K. PÁLSDÓTTIR*, D. FISCHEROVA, D. FRANCHI, A. TESTA, A. DI LEGGE and E. EPSTEIN* ABSTRACT

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1 Ultrasound Obstet Gynecol 2015; 45: Published online 1 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Preoperative prediction of lymph node metastasis and deep stromal invasion in women with invasive cervical cancer: prospective multicenter study using 2D and 3D ultrasound K. PÁLSDÓTTIR*, D. FISCHEROVA, D. FRANCHI, A. TESTA, A. DI LEGGE and E. EPSTEIN* *Department of Obstetrics and Gynecology, Department of Women s and Children s Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Gynecological Oncology Centre, Department of Obstetrics and Gynecology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic; Gynecological Oncology Unit, Division of Gynecology, IEO, Milan, Italy; Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy; Department of Oncology, Catholic University of the Sacred Heart, Rome, Italy KEYWORDS: cervical cancer; deep stromal invasion; diagnostic accuracy; lymph node; power Doppler; three-dimensional ultrasound; transvaginal ultrasound ABSTRACT Objectives To determine how various objective two-dimensional (2D) and three-dimensional (3D) ultrasound parameters allow prediction of deep stromal tumor invasion and lymph node involvement, in comparison to subjective ultrasound assessment, in women scheduled for surgery for cervical cancer. Methods This was a prospective multicenter trial including 104 women with cervical cancer at FIGO Stages IA2 IIB, verified histologically. Patients scheduled for surgery underwent a preoperative ultrasound examination. The value of various 2D (size, color score) and 3D (volume, vascular indices) ultrasound parameters was compared to that of subjective assessment in the prediction of deep stromal tumor invasion and lymph node involvement. Histology obtained from radical hysterectomy or trachelectomy and pelvic lymphadenectomy was considered as the gold standard for assessment. Results All women underwent pelvic lymphadenectomy, with 99 (95%) undergoing subsequent radical surgery; five underwent only pelvic lymphadenectomy because of the presence of a positive sentinel lymph node. Women with deep stromal invasion or lymph node involvement had significantly larger tumors (diameter and volume) but there was no correlation with vascular indices measured on 3D ultrasound. Subjective evaluation was superior (AUC, 0.93; sensitivity, 90.5%; specificity, 97.2%) in the prediction of deep stromal invasion when compared to any objective measurement technique, with maximal tumor diameter at 20.5-mm cut-off (AUC, 0.83; sensitivity, 90.5%; specificity, 61.1%) and 3D tumor volume at 9.1-mm 3 cut-off (AUC, 0.85; sensitivity, 79.4%; specificity, 83.3%) providing the best performance among the objective parameters. Both subjective assessment and objective measurements were poorly predictive of lymph node involvement. Conclusions In women with cervical cancer, subjective ultrasound evaluation allowed better prediction of deep stromal invasion than did objective measurements; however, neither subjective evaluation nor objective parameters were adequate to predict lymph node involvement. 3D vascular indices were ineffective in the prediction of advanced stages of the disease. Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd. INTRODUCTION The current clinical staging system (FIGO (International Federation of Gynecology and Obstetrics)) for cervical carcinoma is inaccurate for approximately one-third of women at an early stage of the disease and for up to two-thirds of women at an advanced stage 1,2. In the revised FIGO staging system, clinicians are encouraged to use imaging modalities 3 as deep stromal infiltration, parametrial involvement, lymph node metastasis and distant metastasis are all prognostic factors 1,4,5. The results of magnetic resonance imaging (MRI) have been shown to be superior to those of computed tomography (CT) scanning in the evaluation of cervical cancer 6,7. The use of positron emission tomography combined with CT (PET-CT) for detection of lymph node metastasis has increased 8. The application of ultrasound to assess tumor extension in cervical carcinoma has been studied Correspondence to: Dr K. Pálsdóttir, Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden ( kolbrun.palsdottir@karolinska.se) Accepted: 22 July 2014 Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER

2 Prediction of metastasis and stromal invasion in invasive cervical cancer 471 previously. Several studies have shown that results of transvaginal and transrectal ultrasound are accurate and comparable to those of MRI in evaluating local extent of the disease New data obtained from a multicenter study including 209 women have shown that ultrasound might even be superior to MRI in detecting residual tumor and parametrial invasion 11.Thegreatest restriction in using ultrasound, as with MRI, is the low sensitivity in detecting lymph node metastasis 10,11. Studies on two-dimensional (2D) color Doppler ultrasound have shown a positive correlation between tumor vascularization, size and stage and the risk of lymph node metastasis in patients with cervical carcinoma 12,13. Other studies have