Diagnostic value of [18F]FDG PET/MRI for staging in patients with ovarian cancer

Purpose To evaluate the diagnostic potential of PET/MRI with 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) in ovarian cancer. Materials and methods Participants comprised 103 patients with suspected ovarian cancer underwent pretreatment [18F]FDG PET/MRI, contrast-enhanced CT (ceCT) and pelvic dynamic contrast-enhanced MRI (ceMRI). Diagnostic performance of [18F]FDG PET/MRI and ceMRI for assessing the characterization and the extent of the primary tumor (T stage) and [18F]FDG PET/MRI and ceCT for assessing nodal (N stage) and distant (M stage) metastases was evaluated by two experienced readers. Histopathological and follow-up imaging results were used as the gold standard. The McNemar test was employed for statistical analysis. Results Accuracy for the characterization of suspected ovarian cancer was significantly better for [18F]FDG PET/MRI (92.5%) [95% confidence interval (CI) 0.84–0.95] than for ceMRI (80.6%) (95% CI 0.72–0.83) (p < 0.05). Accuracy for T status was 96.4% (95% CI 0.96–0.96) and 92.9% (95% CI 0.93–0.93) for [18F]FDG PET/MRI and ceMRI/ceCT, respectively. Patient-based accuracies for N and M status were 100% (95% CI 0.88–1.00) and 100% (95% CI 0.88–1.00) for [18F]FDG PET/MRI and 85.2% (95% CI 0.76–0.85) and 30.8% (95% CI 0.19–0.31) for ceCT and M staging representing significant differences (p < 0.01). Lesion-based sensitivity, specificity and accuracy for N status were 78.6% (95% CI 0.57–0.91), 95.7% (95% CI 0.93–0.97) and 93.9% (95% CI 0.89–0.97) for [18F]FDG PET/MRI and 42.9% (95% CI 0.24–0.58), 96.6% (95% CI 0.94–0.98) and 90.8% (95% CI 0.87–0.94) for ceCT. Conclusions [18F]FDG PET/MRI offers better sensitivity and specificity for the characterization and M staging than ceMRI and ceCT, and diagnostic value for T and N staging equivalent to ceMRI and ceCT, suggesting that [18F]FDG PET/MRI might represent a useful diagnostic alternative to conventional imaging modalities in ovarian cancer.


Background
Ovarian cancer is the most lethal gynecological malignancy, ranking as the fifth-most common cause of cancer death among women. The standard treatment is debulking surgery followed by 6 cycles of chemotherapy. In presumed early ovarian cancer, staging laparotomy including hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy and omentectomy is performed to stage the disease based on the International Federation of Gynecology and Obstetrics (FIGO) and/ or Union for International Cancer Control (UICC) TNM classifications [1]. For patients with advanced disease in which complete debulking is not feasible, neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) may also be acceptable [2]. Accurate preoperative assessment including the differentiation of benign and malignant disease or the diagnosis of nodal, peritoneal or distant disease is necessary for optimal treatment planning.
To characterize ovarian tumors as benign or malignant, magnetic resonance imaging (MRI) with intravenous Tsuyoshi et al. EJNMMI Res (2020) 10:117 administration of contrast provides the highest post-test probability of detecting ovarian cancer when compared with computed tomography (CT), Doppler ultrasonography (US) or MRI without contrast administration [3][4][5]. Positron emission tomography (PET), particularly 2-[ 18 F] fluoro-2-deoxy-d-glucose ([ 18 F]FDG) as a tracer reflecting cellular metabolism, has been shown to be worth consideration alongside conventional imaging modalities. For the detection of lymph node metastasis, distant metastasis, peritoneal disease or recurrent disease in ovarian cancer, [ 18 F]FDG PET/CT could be useful compared with conventional modalities including CT or MRI [6][7][8][9][10]. However, [ 18 F]FDG PET/CT has a limited and controversial role to play in the characterization of ovarian tumors, because the physiologically increased uptake of FDG into the normal ovaries leads to false-positive results or low diagnostic value in differentiating between borderline and benign tumors due to low FDG uptake leading to false-negative results [11].
The new PET modality of [ 18 F]FDG PET/MRI provides high soft-tissue contrast along with functional imaging of FDG uptake and has shown potentially better diagnostic performance than [ 18 F]FDG PET/CT in gynecologic cancers [12,13]. In evaluating and characterizing ovarian tumors, fusion of PET and MRI provides advantageous sensitivity and specificity compared with MRI or [ 18 F]FDG PET/CT [14]. Moreover, in the assessment of tumor resectability at PDS among patients with advanced ovarian cancer, MRI or [ 18 F]FDG PET/CT could provide high specificity and moderate sensitivity [15], suggesting that integrated PET/MRI combining the individual advantages of PET and MRI may have a role to play in the characterization of ovarian tumors or the pretreatment evaluation of ovarian cancer, while integrated PET/MRI has not yet been well studied in ovarian cancer.
The aim of our study was thus to evaluate the diagnostic utility of integrated [ 18 F]FDG PET/MRI for the characterization, whole-body tumor staging and restaging of patients with ovarian cancer, and to compare the diagnostic accuracy of integrated [ 18 F]FDG PET/MRI with that of contrast-enhanced CT (ceCT) or contrastenhanced MRI (ceMRI).

