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Early Cervical Cancer: Predictive Relevance of Preoperative 3-Tesla Multiparametric Magnetic Resonance Imaging

Early Cervical Cancer: Predictive Relevance of Preoperative 3-Tesla Multiparametric Magnetic... Hindawi International Journal of Surgical Oncology Volume 2018, Article ID 9120753, 14 pages https://doi.org/10.1155/2018/9120753 Research Article Early Cervical Cancer: Predictive Relevance of Preoperative 3-Tesla Multiparametric Magnetic Resonance Imaging 1 2 3 4 Hyun Jin Roh, Kyung Bin Kim, Jong Hwa Lee, Hwa Jung Kim, 1 1 Yong-Soon Kwon, and Sang Hun Lee Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea Department of Pathology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea Department of Radiology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea Department of Clinical Epidemiology and Biostatics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea Correspondence should be addressed to Sang Hun Lee; shlee73@uuh.ulsan.kr Received 13 March 2018; Revised 25 June 2018; Accepted 4 July 2018; Published 1 August 2018 Academic Editor:C.H.Yip Copyright © 2018 Hyun Jin Roh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. We assess the predictive significance of preoperative 3-Tesla multiparametric MRI findings. Methods.Atotalof260 patients with FIGO IA2-IIA cervical cancer underwent primary surgical treatment between 2007 and 2016. Univariable and multivariable logistic regression analyses were used to assess the incremental prognostic significance. Results. eTh clinical predictive factors associated with pT2b disease were MRI parametrial invasion (PMI) (adjusted odds ratio (AOR) 3.77, 95% confidence interval(CI) 1.62-8.79; P=0.02) and MRI uterine corpus invasion (UCI) (AOR 9.99, 95% CI 4.11-24.32; P<0.0001). In multivariable analysis, for underdiagnoses, histologically squamous carcinoma versus adenocarcinoma and adenosquamous carcinoma (AOR 2.07, 95% CI 1.06-4.07; P=0.034) and MRI tumor size (AOR 0.76, 95% CI 0.63-0.92; P=0.005) were significant predictors; for overdiagnoses, these results were MRI tumor size (AOR 1.51, 95% CI 1.06-2.16; P=0.023), MRI PMI (AOR 71.73, 95% CI 8.89- 611.38; P<0.0001) and MRI UCI (AOR 0.19, 95% CI 0.01-1.01; P=0.051). Conclusion. PMI and UCI on T2-weighted images through preoperative 3T MRI are useful coefficients for accurate prediction of the pT2b stage; however, careful surveillance is required. Therefore, preoperative decision-making for early cervical cancer patients based on MRI diagnosis should be considered carefully, particularly in the presence of factors that are known to increase the likelihood of misdiagnosis. 1. Introduction classification as the most commonly used method, the overall errorrateofclinicalstagingforcervicalcancercomparedwith surgical staging is between 20 and 66%. Clinical staging has Currently, the International Federation of Gynecology and Obstetrics (FIGO) classification is the most commonly used revealed more inaccurate diagnoses, especially in advanced method to determine the clinical stage of cervical cancer. stages [2–6]. Furthermore, when distinguishing between The FIGO staging guidelines were most recently updated in stages IB and IIB, tumor invasion of the parametrium is one 2009 by the FIGO Committee on Gynecologic Oncology [1]. of the most important considerations. This determination Stage 0 is no longer included in the FIGO 2009 staging [1]. completely