shown that three-dimensional (3D) vascular indices are significantly higher in women with cervical carcinoma when compared to those in women with healthy cervices and that 3D vascular indices may correlate with tumor characteristics 15.Theaimof this study was to determine the value of preoperative 2D and 3D ultrasound variables as compared to subjective assessment in the prediction of deep stromal infiltration and lymph node involvement in patients scheduled for surgery for invasive cervical carcinoma. METHODS This was a prospective multicenter study commencing in December 2007, with the last patients recruited in October The cohort comprised 104 women scheduled for surgery because of histologically proven cervical cancer at FIGO clinical Stages I IIB. Only women with an identifiable tumor on transvaginal sonography (TVS) or transrectal sonography (TRS) were included in the study. The centers participating in the study were the ultrasound units at the Departments of Obstetrics and Gynecology, Lund University Hospital and Karolinska University Hospital, Stockholm, Sweden; the Gynecological Oncology Center, Department of Obstetrics and Gynecology, General University Hospital, Prague, Czech Republic; the Department of Oncology, Catholic University of the Sacred Heart, Rome, Italy and the Gynecologic Oncology Unit, Division of Gynecology, IEO, Milan, Italy. Appropriate ethical approval was acquired in all centers prior to the study. The patients were staged clinically for cervical cancer according to FIGO criteria which are based on clinical examination, cystoscopy with or without sigmoidoscopy and chest X-ray. The criteria for accepting women for surgery differed among centers, with most centers including only women at Stage IB1 or less, but other centers accepted for surgery selected cases with more advanced tumors (Stages IB2 IIB). The final histological diagnosis was based on the findings of the hysterectomy or trachelectomy and lymphadenectomy, which served as the gold standard. The preoperative ultrasound examination was performed at each center by one or two ultrasound experts with more than 10 years of experience in gynecological scanning. High-performance ultrasound systems were used: Voluson E8 (GE Medical Systems, Zipf, Austria) ultrasound system with a 5 9-MHz transducer or iu22 (Philips Healthcare, Best, The Netherlands) ultrasound system with a 3 9-MHz transducer. All patients were examined transvaginally or transrectally in a lithotomy position, with an empty bladder, in sagittal and transverse planes. All examinations were performed according to a predefined protocol, including those carried out for sonographic as well as clinical data. Still images with measurements, videoclips of the conventional gray-scale and power Doppler ultrasound examination and of the 3D gray scale and power Doppler ultrasound examination were recorded and saved for all patients. Results of conventional gray-scale TVS were assessed at the time of examination whereas 3D volumes were analyzed after completion of the study. Conventional 2D ultrasound was used to measure the size of the tumor and to assess subjectively local extent of the disease and presence of enlarged lymph nodes. The tumor was measured (in mm) in three dimensions: in the sagittal projection, the cervical fundal diameter and the anteroposterior diameter were measured; in the transverse plane, the lateral diameter was measured. Echogenicity of the tumor was determined and classified as hypoechoic, isoechoic, hyperechoic or mixed echogenicity. The amount of tumor vascularization was classified subjectively during real-time 2D ultrasound examination using a color score introduced by the IOTA group for assessment of ovarian mass vascularity 17 : absent (1), minimal (2), moderate (3) or high (4). The examiner then evaluated the presence of deep stromal invasion (more than two-thirds) and parametrial invasion (yes/no). The depth of stromal invasion and parametrial invasion was assessed at the level of entry into the uterine arteries. If the tumor invaded through the paracervical fascia, parametrial involvement was suspected 18. All patients were examined first with TVS/TRS; this was complemented by an abdominal ultrasound examination to look for lymph node enlargement within the pelvis. Tumor volume on 3D power Doppler and gray-scale ultrasound examination was measured for each woman. For 2D and 3D power Doppler assessment, we used standardized settings, adjusting the pulse repetition frequency (range, khz) and gain only, so that the uterine vessels were visualized optimally for each woman without any noise disturbance. We used the software program 4D view (GE Medical Systems) or QLAB (Philips Healthcare) to calculate the volume of the tumor, vascularization index (VI), flow index (FI) and vascularization flow index (VFI). Volume calculation was performed subsequent to the study at each center by the principal investigator, using 15 rotational steps. Tumor volumes were made anonymous to avoid bias. Histological examination was performed according to a predetermined protocol including assessment of tumor type, size and location, presence of deep stromal and parametrial invasion and assessment of lymph node metastasis.