Patients
We retrospectively reviewed the medical records of 135 patients with suspected ovarian cancer or recurrence between February 2016 and May 2019 (Additional file 1: Table S1). Of these, 103 patients (mean age, 55.5 years; age range, 11-80 years) who had undergone [ 18

Whole-body PET/MRI
Patients fasted for at least 4 h prior to intravenous injection of 200 MBq of [ 18 F]FDG. Fifty minutes after injection, patients were transferred to a whole-body 3.0-T PET/MR scanner (Signa PET/MR; GE Healthcare, Waukesha, WI). Anatomical coverage was from the vertex to the mid-thigh. PET acquisition was performed in 3-dimensional (3D) mode with 5.5 min/bed position (89 slices/bed) in 5-6 beds with a 24-slice overlap. A 2-point Dixon 3D volumetric interpolated T1-weighted fast spoiled gradient echo sequence was acquired at each table position and was used to generate MR attenuation correction (MR-AC) maps. Dixon-based MR-AC classifies body tissues into soft tissue, fat and air. PET data were reconstructed by ordered subset expectation maximization (OSEM), selecting 14 subsets and 3 iterations, and post-smoothing with a 3-mm Gaussian filter. Reconstructed images were then converted to semiquantitative images corrected by the injected dose and the body weight of the subject as the standardized uptake value (SUV).

Pelvic PET/MRI
After whole-body scanning and a brief break for urination, the patient was repositioned in the PET/MR scanner. The pelvic PET scan was performed as a 3D acquisition in list mode with 15 min/bed position (89 slices/bed) in 1-2 beds with a 24-slice overlap. Regional PET data were reconstructed with OSEM selecting 16 subsets and 4 iterations, and post-smoothing with a 4-mm Gaussian filter. Reconstructed images were then converted to SUV images. For pelvic MRI, T2-weighted images were acquired in the sagittal, transaxial and coronal planes, using the following T2-weighted image parameters: TR, 4000-7000 ms; TE, 146 ms; section thickness, 4 mm; section overlap, 0 mm; flip angle, 100°; FOV, 240 × 240 mm; matrix, 384 × 384; two excitations; and bandwidth, 83.3 kHz.

ceCT
CT examinations covering the chest, abdomen and pelvis were performed using a 64-slice multidetector CT scanner (Discovery CT 750HD; GE Medical Systems, Milwaukee, WI) before and after intravenous administration of nonionic iodinated contrast material (iopamidol, Iopamiron 300; Schering, Berlin, Germany).

