Preoperative 18F-FDG PET/CT tumor markers outperform MRI-based markers for the prediction of lymph node metastases in primary endometrial cancer

This retrospective cohort study was conducted under institutional review board (IRB)–approved protocols with written informed consent from all patients. Preoperative pelvic MRI and whole-body 18F-FDG PET/CT were performed from October 2011 to December 2016 in all patients, n = 215, with histologically confirmed endometrial carcinoma at surgery. All patients had a single primary tumor. Mean (range) time span between MRI and 18F-FDG PET/CT was 4 (0–38) days. The mean (range) time interval between MRI examination and primary treatment was 16 (0–98) days and between PET/CT and primary treatment 16 (0–102) days. The shortest interval (zero days) between preoperative imaging and treatment was recorded in two patients having inoperable disease (FIGO IV) who started chemotherapy at the day of the imaging examination. All patients were diagnosed and treated at the same university hospital serving a population of ~ 1 million inhabitants. Clinical data (e.g., age, menopausal status, height, body weight) were registered, and patients were staged according to the FIGO 2009 criteria [3]. Depths of myometrial invasion (MI), cervical stroma invasion (CI), and lymph node metastases (LNM) were evaluated by the pathologists using standard procedures. Patient follow-up data have been collected from patient records and from correspondence with the responsible physicians/gynecologists. For patients considered radically treated (203/215 patients), standard-of-care follow-up is clinical examinations quarterly during the first 2 years and biannually until 5 years after primary diagnosis. For patients not considered radically treated (12/215 patients), the follow-up is individualized, normally with frequent follow-ups. Mean (range) follow-up time for survivors was 33 (0–66) months and date of last follow-up was 16 August 2018. Progression was defined as local recurrence/progression in the pelvis or new metastases in the abdomen or at distant locations.

Pelvic MRI was acquired on a Siemens Avanto 1.5-T scanner for 156/215 patient and on a Siemens Skyra 3-T scanner for the remaining 59/215 patients. Prior to imaging, 20 mg butylscopolamine bromide (Buscopan, Boehringer Ingelheim) was administered intravenously to reduce bowel peristalsis. The MRI protocol included sagittal and axial oblique (perpendicular to the long axis of the uterus) T2-weighted images and axial oblique T1-weighted gradient-echo images before and 2 min after administration of 0.1 mmol gadolinium/kg body weight (Dotarem, Guerbet). Diffusion-weighted imaging (DWI) was performed using an axial oblique 2D echo-planar imaging sequence with b values of 0 and 1000 s/mm², and apparent diffusion coefficient (ADC) maps were generated. Information on 1.5-T and 3-T scanner protocols are given in Suppl. Table 1.

The de-identified MRI images were evaluated by three radiologists with 2–10 years of experience, who were blinded to clinical data, tumor stage, and patient outcome. Maximum tumor diameter was measured in three orthogonal planes: anteroposterior (AP) and transverse (TV) diameters on CE paraxial T1-weighted images and the craniocaudal (CC) tumor diameter on sagittal T2-weighted images (Fig. 1). Tumor volume (V_MRI) was estimated by assuming the shape of an ellipsoid: V_MRI = 4/3π(AP/2 × TV/2 × CC/2). In addition, for a subgroup of 60 patients (randomly selected), 3D tumor masks were outlined by one of the radiologists (JAD) in order to compare the MRI tumor volume estimated by the ellipsoid method with a supposedly more exact 3D tumor volume measurement. MRI findings suggesting deep (≥ 50%) myometrial invasion (DMI) and pelvic or paraaortic LNM (MRI-positive lymph nodes (LN), defined as enlarged LN with a maximum short-axis diameter of ≥ 10 mm) were recorded by all three readers. Since this study was focused on patient-based analysis, the number, shape, and position of the enlarged LNs were (although registered) not taken into account for prediction of LNM at surgical staging. The mean tumor apparent diffusion coefficient (ADC_mean) was measured in a region of interest (ROI) drawn in the ADC map depicting the largest cross-sectional tumor diameter. Consensus values for the three readers were established using the median value for continuous variables and the majority reading for categorical variables.

18F-FDG PET/CT was performed on a Siemens Biograph 40 True Point scanner, with scan range coverage from the skull base to the mid-thigh. All patients were instructed to fast for 6 h prior to scanning and had an i.v. injection of 4.6 MBq 18F-FDG/kg body weight or 370 MBq 18F-FDG approximately 60 min prior to scanning. The PET images were acquired with 3 min per bed position and reconstructed with correction for scatter and attenuation based on the CT images. The CT protocol was changed during the study period, from diagnostic CE CT to low-dose CT. Thus, attenuation correction of the PET signal was performed using diagnostic CE CT (120 kV, 240 reference mAs) in 11/215 patients and low-dose CT (120 kV and 50 reference mAs) in 204/215.