depends on the attending gynecologist’s findings The clinical FIGO classification is exclusively used because via manual palpation, which is intrinsically subjective [7]. cancer staging is a generally accepted universal stratification As complementary measures, the National Comprehensive Cancer Network (NCCN) suggests the use of imaging meth- system for communication purposes among institutions. Despite continuous studies for the accurate staging of cervical ods such as CT, MRI, and combined PET-CT in guiding cancer, the reality is that no entirely accurate method exists treatment options and individual treatment design, but this at present. Regarding the limitations of the clinical FIGO practice guideline is not generally accepted for formal and 2 International Journal of Surgical Oncology ocia ffi l staging purposes. Accurate staging of cervical cancer Patients with the following criteria were excluded: (a) is essential when making the therapeutic decision between previously treated with radiotherapy and/or chemotherapy for cervical cancer, (b) contra-indication to the MRI pro- radiation and surgery [8, 9]. For early-stage disease, such as cedure including patients unwilling to go through contrast- stage I and selected IIA, surgery or radiation therapy can enhanced MRI, (c) a previous diagnosis of vulva and vaginal be applied as treatment options [8, 9]. eTh re are various cancer, and (d) concomitant pregnancy. treatments for voluminous stage IB according to the location andsizeofthetumor. Foradvancedstages(stageIIB and 2.2. Conventional Staging Work-Up. FIGO staging was deter- greater), radiation therapy is typically chosen [8–13]. us, Th various methods for the accurate prognostic detection of mined based on findings from physical examination, such as bimanual pelvic examination, endoscopic studies (cystoscopy parametrial invasion have been proposed [14–20]. However, and sigmoidoscopy), and radiologic studies (chest radio- more information is required to formulate accurate deci- graphy, intravenous pyelogram, and barium enema) aeft r sions regarding treatment for individual patients. With the histologic confirmation of invasive cervical cancer. introduction of more sophisticated MRIs, such as “multi- parametric” imaging (the combination or morphologic and functional MRI sequences, including T2-weighted (T2W), 2.3. Surgical Technique. All 260 patients underwent surgery. diffusion-weighted (DW), and magnetic resonance spectro- Regarding the surgical procedure types, hysterectomy scopic imaging and higher field-strength capabilities (3T (laparoscopic, transabdominal, or transvaginal), radical versus 1.5T MRI)), an improvement in staging cervical cancer hysterectomy (laparoscopic, transabdominal, robotic), and radical trachelectomy for fertility preservation were is expected. A few studies have reported that the accuracy of PMI by MRI is associated with the primary tumor size and permitted. All patients underwent pelvic lymph node sampling or dissection. For patients with large tumors (> uterine corpus invasion in patients with clinically localized 2 cm), para-aortic lymph node sampling was performed. cervical cancer who underwent radical hysterectomy (RH) [14–16, 18–21]. Therefore, the present study aimed to optimize the pre- 2.4. MRI Scanning dictability of staging for cervical cancer by analyzing the incremental predictive significance of preoperative 3-Tesla 2.4.1. MRI Protocol. All MRI