluation of Peritoneal Thickening of Undetermined Origin

Abstract The aim of this study was to assess the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for the differentiation of peritoneal thickening of undetermined origin. This retrospective study included 103 patients (44 men and 59 women, age 59.2 ± 14.8 years) who had undergone 18F-FDG PET/CT for the evaluation of peritoneal thickening of undetermined origin. All 18F-FDG PET/CT images were visually interpreted, and the maximal standardized uptake values (SUVmax) were measured. We compared the role of 18F-FDGPET/CT with that of CT alone in detecting peritoneal thickening of undetermined origin. We also compared the differences between malignant and tuberculous peritoneal thickening in PET/CT parameters and clinical characteristics. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy in detecting the primary cause of the peritoneal thickening were 76.2%, 78.9%, 94.1%, 42.9%, and 81.2%, respectively, for 18F-FDG PET/CT, and 58.3%, 84.2%, 94.2%, 31.4%, and 63.1%, respectively, for CT imaging. Malignant peritoneal thickening had significantly higher SUVmax than nontuberculous benign peritoneal thickening. However, tuberculous peritoneal thickening also had a high SUVmax. There were some factors that were significantly different between patients with tuberculous peritoneal thickening and those with malignant peritoneal thickening in our study; these included age, pattern of peritoneal thickening, and presence of ascites. 18F-FDG PET/CT is useful for detecting the underlying cause of peritoneal thickening. Special attention should be paid to peritoneal tuberculosis, which has a high SUVmax and may mimic malignant peritoneal thickening. Multiple PET/CT parameters which were different in patients with tuberculous and malignant causes could be taken into consideration to make the differential diagnosis.


INTRODUCTION
P eritoneal thickening is a persistent problem that can be caused by several diseases. [1][2][3][4] Identification of the cause of peritoneal thickening is often critical for optimal management and prognostication. Serum and peritoneal fluid biochemical tests and fluid cytology have low positive rates. The utility of peritoneal biopsy is limited because of its invasiveness, although it has high diagnostic accuracy. 5 Conventional imaging methods used to characterize peritoneal thickening, such as unenhanced computed tomography (CT) attenuation, enhanced CT, or magnetic resonance imaging, have some limitations in differentiating between the presence and absence of primary lesions, even if peritoneal thickening is identified. 6,7 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been widely used to differentiate between benign lesions and malignant tumors. [8][9][10][11] Integrated PET/CT is not only complementary to conventional imaging, but also may be more sensitive because the metabolic alterations of malignant tumors may precede gross anatomical changes. 8,12 However, 18 F-FDG accumulates not only in malignant tumors but also in several benign lesions that may mimic malignant lesions and thus limit the specificity of 18 F-FDG PET/CT imaging. 13 So far, few studies have examined the role of 18 F-FDG PET/CT in the evaluation of peritoneal thickening of undetermined origin. The purpose of this study was to assess the value of 18 F-FDG PET/CT in determining the cause of peritoneal thickening.

Patients
We performed a retrospective analysis of 18 F-FDG PET/CT obtained in 103 patients (44 men and 59 women; age range, 23-77 years; mean age, 59.2 AE 14.8 years) with peritoneal thickening. The examinations were performed between January 2010 and April 2015 to determine the primary cause of the peritoneal thickening and to differentiate malignant from benign peritoneal thickening. The Institutional Review Board of Shanghai Jiao Tong University-affiliated Ren Ji Hospital approved this study, and all patients gave written informed consent.
There were 84 patients with malignant peritoneal thickening and 19 patients with benign peritoneal thickening among the 103 patients. Among the 84 patients with malignant peritoneal thickening, the presence of primary malignant lesions was diagnosed by pathologic examination and clinical follow-up over 6 months. Among the 19 patients with benign peritoneal thickening, pathologic examinations confirmed the cause in 7 patients. In the other 12 patients, the causes of the peritoneal thickening included peritoneal tuberculosis (7), bacterial peritonitis (2), nephritic syndromes (2), and hepatic cirrhosis (1); these cases were diagnosed by clinical follow-up over 6 months.

PET/CT
Whole body scanning was performed by using a whole body PET/CT scanner (Biograph mCT; Siemens). All patients received an intravenous injection of 3.7 MBq/kg of 18 F-FDG after fasting at least 6 hours and resting for 1 hour. The mean uptake time was 50 AE 6 minutes. Blood glucose measurements were obtained in all patients before the administration of 18 F-FDG and were less than140 mg/dL at the time of injection.
CT was performed on the 64-slice CT (Biograph mCT; Siemens) without contrast administration. A standardized protocol was followed, involving120 kV, 140 mA, and a section thickness of 5.0 mm, which was matched to the section thickness of the PET images. PET image datasets were reconstructed iteratively with CT data for attenuation correction.