A physician with > 2 years of PET/CT experience and who was blinded for clinical findings, MRI findings, and surgical staging results reviewed all images retrospectively on a Segami Oasis workstation. Metabolic tumor volume (MTV) was calculated by segmenting a volume of interest (VOI) including all putative tumor voxels with body weight standardized uptake value (SUV) > 2.5. The selection of SUV threshold was based on clinical experiences of SUV levels in healthy background tissue. The mean and maximum SUV values within this VOI, SUV_mean, and SUV_max, respectively, were also recorded in addition to the presence of increased 18F-FDG uptake in lymph nodes (SUV_max > 2.5), interpreted as likely LNM (PET-positive LN) (Fig. 1).

Median values with 95% confidence interval (CI) were assessed for all imaging-derived tumor parameters. Correlation analyses were performed using Spearman’s rank-order correlation test, and interobserver reliability was assessed using intraclass correlation coefficient (ICC) for continuous variables and Fleiss kappa statistics for categorical variables. The Mann-Whitney U test was used to analyze differences in imaging parameters in relation to surgicopathological stage and tumor grade. Receiver operating characteristic (ROC) analyses were employed to compare the diagnostic performance of the different imaging parameters for predicting LNM, and optimal cutoff values for MTV and V_MRI were identified from the ROC curves using the Youden index. Patient-based logistic regression analysis for prediction of LNM was conducted for the categorized imaging variables as well as for the detection of LNM on conventional PET/CT and MRI reading (PET- and MRI-positive LN). Sensitivity, specificity, and accuracy were compared by McNemar’s test. The prognostic value of the imaging parameters was explored using the Kaplan-Meier with log-rank test and the Cox proportional hazard model. Analyses were performed in SPSS 24.0 (IBM Corp.) and STATA 15.1 (StataCorp). The reported p values were generated by two-sided tests and considered significant when less than 0.05.

A total of 215 patients with endometrial cancer were included in the study (Table 1), and all patients were treated according to the Norwegian national guidelines for endometrial cancer. Altogether, 98% (211/215) of the patients underwent primary surgical resection with hysterectomy and bilateral salpingo-oophorectomy. One patient (1/215) underwent tumor debulking without hysterectomy (grade 3, FIGO IVB); two patients (2/215) were deemed medically ineligible for surgical treatment (both grade 3, FIGO IVA and IVB, respectively); and one patient (1/215) who wished to preserve fertility, refrained from surgery (grade 1, FIGO IA). The histological diagnoses of these four patients are based on uterine biopsies and recorded FIGO stage on findings from diagnostic imaging.

Pelvic lymph node dissection (PLND) was performed in 138 patients and revealed LNM in 12% (16/138) of the patients while paraaortic lymph node dissection (PALND) in 43 patients revealed paraaortic LNM in 2% (1/43). Median (range) of nodes examined was 13 (1–35) for PLND and 19 (5–54) for PALND. Patients undergoing lymphadenectomy had significantly lower BMI, and a higher proportion of the patients had high-grade tumors, non-endometrioid subtype, DMI; received adjuvant treatment; and experienced disease progression (Suppl. Table 2).

Adjuvant therapy was given in 36% (78/215) of the patients; chemotherapy in 33% (72/215), external radiation in 1% (2/215), internal radiation in 1% (2/215), and hormonal treatment in 1% (2/215).

The interobserver reliability for the MRI tumor measurements assessed by the three readers was high with ICC (95% CI) of 0.947 (0.934–0.958) for AP diameter, 0.912 (0.879–0.935) for TV diameter, 0.942 (0.923–0.957) for CC diameter, and 0.919 (0.897–0.937) for ADC_mean. For assessment of enlarged lymph nodes based on MRI, the agreement between the three readers was only moderate with an overall Fleiss kappa (95% CI) of 0.425 (0.280–0.482). In 8/215 patients, two of the MRI readers recorded MRI-positive LN, whereas the last reader did not. Two of these eight patients were finally staged with LNM.

There were strong-to-moderate positive correlations between the 18F-FDG PET/CT tumor parameters and V_MRI (r = 0.56–0.83 (range), p < 0.001 for all) while only weak negative correlations between ADC_mean and the other imaging parameters (r = − 0.38–0.43 (range), p < 0.001 for all) (Table 2)_. For the subgroup of 60 patients in whom full 3D tumor segmentation was conducted, the calculated tumor volumes from the 3D method (mean of 14 ml) and the ellipsoid method (mean of 17 ml) yielded an ICC (absolute agreement) of 0.968 (95% CI 0.936–0.982), demonstrating an overall excellent agreement.

All the F18-FDG PET/CT tumor parameters had significantly higher primary tumor values in patients with DMI, high histological grade (endometrioid grade 3), and advanced stage (FIGO III and IV) (p ≤ 0.001 for all; Table 3). SUV_max and MTV were also significantly higher in patients with LNM (p = 0.04 and p < 0.001, respectively), while MTV was the only F18-FDG PET/CT imaging parameter that was significantly associated with CI (p = 0.003) (Table 3).