examinations were scanned on (3T) multiparametric MRI findings for predicting pathologic a3Twhole-bodyMRIscanner(InteraAchieva3T, Philips T2b and predictive factors associated with MRI stage mis- Medical System, Best, the Netherlands) using phased-array diagnosis in patients with early cervical cancer underwent techniques involving pelvic or torso phased-array coils. Mul- radical hysterectomy. tiparametric imaging sequence parameters (Table S1 in the Supplementary Appendix) included multiplanar T2W, T1- weighted (T1W), and DW imaging with multiple b value 2. Methods and Methods (0-800 s/mm2) of the cervix. Gadopentetate dimeglumine contrast (Magnevist; Schering, Berlin, and Germany) in all 2.1. Patient Selection and Treatment. The cohort in this the patients was administered intravenously at a weight- study included 260 documented cervical cancer patients with based dosing of 0.2 ml/kg with a bolus injection rate of clinical FIGO stages IA2 and IIA who underwent primary 2 ml/sec using an automatic injector, which was followed by surgical treatment between January 2007 and December 2016 a 20-ml saline bolus injection. following a 3T MP MRI examination at Ulsan University Hospital. Patient age ranged from 24 to 75 with a mean value 2.4.2. MRI Interpretation. AllMRimageswereassessed of 49.3 years. Tissue diagnosis of cervical cancer was per- retrospectivelybasedonalltheavailableclinicaldatabya formed through biopsy specimens for all patients. Clinical gynecological radiologist with more than 10 years of expe- and MR imaging data were recorded retrospectively based rience in the field of gynecologic cancer imaging. A gyne- on the patients’ medical records and PACs system by one cological radiologist described each MRI finding including author. the presence of primary tumor; depth of stromal invasion (no Inclusion criteria were (a) biopsy-documented invasive invasion, partial invasion, and complete invasion); extension cervical cancer by a loop electrosurgical excision procedure to uterine corpus, vagina, parametrium, pelvic sidewall, (LEEP) or a cone biopsy or punch biopsy; at least 7 days urinary bladder, and rectum; and pelvic and para-aortic aer ft a biopsy, MRI was performed to prevent false-positive lymph node metastasis. At the end of the imaging evaluation findings due to biopsy inflammation, (b) clinical FIGO stage session, multiparametric MRI staging was determined by IA, IB, or IIA, (c) histology of squamous cell carcinoma or MRI T category using both FIGO and TNM stratification adenocarcinoma or adenosquamous carcinoma, (d) no med- criteria (i.e., AJCC-TNM Cancer Staging System, 7th edition) ical or surgical contraindications to radical hysterectomy with [22, 23] as shown in Table S2. When no tumor was identified pelvic lymph node dissection (PLND) with or without para- by MR imaging despite findings of malignant cells on biopsy, aortic lymph node sampling (PALS) and dissection (PLND), a radiologic stage of MRI-invisible IB1 was assigned in (f)havinganEastern CooperativeOncologyGroup (ECOG) previous study. However, in this study, MRI-invisible IB1 was performance status of 0-1, and (g) provided informed con- independently classified as MRI-invisible-T0 stage (Figures 4 sent. and5)ratherthanincludedintheMRIIB1stage. International Journal of Surgical Oncology 3 2.4.3. Histopathologic Analysis. The procedure was per- predicting parametrial invasion (PMI) was 83%. eTh sensitiv- formed and the surgical