Image Interpretation
PET/CT images were assessed by 2 experienced nuclear medicine physicians on a workstation (Medx) in all standard planes. They had at least 5 years experiences in PET/CT images. Where discrepancies occurred, they reached a consensus. When increased uptake, greater than the background activity of the organ, was identified, the abnormal focal lesion was considered to be a potential primary lesion combined with the patients' age, sex, past history, gastroscopy, and enteroscopy. They were blinded to the gold standard outcome. The gold standard outcome was obtained by biopsy or clinical follow-up. For quantitative analysis, irregular regions of interest were placed over the most intense area of 18 F-FDG accumulation. The maximal standardized uptake value (SUV max ) was calculated using the following formula: maximum pixel value with the decay-corrected region-of-interest activity (MBq/mL)/(injected dose [MBq]/body weight [g]). The CT manifestations of the primary origin were evaluated according to the standard CT diagnostic routine. We then assessed the diagnostic accuracy of 18 F-FDG PET/CT versus CT alone in the detection of original lesions. The diagnostic endpoints included: whether PET/CT or CT can detect peritoneal thickening; whether PET/CT can identify the site of primary for malignant peritoneal thickening; and whether the SUV max values can distinguish malignant from benign peritoneal thickening or differentiate malignant from nontuberculous benign thickening.

Statistical Analysis
The primary analysis was of the diagnostic performance of 18    istical differences between the groups were compared using one-way ANOVA and the t-test. P < 0.05 was considered statistically significant. All statistical analysis was performed using SPSS version 13.0 (SPSS Inc., Chicago, IL).

Detection of Primary Lesions
Among the 84 patients with malignant peritoneal thickening, PET/CT detected the primary lesion in 64 (76.2%). In the 20 patients in whom PET/CT gave false-negative results, malignant disease was confirmed by pathologic examination; these patients included 7 with unknown primary lesions, 3 with poorly differentiated ovarian adenocarcinoma, 3 with carcinoma of the small intestine, 2 with gastric carcinoma (Figure 1), 2 with colon carcinoma, 2 with lung cancer, and 1 with liver  cancer. There were 4 patients with false-positive results. In these 4 patients, increased 18 F-FDG uptake in the peritoneum was initially considered to represent peritoneal metastasis from unknown primary tumors, but peritoneal biopsy confirmed peritoneal tuberculosis (Figure 2).
The sensitivity, specificity, PPV, NPV, and accuracy in detecting the primary cause of peritoneal thickening were 76.2%, 78.9%, 94.1%, 42.9%, and 81.2%, respectively, for 18 F-FDG PET/CT, and 58.3%, 84.2%, 94.2%, 31.4%, and 63.1%, respectively, for CT imaging (Table 1). Thus, compared with conventional CT imaging, PET/CT appears to have superior sensitivity and accuracy for the detection of primary malignant lesions. Figure 3 shows the images of 1 patient with discordant results for CT and PET/CT. In this patient with ovarian cancer, CT could not confirm metastasis in the hepatic peritoneum; however, PET detected high uptake in the hepatic peritoneum, suggesting a metastatic lesion, which was finally confirmed by pathology.

Characteristics of Peritoneal Thickening
Although there was no significant difference in the SUV max between malignant peritoneal thickening and benign peritoneal thickening (5.407 AE 3.174 vs 4.189 AE 2.378; P ¼ 0.12), the SUV max was significantly higher in malignant peritoneal thickening than in nontuberculous benign peritoneal thickening (5.407 AE 3.174 vs 2.600 AE 2.036; P ¼ 0.02; Figures 4-6). Among the 19 cases of benign peritoneal thickening, the SUV max of the thickened peritoneum was significantly higher in tuberculous peritoneal thickening than in nontuberculous benign peritoneal thickening (5.117 AE 2.110 vs 2.600 AE 2.036; P ¼ 0.02; Figure 2 and Figures 4-6). Tuberculous peritoneal thickening showed a hypermetabolic pattern, with SUV max in the range of 1.7 to 8.6. Thus, there was no significant difference between malignant peritoneal thickening and tuberculous peritoneal thickening in SUV max , and benign tuberculous peritoneal thickening could mimic malignant peritoneal thickening on 18 F FDG PET/CT.
To determine whether PET/CT can help differentiate between malignant and tuberculous peritoneal thickening, we further compared the differences between these 2 peritoneal thickening in PET/CT parameters and clinical characteristics ( Table 2). The following significant differences were found (expressed as malignant vs tuberculous peritoneal thickening): age (61.  sex, SUV max of peritoneum, presence of primary lesions, and SUV max of the primary lesion, were not good discriminators (P > 0.05 in all cases).