Image interpretation
Images were analyzed on a dedicated workstation (Advantage Workstation 4.6; GE). Two board-certificated radiologists/nuclear medicine physicians, each with double certifications and specializing in gynecological imaging, evaluated the [ 18 F]FDG PET/MRI, ceCT and ceMRI images retrospectively and reached consensus decisions. Images were evaluated for the following: (a) characterization; (b) tumor extension into the uterus, fallopian tubes or ovaries (T2a); (c) tumor extension into other nearby pelvic organs such as the bladder, sigmoid colon or rectum (T2b); (d) tumor extension into organs outside the pelvis, no bigger than 2 cm in extent (T3b); (e) tumor extension into organs outside the pelvis, larger than 2 cm in extent (T3c); (f ) pelvic or para-aortic lymph nodes (N); (g) distant metastasis (M); (h) residual disease for IDS after NAC; and (i) recurrence. The present study applied the TNM classification to evaluate the diagnostic value of the imaging modalities, because this anatomically based system separately records the primary and regional nodal extent of the tumor and the absence or presence of metastases. Diagnostic performance of [ 18 F]FDG PET/MRI and ceMRI for assessing the characterization and extent of the primary tumor and [ 18 F] FDG PET/MRI and ceCT for assessing nodal and distant metastases was evaluated. Both readers were blinded to the results of other imaging studies, histopathologic findings and clinical data. Each dataset was reviewed as the consensus decisions of the two readers after a minimum interval of three weeks to avoid any decision threshold bias due to reading-order effects. For CT and MRI interpretation, several previous standard criteria related to primary tumor and nodal or distant metastatic staging of ovarian cancer were used as the reference criteria [16]. Swollen lymph nodes larger than 1 cm in short-axis diameter were graded as malignant. For [ 18 F]FDG PET/ MRI interpretations, the classification of lymph nodes as cancer-positive was based on the presence of focally appreciable metabolic activity above that of normal muscle; or asymmetric metabolic activity greater than that of normal-appearing lymph nodes at the same level in the contralateral pelvis, in a location corresponding to the lymph node chains on CT or MRI images, with reference to previous reports [12,13]. Furthermore, the presence of a central unenhanced area suggesting central necrosis or peripheral low attenuation suggesting a fatty hilum within lymph nodes was considered a benign sign. Tumor invasion of neighboring structures was decided primarily on the basis of CT or MRI findings, with reference to the [ 18 F]FDG PET findings.

Reference standard
Histopathological results were used as the standard of reference for the characterization, T, N and M staging, determination of residual disease after NAC and determination of recurrence. Because clinical and ethical standards of patient management do not require surgery or sampling of all detected lesions, a modified reference standard was used for lesions without histopathological sampling to take into account all prior and follow-up imaging. A decrease in size and/or SUVmax under therapy or an increase in size and/or SUVmax without therapy was regarded as a sign of malignancy. PET-negative and inconspicuous lesions with constant size were rated as benign.

Statistical analysis
The McNemar test was used to determine the statistical significance of differences in the accuracy of T, N and M staging as determined by PET/MRI, ceCT and ceMRI. Statistical analysis was performed using PRISM version 6.0 software (GraphPad, San Diego, CA). Differences at the level of p < 0.05 were considered statistically significant.