specimens of the 260 radical hys- ity, specicfi ity, positive predictive value (PPV), and negative terectomy and trachelectomy patients were prepared accord- predictive value (NPV) of 3T multiparametric MRI for ingtostandardmethods. predicting pathologic parametrial invasion were 62%, 88%, Allsurgicalspecimens were xfi ed informalin andembed- 53%, and 91%, respectively ded in paraffin. A dedicated and experienced gynecologic oncology pathologist reviewed all of the H&E-stained sec- 3.3. Logistic Regression MVA: Pathologic T2b Disease Out- tions for all patients. The overall stage was determined come. A subset of 203 women (excluding 57 with MRI T0 according to both FIGO and TNM stratification criteria. eTh stage) was stratified according to the MRI finding. Based on TNM classification based on the American Joint Committee a univariable analysis of these women that excluded those on Cancer (AJCC) staging system, 7th edition (2010), was the with MRIT0stage,MRI PMI(AOR3.77,95%CI1.62-8.79; radical hysterectomy T category [23]. P=0.002), and MRI uterine corpus invasion (UCI) (AOR 9.99, In addition to pTNM classification based on AJCC stag- 95% CI 4.11-24.32; P<0.0001) were associated with increased ing manual, if no tumor was found in the cervix in the surgical odds of having pT2b disease aer ft adjusting clinical predictive specimen aer ft positive biopsy for infiltrating carcinoma, we factorsasshownin Table2. stratified as pT0b1 stage, which was classified as a class A0 in Meigs J.V. et al. at surgical and pathologic classification of the 3.4. Logistic Regression MVA: Underdiagnosis and Overdiag- uterine cervix [3]. nosis. eTh accuracy of MRI staging with regard to the histologic specimens from 260 cervical cancer patients with 2.5. Statistical Analysis. The distributions of the study clinical FIGO stages IA-IIA was 69%, whereas the overall cohort’s clinical and pathologic characteristics were calcu- error rates varied from 15% for MRI T1b to 46% for MRI T2b. latedand arepresentedin Table1.Theclinicalpredictive According to our findings, the MRI stage underdiagnosed factors were analyzed by the distributions of categorical 18% of patients and overdiagnosed 14%. factors stratified by MRI T category (T0, T1b, T2a, and T2b). The underdiagnosis rates were 46%, 13%, and 20% for Continuous variables were compared using ANOVA MRI stages T0, Tb1, and T2a, respectively. The overdiagnosis or the Kruskal-Wallis test, and categorical variables were rates were 2%, 70%, and 46% for MRI stages Tb1, T2a and compared using the휒2 test or Fisher’s exact test. T2b, respectively (Tables 4, and 5). eTh factors influencing the Accuracy was calculated using the n fi al surgical pathol- accuracy of MRI staging were further investigated (Table 3). ogy examinations as the reference. A logistic regression mul- In the underdiagnosis cases (Figures 6 and 7), the tivariable analysis (MVA) (Tables 2 and 3) was used to assess predictive factors included a histology of squamous versus the clinical factors for predicting upstaging to pT2b and adenocarcinoma and adenosquamous carcinoma (AOR 2.07, the clinical factors associated with MRI stage misdiagnosis 95% CI 1.06-4,07; P=0.034) and MRI tumor size (AOR in FIGO IA-IIA cervical cancer patients underwent radical 0.76, 95% CI 0.63-0.92; P=0.005). In the overdiagnosis cases hysterectomy, adjusting for age, menopause, parity, and BMI, (Figures 2 and 3), the predictive factors included