DISCUSSION
In patients with peritoneal thickening, the decision to perform surgery or undertake other treatments is ultimately made on the basis of multiple factors, including the patient's symptoms, the physical examination findings, and laboratory test results. PET/CT findings that suggest either benign or malignant causes of peritoneal thickening can help guide treatment in these patients. In this study, the most common cause of malignant peritoneal thickening was gastric cancer, followed by ovarian cancer and pancreatic cancer. The most common cause of benign peritoneal thickening was peritoneal tuberculosis.
Peritoneal thickening is known to be caused by various diseases from the entire body. Early diagnosis of the primary lesion is crucial for making an effective treatment plan and predicting prognosis. Peritoneal biopsy may have a relatively high diagnostic accuracy, but its utility is limited because of its invasiveness. 5 PET/CT can be used to detect abnormal uptake of the whole body. 14,15 Thus, PET/CT offers the advantage of locating both the primary lesions and peritoneal thickening. However, few studies have discussed the role of PET/CT in detecting the primary cause of peritoneal thickening, and most have focused upon its use for detecting peritoneal carcinoma. 16,17 Therefore, we first assessed the value of PET/CT in locating the primary lesion in patients with peritoneal thickening. Our study demonstrated that the sensitivity and accuracy of PET/CT for detecting the primary lesions were superior to those of conventional CT imaging. The addition of PET/CT can reveal more information about the primary lesion and aid selection of therapeutic strategies. Our findings suggest that PET/CT should be performed in all patients with peritoneal thickening of undetermined origin so that the appropriate treatment can be determined.
However, false-positive or false-negative results are possible with PET/CT. In our study, false-positive findings were found in 4 patients (4.7%) with peritoneal tuberculosis. Previous reports show that 18 F-FDG could accumulate at sites of inflammation and granulomatous disease, 18,19 and our study findings were consistent with these reports. In these falsepositive cases, increased 18 F-FDG uptake may be caused by overexpression of glucose transporter isotypes and glycolytic enzymes in inflammatory cells.
Now that there were false-positive findings and benign peritoneal thickening may mimic malignant peritoneal thickening, we tried to determine whether PET/CT could help differentiate between benign and malignant peritoneal thickening. Our results showed that malignant peritoneal thickening had significantly higher SUV max than nontuberculous benign peritoneal thickening; however, tuberculous peritoneal thickening also had high SUV max and could thus mimic malignant peritoneal thickening. Previous studies have also reported that tuberculous peritonitis shows a hypermetabolic pattern that might mimic peritoneal carcinoma. [20][21][22] Tuberculosis is composed of lymphocytes and macrophages. These inflammatory cells have markedly increased glycolysis, which is the cause of increased 18 F-FDG uptake. 22 However, there were multiple PET/CT parameters that were significantly different in patients with tuberculous compared with those with malignant causes of peritoneal thickening in our study. These included age, pattern of peritoneal thickening, and presence of ascites. Patients with malignant peritoneal thickening were older than patients with tuberculous peritoneal thickening; they were also more likely to have ascites and an irregular pattern of peritoneal changes. So, when we make the differential diagnosis between malignant and tuberculous peritoneal thickening, these PET/CT parameters should be taken into consideration.
To the best of our knowledge, this is the 1st large study on the ability of 18 F-FDG PET/CT to characterize peritoneal thickening of undetermined origin. This study has some limitations. First, the study was retrospective and there was unavoidable selection bias. Second, we had a small and heterogeneous sample, with patients having a variety of different malignancies and therapies.
Based on our results the use of PET/CT led to high sensitivity and specificity in diagnosing peritoneal thickening of undetermined origin. Malignant peritoneal thickening had a significantly higher SUV max than nontuberculous benign peritoneal thickening. However, tuberculous peritoneal thickening also has a high SUV max , which may mimic malignant peritoneal thickening. Multiple factors that were found to be different between patients with tuberculous and malignant peritoneal thickening should be taken into consideration when making the differential diagnosis. The change in SUV max or metabolic tumor volume in the follow-up scans can be mentioned in future studies which may comment upon sensitivity and other parameters. Further large prospective studies, with histological examination as the reference standard, are needed to confirm our results and determine whether they can be applied to healthy patients with incidentally discovered peritoneal thickening.