V_MRI was significantly higher in patients with DMI (p < 0.001), CI (p = 0.03), LNM (p = 0.001), high histological grade (p < 0.001), and advanced FIGO stage (p < 0.001). Low tumor ADC_mean was significantly associated with DMI (p < 0.001), high histological grade (p < 0.001), and advanced FIGO stage (p = 0.03) (Table 3).

MTV yielded the highest area under the ROC curve (AUC) for prediction of LNM (AUC = 0.80; Fig. 2). The AUC for predicting LNM was significantly higher for MTV compared with that for V_MRI, yielding the second highest AUCs (p = 0.03). Based on the ROC curves (Fig. 2), the optimal cutoff values for MTV and V_MRI were 27 ml and 10 ml, respectively. Using these cutoff values for predicting LNM, MTV > 27 ml yielded significantly higher specificity (p < 0.001) and accuracy (p < 0.001) while similar sensitivity (p = 1.00) to V_MRI > 10 ml (Table 4). Furthermore, MTV > 27 ml yielded an odds ratio (OR) of 12.2 (p < 0.001), whereas V_MRI > 10 ml yielded an OR of 9.7 (p = 0.003) for prediction of LNM (Table 4).

The sensitivity for PET-positive LN was higher than for MRI-positive LN (50% vs 31%, respectively), although not statistically significant (p = 0.25) (Table 4). The specificity and accuracy were similar for PET- and MRI-positive LN, but PET-positive LN yielded an OR of 12.6 (p < 0.001) while MRI-positive LN yielded an OR of 7.5 (p = 0.003) (Table 4).

In multivariate analyses including imaging variables as well as preoperative high-risk status (endometrial biopsy/curettage indicating endometrioid grade 3/non-endometrioid histology vs endometrioid grades 1–2), only PET-positive LN remained an independent significant predictor of LNM (OR = 7.8, p = 0.008), while MTV > 27 ml tended to the same (OR = 4.5, p = 0.10) (Table 4).

Stratifying patients according to MTV >/≤ 27 ml resulted in a false positive rate of 26% (32/122) and a false negative rate of 19% (3/16) in predicting LNM. Corresponding figures when based on PET-positive LN yielded a smaller false positive rate of 7% (9/122), however, with a much higher false negative rate of 50% (8/16). Among patients surgically staged with LNM, 69% (11/16) were assessed as LN negative on PET and/or MRI. Applying the volume cutoff values to this patient subgroup demonstrated MTV > 27 ml in 73% (8/11) and V_MRI > 10 ml in 82% (9/11).

Combining lymph node visual assessment on PET and MTV >/≤ 27 ml in a unified prediction model yielded similar diagnostic performance metrics compared with that of MTV > 27 ml alone (Suppl. Fig. 1).

In total, 30 out of the 215 (14%) patients experienced progression. Among these, eleven patients received adjuvant chemotherapy and three patients (with inoperable disease) had primary chemotherapy. Hormonal treatment was given to two of the 30 patients, one as primary treatment (due to fertility wishes) and one as adjuvant treatment. Patients with higher MTV and with PET-positive LN and MRI-positive LN had significantly reduced PFS with univariate hazard ratios (HRs) of 1.003 (p = 0.017), 4.0 (p = 0.001), and 5.6 (p < 0.001), respectively. High V_MRI was not significantly associated with reduced survival (Table 5). When adjusting for preoperative high-risk status and patient age, PET- and MRI-positive LN remained significantly associated with reduced survival (HR = 3.3, p = 0.004; and HR = 4.3, p = 0.001, respectively), while MTV was not (Table 5).

When stratifying according to the proposed volume cutoff values for prediction of LNM, both MTV > 27 ml and V_MRI > 10 ml were significantly associated with reduced progression-free survival (Fig. 3), both in the univariate analyses (HR = 3.6, p < 0.001; and HR = 4.1, p = 0.001, respectively) and in multivariate analyses (HR = 2.7, p = 0.010; and HR = 3.2, p = 0.006, respectively) (Table 5).

In patients surgicopathologically staged as FIGO I–II (n = 189), large MTV, V_MRI > 10 ml, and MRI-positive LN tended to predict poor PFS with HRs of 1.009 (p = 0.07), 2.2 (p = 0.09), and 3.9 (p = 0.07), respectively (Suppl. Table 3). For patients with FIGO stages III–IV (n = 26), none of the imaging markers significantly predicted survival (Suppl. Table 3). Among patients primary staged as FIGO I–II, 10% (19/189) eventually developed progression; in these nineteen patients, 37% (7/19) had MTV > 27 ml and 58% (11/19) had V_MRI > 10 ml.