MRI tumor cesarean section, history of at least one normal delivery, size (AOR 1.51, 95% CI 1.06-2.16; P=0.023), MRI uterine menopause, SCC ag, grade, MRI stage, clinical FIGO stage, corpus invasion (AOR 0.13, 95% CI 0.03-0.49; P=0.003), and MRI tumor size, MRI Pelvic LN invasion, MRI parametrial MRI parametrial invasion (AOR 73.73, 95% CI 8.89-611.38; invasion, MRI uterine corpus invasion, MRI deep stromal P<0.0001) aer ft preoperative predictors associated with MRI invasion, and MRI vaginal invasion. stage misdiagnosis were adjusted as shown in Table 3. Unadjusted and adjusted odds ratios (UORs and AORs, The area under receiver operating characteristics curve respectively)werecalculatedforeach clinical covariate,and analysis of the cut-off lesion size measured on MRI for these values were reported with 95% confidence intervals optimal accuracy to predict the effect of large tumor size on (CIs). Area under the receiver operating characteristic (ROC) misdiagnosis (overdiagnosis and underdiagnosis) is shown in curve (A ) was used to determine the cut-off lesion size Figure 1. measured on MRI for optimal accuracy to predict the effect With overdiagnosis, a tumor cut-off size of 2.9 cm of large tumor size on misdiagnosis (overdiagnosis and (approximated on T2W images) was observed with 80% underdiagnosis). A P value<0.05 was considered statistically sensitivity and 53% specificity (AZ=0.68, 95% CI 0.60-0.77; significant. IBM SPSS 21.0 statistics software was used (IBM Table 6), in underdiagnosis, a tumor cut-off size 0.25 cm Institute, Inc., Armonk, NY, USA). (approximatedonT2W images)was observed with57% sensitivity and 83% specificity (AZ=0.64, 95% CI 0.54-0.75; 3. Results Table 6) 3.1. Description of the Study Cohort Stratified by MRI T Category. The clinical and pathologic characteristics of the 4. Discussion 260 women in this study cohort are shown in Table 1 and categorized by MRI T category (T0, T1b, T2a, and T2b). Previous studies have evaluated the ability of 1.5 T MRI to determinethepresenceofparametrialinvasionandhavecon- 3.2. Performance Characteristics of 3T Multiparametric MRI. sidered whether the information from 1.5 T MRI might mean- The overall accuracy of 3T multiparametric MRI for ingfully supplement the known predictive factors, including 4 International Journal of Surgical Oncology Table 1: Comparison of the distribution of clinical and pathologic characteristics of the 260 women in the cohort study stratified by MRI staging. MRI MRI MRI MRI Clinical characteristics P-value T0 T1b T2a T2b (n=57) (n=139) (n=10) (n=54) Age(y)∗ 0.207 47.6 49.5 47.9 52.1 Parity∗ 0.773 2.1 2.2 1.9 2.3 Operative procedure 0.01 Open modified radical hysterectomy 2(3.5) 1(0.7) 0(0) 0(0) Open radical hysterectomy 9(15.8) 47(33.8) 2(20.0) 25(46.3) Laparoscopic modified radical hysterectomy 20(35.1) 9(6.5) 0(0) 1(1.9) Laparoscopic radical hysterectomy 22(38.6) 77(55.4) 8(80.0) 28(51.9) Laparoscopic radical trachelectomy 3(5.3) 3(2.2 0(0) 0(0) Robotic radical hysterectomy 1(1.8) 1(0.7) 0(0) 0(0) Robotic trachelectomy 0(0) 1(0.7) 0(0) 0(0) Menopause 0.004 No 37(64.9) 79(56.8) 5(50) 21(38.9) Yes 20(35.1)) 60(43.2) 5(50) 33(61.1) Cesarean section 0.101 No 54(94.7) 122(87.8) 7(70) 46(85.2) Yes 3(5.3) 17(12.2) 3(30) 8(14.8) History of at least one normal delivery 0.381 No 7(12.3) 18(12.9) 5(50) 8(14.8) Yes 50(87.7) 121(87.1) 5(50) 46(85.2) BMI 0.948 24.1 23.9 24.3 23.8 SCC Ag (ng/ml) ∗ <0.0001 0.9 2.7 3.9 10.1 