3 472 Pálsdóttir et al. Statistical analysis The chi-square test was used to compare categorical data, the Student s t-test for normally distributed continuous data and the Mann Whitney U-test for non-normally distributed data. A P-value < 0.05 was considered significant. Receiver operating characteristics (ROC) curves with 95% CI were used to determine cut-off values and the specificity and sensitivity for different sonographic variables in the prediction of deep stromal invasion and lymph node metastasis. Areas under the curve (AUC) were calculated for subjective evaluation and for continuous 2D and 3D ultrasound parameters. All calculations were performed using SPSS (Statistical Package for Social Sciences) software, version 20 (IBM, Armonk, NY, USA). RESULTS Clinical and histological characteristics of patients included in the study are presented in Table 1. All 104 women underwent complete pelvic lymphadenectomy, among whom 99 underwent radical surgery; surgery was not performed for the remaining five because of a positive sentinel lymph node. Table 2 shows the 2D and 3D ultrasound variables of the cervical tumor in relation to the occurrence of deep stromal invasion. Women with deep stromal invasion revealed by histology had tumors that were significantly larger in all dimensions and volume, and a higher color score, whereas the 3D vascular indices (VI, FI and VFI) did not differ between those with deep stromal invasion and those without. Table 3 shows the various 2D and s of the tumor in relation to the occurrence of lymph node metastasis. In women with lymph node metastasis, the tumors were significantly larger in all diameters except cervical fundal diameter and were greater in volume as compared to those in women without signs of lymph node metastasis, whereas there was no difference in 3D vascular indices or color scores between these groups. Table 4 and Figure 1a show the effectiveness of subjective ultrasound evaluation in predicting deep stromal invasion as compared to objective 2D and 3D ultrasound measurements. Subjective evaluation was superior to all objective measurements (AUC, 0.93). Maximal tumor diameter (AUC, 0.83 at 20.5-mm cut-off) and tumor volume (AUC, 0.85 at 9.1-mm 3 cut-off) performed best among objective measurements. The 3D power Doppler vascular indices showed no diagnostic value in predicting deep stromal invasion. Subjective ultrasound assessment to predict deep stromal invasion was compared to the maximal tumor diameter using different cut-off levels. With greater tumor diameter cut-off levels, sensitivity increased but specificity decreased simultaneously. We found no cut-off value that performed as well as subjective evaluation (data not shown). Table 5 and Figure 1b show the effectiveness of subjective ultrasound evaluation and objective 2D and 3D ultrasound measurements in Table 1 Clinical and histological characteristics of 104 patients undergoing surgery for cervical cancer Characteristic n (%) Cervical conization 25 (24) Hematometra 12 (12) Clinical stage of cancer IA2 7 (7) IB1 81 (78) IB2 12 (12) IIA 3 (3) IIB 1 (1) Surgical procedure Radical surgery 99/104 (95) Hysterectomy 94/99 (95) Trachelectomy 5/99 (5) Histological finding from radical surgery Deep stromal invasion 63/99 (64) Parametrial invasion 7/99 (7) Histological finding from all surgical procedures Positive lymph nodes 28/104 (27) Squamous cell cancer 66/104 (63) Adenocarcinoma 38/104 (37) predicting lymph node metastasis. Neither subjective evaluation nor any of the measurement techniques allowed prediction of lymph node involvement with an acceptable accuracy; ROC curves of the 3D vascular indices were close to the diagonal reference line, indicating that they were ineffective in assessment (Figure 1b). We performed a subanalysis to clarify if histological type (adenocarcinoma or squamous cell cancer) or tumor echogenicity had an effect on the incidence of lymph node metastasis but found no significant differences. Additionally, a subanalysis of women with clinical Stages IB1 was performed only to determine whether the methods were more effective in this subgroup of women. We found that, irrespective of ultrasound variable, the accuracy of prediction of lymph node metastasis was just as poor in this subgroup. It was not possible to analyze how the different 2D and 3D variables predicted parametrial invasion as there were too few cases with parametrial invasion (n = 7) in the group of patients that underwent radical surgery. DISCUSSION In this prospective multicenter study we have shown that subjective ultrasound evaluation using TVS or TRS was superior to objective measurements of volume or size, irrespective of the cut-off level, to predict deep stromal invasion in patients with cervical carcinoma. We have shown that women with larger tumors are more likely to have lymph node involvement but we could not find a clear cut-off value with acceptable sensitivity and specificity. Subjective evaluation failed to detect many cases of lymph node metastasis, especially in women with small tumors; however, the enlarged lymph nodes that were detected by