Table 5 Comparison of [ 18 F]FDG PET/MRI with ceMRI and/or ceCT for patient-based T, N and M staging, detection of residual disease after neoadjuvant chemotherapy and detection of recurrence
The spread of ovarian cancer into adjacent organs such as the uterus, sigmoid colon, bladder and rectum may be better appreciated on MRI than on CT in ovarian cancer, as seen for other gynecologic cancers [19][20][21]. In terms of [ 18 F]FDG PET/CT, limited data are available regarding the assessment of extension into adjacent organs in gynecologic cancers. The results of [ 18 F]FDG PET/CT were comparable to those of ceMRI and transvaginal US Fig. 2 a A 67-year-old woman with right ovarian tumor. Axial T2-weighted PET/MR image shows a papillary solid part with FDG uptake invading the posterior uterine myometrium (arrow) in a polycystic right ovarian tumor. b Axial T1-weighted contrast-enhanced MR image shows the papillary solid part with good enhancement (arrow) and unclear findings of growth into the uterus. Histopathologic examination confirmed carcinosarcoma with growth into the posterior uterine myometrium (T2a). c A 62-year-old woman with suspected ovarian cancer. Axial T2-weighted PET/MR image shows the omental cake with FDG uptake (arrow). d Contrast-enhanced CT shows thickening of the omentum with good enhancement (arrow). These findings strongly suggest potential malignancy with carcinomatous peritonitis and histopathologic examination confirmed high-grade serous carcinoma with carcinomatous peritonitis (T3c)  b Contrast-enhanced CT shows right pelvic lymph nodes less than 1 cm in short-axis diameter without enhancement (arrow). After NAC, these lymph nodes are decreased in size and SUV, suggesting these nodes as a sign of malignancy (N1) Fig. 4 a A 66-year-old woman with pathologically confirmed ovarian cancer. Axial T2-weighted PET/MR image shows a right parasternal lymph node with FDG uptake (arrow). b Contrast-enhanced CT shows a right parasternal lymph node less than 1 cm in short-axis diameter with slightly enhancement (arrow). After NAC, this lymph node decreased in size and SUV, suggesting that this node as a sign of malignancy (M1)  In terms of predicting treatment response, particularly for NAC, the concentration of CA-125 before and after the third course of NAC could provide an independent predictor for completion of IDS [28]. In terms of [ 18 F]FDG PET/CT, reductions in SUV before and after the third to fourth courses of NAC could be associated with histopathological response and may allow differentiation between responders and non-responders [29]. No reports appear to have described [ 18 F]FDG PET/MRI for ovarian cancer. In cervical cancer, [ 18 F]FDG PET/MRI in pre-and post-treatment examinations could differentiate between radiotherapy responders and non-responders [30]. This suggests that [ 18 F]FDG PET/MRI might be useful to identify NAC responders or non-responders in ovarian cancer. However, our results did not show superiority over ceCT for detecting residual disease after NAC for IDS, because some patients had micro-metastasis or peritoneal carcinomatosis less than a few millimeters that could not be detected on [ 18 F]FDG PET/MRI.
With epithelial ovarian cancer, more than half of patients experience disease recurrence within two years, irrespective of the effectiveness of first-line chemotherapy. Early detection of recurrence can help in planning optimal treatment, including chemotherapy, radiation or secondary cytoreductive surgery. CA-125 has often been used in monitoring to detect recurrent disease in cases of initially high CA-125, although the National Comprehensive Cancer Network guidelines recommend delaying treatment until clinical evidence indicates relapse [31]. In a meta-analysis of diagnostic accuracy for detecting recurrent disease with CA-125, [ 18 F]FDG PET/CT, CT and MRI, [ 18 F]FDG PET/CT offered the highest sensitivity of 91%, compared with 69% for CA-125, 79% for CT and 75% for MRI, suggesting that [ 18 F]FDG PET/ CT could be a useful tool for detecting recurrence, particularly in patients with increased CA-125 and negative CT or MRI [9]. In terms of [ 18 F]FDG PET/MRI, a meta-analysis showed that [ 18 F]FDG PET/MRI provides excellent diagnostic performance with 96% sensitivity and 95% specificity for restaging female patients with suspected recurrence of gynecological pelvic malignancies [12]. Although no significant differences were identified in comparisons with ceCT in the present study, likely because of the small sample size, [ 18 F]FDG PET/MRI could detect recurrent lesions in all patients, suggesting that [ 18 F]FDG PET/MRI might also prove useful for detecting recurrent ovarian cancer.
This study had several limitations. First, this investigation used a retrospective design, and not all MRI examinations were performed at our institution. However, our readers re-evaluated the images from other hospitals and were blinded to the initial imaging findings. Second, the sample size of this study was small, particularly in the detection of residual disease for IDS after NAC and detection of recurrence. In these situations, further studies with larger sample sizes are needed to clarify the diagnostic performance of [ 18 F] FDG PET/MRI. Third, we could not evaluate histopathological correlations with imaging in patients who had not yet undergone lymphadenectomy. We thus performed node-specific comparisons between imaging and histopathology in all other patients. Fourth, the population included was very heterogeneous and the results of diagnostic performance may reflect different clinical settings. However, we included all patients with suspected ovarian cancer between February 2016 and May 2019, suggesting that this study population may better reflect clinical situations, where preoperatively distinguishing pathologies is often difficult using imaging modalities, particularly for malignant surface epithelial-stromal tumors, sex cord stromal tumors and germ cell tumors [32]. [ 18 F]FDG PET/MRI combines the individual advantages of PET and MRI for whole-body and detailed regional scans, and could provide additional value when the classification of a malignant or benign ovarian tumor is in doubt. Moreover, [ 18 F]FDG PET/MRI offers better sensitivity for detecting distant metastasis than ceCT, suggesting that this modality might enable improved treatment planning.
Additional file1: Characteristics of patients excluded from the present study.