CEA(U/ml) ∗ 0.098 2.7 4.9 11.1 12.3 CA 125(U/ml) ∗ 0.441 18.8 15 21.4 22.8 Histology 0.166 Squamous 35(61.4) 94(67.6) 8(80.0) 41(75.9) Adenocarcinoma 21(36.8) 38(27.3) 2(20.0) 11(20.4) Adeno-squamous 1(1.8) 7(5) 0(0.0) 2(3.7) Grade 0.132 24(42.1) 20(14.4) 0(0.0) 8(14.8) 19(33.3) 77(55.4) 5(50.0) 29(53.7) 3 5(8.8) 32(23.0) 4(40.0) 13(24.1) Unknown 9(15.8) 10(7.2) 1(10.0) 4(7.4) Biopsy type <0.0001 Punch biopsy 21(36.8) 106(76.3) 8(80.0) 41(77.4) LEEP 36(63.2) 33(23.7) 2(20.0) 12(22.6) Clinical FIGO tumor stage <0.0001 IA 15(26.3) 0(0.0) 0(0.0) 0(0.0) IB1 42(73.7) 102(73.4) 4(40.0) 20(37.0) IB2 0(0.0) 23(16.5) 3(30.0) 26(48.1) IIA1 0(0.0) 6(4.3) 2(20.0) 4(7.4) IIA2 0(0.0) 8(5.8) 1(10.0) 4(7.4) RH T category (final pathologic stage ) <0.0001 T1a 15(26.3) 0(0.0) 0(0.0) 0(0.0) T0b1 16(28.1) 3(2.2) 0(0.0) 0(0.0) T1b1 26(45.6) 96(66.9) 6(60.0) 11(20.4) International Journal of Surgical Oncology 5 Table 1: Continued. MRI MRI MRI MRI Clinical characteristics P-value T0 T1b T2a T2b (n=57) (n=139) (n=10) (n=54) T1b2 0(0.0) 25(18.0) 1(10.0) 11(20.4) T2a1 0(0.0) 1(0.7) 0(0.0) 3(5.6) T2a2 0(0.0) 1(0.7) 1(10.0) 0(0.0) T2b 0(0.0) 16(11.5) 2(20.0) 29(53.7) Pathologic Tumor size <0.0001 0.601 2.93 4.24 4.68 Pathologic tumor size <0.0001 0-≤1 43(75.4) 19(13.7) 0(0.0) 0(0.0) 1-≤2 10(17.5) 21(15.1) 0(0.0) 2(3.7) 2-≤3 2(3.5) 46(33.1) 2(20.0) 9(16.7) 3-≤4 2(3.5) 21(15.1) 4(40.0) 11(20.4) 4-≤5 0(0.0) 18(12.9) 3(30.0) 14(25.9) 5-≤6 0(0.0) 13(9.4) 0(0.0) 7(13.0) 6-≤7 0(0.0) 1(0.7) 0(0.0) 7(13.0) >7 0(0.0) 0(0.0) 1(10.0) 4(7.4) LVSI <0.0001 Yes 4(7.0) 53(38.1) 7(70.0) 36(66.7) No 53(93.0) 86(61.9) 3(30.0) 18(33.3) Pathologic deep stromal invasion <0.0001 Inner 1/3 48(84.2) 27(19.4) 2(20.0) 0(0.0) Middle 1/3 6(10.5) 44(31.7) 3(30.0) 2(3.7) Outer 1/3 3(5.3) 68(48.9) 5(50.0) 52(96.3) Pathologic parametrial invasion <0.0001 No 57(100.0) 124(89.2) 8(80.0) 25(46.3) Yes 0(0.0) 15(10.8) 2(20.0) 29(53.7) Pathologic parametrial invasion laterality <0.0001 Negative 57(100.0) 124(89.2) 8(80.0) 22(40.7) Unilateral 0(0.0) 8(5.8) 1(10.0) 14(25.9) Bilateral 0(0.0) 7(5.0) 1(10.0) 18(33.3) Pathologic pelvic LN involvement <0.0001 Negative 55(96.5) 115(82.7) 6(60.0) 30(55.6) Positive 2(3.5) 24(17.3) 4(40.0) 24(44.4) Pathologic para-aortic LN involvement 0.001 Negative 51(89.5) 120(86.3) 9(90.0) 45(83.3) Positive 0(0.0) 10(7.2) 1(10.0) 8(14.8) Not done 6(10.5) 9(6.5) 0(0.0) 1(1.9) Pathological uterine involvement No 56(98.2) 125(89.9) 8(80.0) 26(48.1) Yes 1(1.8) 14(10.1) 2(20.0) 28(51.9) MRI tumor size∗ <0.0001 0.00 2.89 4.06 4.61 MRI pelvic LN involvement Negative 57(100.0) 128(92.1) 7(70.0) 36(66.7) Positive 0(0.0) 11(7.9) 3(30.0) 18(33.3) MRI para-aortic LN involvement 0.46 Negative 57(100.0) 137(98.6) 10(100.0) 53(98.1) Positive 0(0.0) 2(1.4) 0(0.0) 1(1.9) MRI uterine corpus invasion 6 International Journal of Surgical Oncology Table 1: Continued. MRI MRI MRI MRI Clinical characteristics P-value T0 T1b T2a T2b (n=57) (n=139) (n=10) (n=54) No 57(100.0) 127(91.4) 8(80.0) 27(50.0) Yes 0(0.0) 12(8.6) 2(20.0) 27(50.0) MRI deep stromal invasion No invasion 57(100.0) 2(1.4) 0(0.0) 0(0.0) Partial invasion 0(0.0) 79(56.8) 6(60.0) 3(5.6) Complete invasion 0(0.0) 58(41.7) 4(40.0) 51(94.4) eTh data are presented as the number ( %)orthemean± SD. FIGO, International Federation of Gynecology and Obstetrics; RH, radical hysterectomy; LVSI, lymphovascular stromal invasion; LN, lymph node; CA 125, carbohydrate antigen 125; CEA, carcinoembryonic antigen; CA 