4 Prediction of metastasis and stromal invasion in invasive cervical cancer 473 Table 2 Two-dimensional (2D) and three-dimensional (3D) ultrasound parameters of tumors present in 99 women undergoing radical surgery for cervical cancer, according to occurrence of deep stromal invasion Deep stromal invasion Variable No (n = 36) Yes (n = 63) P* Cervical fundal diameter (mm) 17.1 ± ± 12.7 < Anteroposterior diameter (mm) 16.4 ± ± 11.1 < Lateral diameter (mm) 20.6 ± ± 11.8 < Maximum diameter (mm) 21.5 ± ± 11.9 < Color score Low moderate High Volume (mm 3 ) 3.0 ( ) 16.4 ( ) < Vascularization index (%) 33.0 ( ) 30.4 ( ) 0.77 Flow index 38.8 ( ) 38.6 ( ) 0.45 Vascularization flow index 13.2 ( ) 11.6 ( ) 0.61 Data are given as mean ± SD, median (range) or n. P < 0.05 was considered statistically significant. *Student s t-test was used for 2D diameters, chi-square test for color score and Mann Whitney U-test for s. Significant. Table 3 Two-dimensional (2D) and three-dimensional (3D) ultrasound parameters of tumors in 104 women in relation to lymph node involvement Lymph node involvement Variable No (n = 76) Yes (n = 28) P* Cervical fundal diameter (mm) 24.0 ± ± Anteroposterior diameter (mm) 22.9 ± ± Lateral diameter (mm) 28.1 ± ± Maximum diameter (mm) 29.8 ± ± Color score Low moderate High Volume (mm 3 ) 9.5 ( ) 15.7 ( ) 0.03 Vascularization index (%) 33.3 ( ) 30.3 ( ) 0.81 Flow index 39.8 ( ) 38.0 ( ) 0.52 Vascularization flow index 13.2 ( ) 12.3 ( ) 0.76 Data are given as mean ± SD, median (range) or n. P < 0.05 was considered statistically significant. *Student s t-test was used for 2D diameters, chi-square test for color score and Mann Whitney U-test for s. Significant. ultrasound were true positives. The 3D power Doppler vascular indices were of no value in predicting more advanced stages of the disease. The diagnostic challenge is to detect lymph node metastasis, which has been confirmed in another similar study. Epstein et al. found histological evidence of microscopic metastasis in lymph nodes of normal size, making them impossible to detect on ultrasound and even on MRI (detection rate, 3/38 on ultrasound and 4/38 on MRI) 11. The value of tumor size has been addressed recently in a histopathology study on women undergoing surgery for cervical cancer at Stage IB1, showing an increased frequency of lymph node metastasis and a worse prognosis for cases with tumors > 2 cm at diagnosis 19. This is in line with the results of our study in which larger tumors, as measured on ultrasound, had a significantly higher risk of deep stromal invasion and lymph node metastasis. It is important to be aware of the uncertainty of what exactly 3D power Doppler measures, but it is stated that VI measures the number of color voxels in a volume, representing the vessels in the tissue of interest, that FI is believed to represent the intensity of flow at the time of examination and that VFI is a combination of vascularization and flow information Alcazar et al. found no correlation between 3D vascular indices and the presence of lymph node metastasis 23. Other studies, with results consistent with ours, have shown that 3D vascular indices do not correlate with most tumor characteristics 14,15,23. However, two of the studies found higher 3D vascular indices in advanced stages of the disease 15,23 or in poorly differentiated tumors 23. These studies differ from ours as we did not include patients with cervical carcinoma at Stages III IV or healthy patients as controls. We found a positive correlation between deep stromal invasion and color score, which is consistent with the