19-9, carbohydrate antigen 19-9; MRI, magnetic resonance imaging. Figure 1: Comparison of finial pathologic stage versus multiparametric MRI radiologic stage versus clinical FIGO stage. primary tumor size, the depth of cervical stromal invasion, FIGO stages IA-IIA2 cervical cancer underwent radical hys- and extension to the uterine corpus in patients with cervical terectomy. cancer patients [7, 15–20, 24, 25]. In 2005, Hricak et al. reported a prospective 25-center However, few studies using 1.5 T MRI have attempted clinical study of 172 patients. In the detection of advanced to identify established factors associated with upstaging stage (≥IIB), the sensitivity, specificity, NPV, and PPV for at the radical hysterectomy in patients with early cervical MRIwere53%,74%,85%,and 37%,respectively.Inourstudy, cancer IA-IIA. To determine an optimal treatment plan for the sensitivity, specificity, NPV, and PPV of 3T multipara- patients scheduled to undergo radical hysterectomy, accu- metric MRI to predict pathologic parametrial invasion were rate risk assessment is necessary because the decision to 62%, 88%, 91%, and 53%, respectively. Our results for 3T use concurrent chemoradiation therapy with radical hys- multiparametric MRI are higher than those reported in prior terectomy depends on the patient’s clinicopathologic risk studies [17]. factors. The identification of high-risk factors is essential Hicak et al. [21] indicated a strong correlation between to avoid overtreatment, which carries substantial acute and parametrial invasion and uterine corpus invasion and Peter chronic adverse effects [4, 26]. er Th efore, we assessed the de Boer’s systemic review [20] noted a high accuracy rate for predictive relevance of preoperative 3T MRI findings in MRI in detecting cancer involvement of the uterine internal predicting pathologic stage T2b and the clinical factors os in cervical cancer. This study confirmed the results of those associated with MRI stage misdiagnosis in patients with two studies of MRI parametrial invasion and MRI uterine International Journal of Surgical Oncology 7 Table 2: Adjusted odds ratios with 95% confidence intervals (CI) and ass ociated P values from the logistic regression predicting pathologic category T2b in the 203 study cohort patients. Univariable analysis Multivariable analysis No. of events(% Clinical characteristics No. of patients of patients) UOR (95% CI) P AOR (95% CI) p Age(y) 203 1.05(1.02-1.09) 0.001 1.05(1.01-1.09) 0.009 47(23.2) Parity 203 0.99(0.76-1.31) 0.992 47(23.2) BMI 203 47(23.2) 1.04(0.95-1.13) 0.424 Cesarean section No 175 1 0.476 42(24) Yes 28 0.69(0.25-1.92) 5(17.9) History of at least one normal delivery 203 0.401 No 31 1 9(29) Yes 172 0.69(0.29-1.63) 38(22.1) Menopause 203 0.007 No 105 1 16(15.2) Yes 98 2.57(1.30-5.09) 31(31.6) Histology 0.374 Squamous 143 1 31(21.7) Adenocarcinoma 51 1.51(0.73-3.09) 15(29.4) Adenosquamous 9 0.45(0.05-3.75) 1(11.1) Grade 0.45 128 1 7(25) 2 111 0.83(0.32-2.18) 24(21.6) 349 10(20.4) 0.77(0.26-2.31) Unknown 15 2.00(0.52-7.65) 6(40) SCC ag(ng/mL) 203 1.04(1.01-1.06) 0.012 47(23.2) MRI T stage <0.0001 T1b 103 1 16(11.5) T2a 10 1.92(0.38-9.86) 2(20) T2b 54 29(53.7) 8.92(4.23-18.82) Clinical FIGO stage <0.0001 IB1 126 1 20(15.8) IB2 52 19(36.5) 7.41(3.04-16.12) IIA1 12 2.67(0.65-11.03) 3(25) IIA2 13 5.00(1.44-17.41) 5(38.5) MRI tumor size 203 1.84(1.46-2.32) <0.0001 47(23.2) MRI pelvic LN involvement 0.013 Negative 171 1 