5 474 Pálsdóttir et al. Table 4 Prediction of deep stromal invasion in women undergoing surgery for cervical cancer using subjective evaluation and objective two-dimensional (2D) and three-dimensional (3D) ultrasound measurements Variable Cut-off AUC (95% CI) Sensitivity (% (n))* Specificity (% (n)) PPV (% (n/n)) NPV (% (n/n)) Subjective evaluation 0.93 ( ) 90.5 (57) 97.2 (35) 98.3 (57/58) 85.4 (35/41) Cervical fundal diameter 25.5 mm 0.77 ( ) 60.3 (38) 86.1 (31) Anteroposterior diameter 15.5 mm 0.81 ( ) 90.5 (57) 55.6 (20) Lateral diameter 20.5 mm 0.81 ( ) 87.3 (55) 63.9 (23) Maximum diameter 20.5 mm 0.83 ( ) 90.5 (57) 61.1 (22) Volume 9.1 mm ( ) 79.4 (50) 83.3 (30) Vascularization index NA 0.48 ( ) Flow index NA 0.48 ( ) Vascularization flow index NA 0.47 ( ) *63 women had deep stromal invasion. 36 women had no deep stromal invasion. AUC, area under the receiver operating characteristics curve; NA, not applicable; NPV, negative predictive value; PPV, positive predictive value. Table 5 Prediction of lymph node metastasis in women undergoing surgery for cervical cancer using subjective evaluation and objective two-dimensional (2D) and three-dimensional (3D) ultrasound measurements Variable Cut-off AUC (95% CI) Sensitivity (% (n))* Specificity (% (n)) PPV (% (n/n)) NPV (% (n/n)) Subjective evaluation 0.69 ( ) 42.9 (12) 96.1 (73) 80.0 (12/15) 82 (73/89) Cervical fundal diameter 30.5 mm 0.58 ( ) 53.6 (15) 69.7 (53) Anteroposterior diameter 30.4 mm 0.62( ) 50.0 (14) 73.7 (56) Lateral diameter 30.5 mm 0.64 ( ) 64.3 (18) 59.2 (45) Maximum diameter 33.5 mm 0.62 ( ) 60.7 (17) 59.2 (45) Volume 15.0 mm ( ) 60.7 (17) 67.1 (51) Vascularization index NA 0.49 ( ) Flow index NA 0.47 ( ) Vascularization flow index NA 0.48 ( ) *28 women had lymph node metastasis. 76 women had no lymph node metastasis. AUC, area under the receiver operating characteristics curve; NA, not applicable; NPV, negative predictive value; PPV, positive predictive value. (a) 1.0 (b) Sensitivity Sensitivity Specificity Specificity Figure 1 Receiver operating characteristics curves for the prediction of deep stromal invasion (a) and lymph node metastasis (b) in cervical cancer, comparing subjective evaluation to two-dimensional (2D) and three-dimensional (3D) ultrasound parameters., Subjective evaluation;, cervical fundal tumor diameter;, anteroposterior tumor diameter;, lateral tumor diameter;, maximal tumor diameter;, 3D tumor volume;, vascularization index;, flow index;, vascularization flow index;, reference line.

6 Prediction of metastasis and stromal invasion in invasive cervical cancer 475 findings of Testa et al. 14. On the other hand, there was no correlation between color score and the presence of lymph node metastasis. In theory, this could be explained by tumor necrosis of the larger and more locally spread tumors. As we found higher color scores in tumors with deep stromal invasion, we would have expected the vascularity indices to support this finding, which was not the case. These differences could also be the result of bias, as the examiners might take into account the gray-scale findings when estimating color score subjectively. To our knowledge, few studies have considered the clinical value of different 3D TVS measurements in predicting deep stromal invasion and lymph node metastasis in patients with early-stage cervical cancer. Our study is unique as it includes only women with cervical cancer undergoing radical surgery and systematic lymphadenectomy; thus, this is the first study that allows assessment of the diagnostic accuracy of various 2D and s as compared to a subjective assessment. The strength of the study is the prospective design and the structured examination procedure. A source of possible bias is the heterogeneity in tumor stages among the study population, as some centers included selected women with large tumors for surgery. We know that women with larger tumors are more likely to have lymph node metastasis, which explains the relatively high incidence (27%) in our study population. The heterogeneity of the study population increases the risk for statistical errors which could affect the validity of the results. However, a subanalysis including only women with tumors at clinical Stage IB1 was performed and no significant difference in the results was found. We included only patients with tumors that could be visualized on ultrasound, which could be perceived to introduce selection bias. However, we think this source of bias is unlikely as we were interested only in comparing visible tumors subjectively to their objective measurements. In the future, it would be interesting to determine whether the assessment of tumor extension could be performed equally well using saved 3D tumor volumes, as on 2D videoclips, and to assess the reproducibility of such evaluations. In this study we did not measure systematically the minimal margin between the tumor and the pericervical fascia, which could prove to be of clinical value. This study shows that assessment of tumor volume and 3D vascular indices does not improve the prediction of deep stromal invasion or lymph node metastasis in women scheduled for surgery for cervical cancer. 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