34(19.9) Positive 32 2.76(1.24-6.13) 13(40.6) MRI parametrial invasion <0.0001 0.002 No 146 11 18(12.3) Yes 57 7.37(3.59-15.08) 3.77(1.62-8.79) 29(50.9) MRI parametrial invasion <0.0001 Negative 146 1 17(11.6) Unilateral 46 6.37(2.95-13.76) 21(45.7) Bilateral 11 34.15(6.80-171.43) 9(81.8) MRI vaginal involvement 0.60 No 193 1 44(22.8) Yes 10 1.45(0.36-5.85) 3(30) 8 International Journal of Surgical Oncology Table 2: Continued. No. of events(% Univariable analysis Multivariable analysis Clinical characteristics No. of patients of patients) UOR (95% CI) P AOR (95% CI) p MRI uterine corpus invasion <0.0001 <0.0001 No 162 11 19(11.7) Yes 41 16.21(7.19-36.57) 9.99(4.11-24.32) 28(68.3) Figure 2: Stage IB1 cervical adenocarcinoma in a 42-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show a moderated lobulated mass of uterine cervix with a focal disruption (arrow) of peripheral rim. The maximum diameter of the lesion is measured 3.6cm on the T2-weighted sagittal image. At histopathological finding, no parametrical lesion was found. MRI stage T2b ( ≤ 4cm) was overdiagnosed as final pathologic stage T1b1. Figure 3: Stage IB2 squamous cervical carcinoma in a 49-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show a 6cm sized lobulated concentric tumoral thickening of whole cervical stroma with an ill-defined peripheral margin (arrow) and invasion to endomyometrium(arrowhead); the maximum diameter of the lesion is measured 6cm on the T2-weighted sagittal image. At histopathological finding, no parametrial lesion was found. MRI stage T2b ( > 4 cm) was overdiagnosed as final pathologic stage T1b2. corpus invasion as credible predictive factors for predicting over RH in cases of suspected pT2b cervical cancer, whereas pT2b. clinicians are more likely concerned with the predictive It is noteworthy that radiologists have been providing values of the diagnosis than its specicfi ity or sensitivity. high specificity readings to prevent unnecessary abolition of Generally, in cases of FIGO stages≥IIB, gynecologists would curative surgery while favoring external beam radiotherapy get the greatest benetfi from tests with a high NPV for a International Journal of Surgical Oncology 9 Table 3: Univariable and multivariable analysis of factors associated with diagnostic inaccuracy of preoperative MRI staging. Under-diagnosis Over-diagnosis Univariable Multivariable Univariable Multivariable UOR 95% AOR 95% Over- all P AOR 95% CI Over- all P UOR 95% CI Over-all P Over- all P CI CI 1.02 0.99 Age(y) 0.254 0.409 (0.99-1.05) (0.95-1.02) Menopause 0.605 0.394 No 1 1 1.19 1.37 Yes (0.62-2.27) (0.66-2.83) 1.08 1.13 Parity 0.584 0.449 (0.83-1.39) (0.82-1.55) History of at least one 0.751 0.314 normal delivery No 1 1 0.86 0.62 Yes (0.35-2.15) (0.43-1.58) Histology 0.521 0.159 Squamous 1 1 2.11 0.25 Adenocarcinoma (1.07-4.16) (0.074-0.87) 1.72 1.38 Adeno-squamous (0.33-9.05) (0.27-7.17) 0.031 0.034 0.055 0.064 Squamous 1 1 1 1 Adenocarcinoma or 2.07 2.07 0.38 0.34 adenosquamos (1.07-3.99) (1.06-4.07) (0.14-1.02) (0.11-1.07) 0.96 1.01 SCC ag(ng/mL) 0.257 0.341 (0.89-1.03) (0.99-1.04) 0.76 0.76 1.46 1.51 MRI tumor size 0.004 0.005 0.001 0.023 (0.63-0.92) (0.63-0.92) (1.18-1.81) (1.06-2.16) MRI parametrial 0.029 <0.0001 <0.0001 invasion No 1 1 1 73.73 0.11 11.94 Yes (8.89- (0.14-0.79) (5.21-27.35) 611.38) MRI uterine corpus 0.347 0.363 0.003 invasion No 1 1 1 1.49 1.54 0.13 Yes (0.65-3.49) (0.61-3.90) (0.03-0.49) MRI deep stromal 0.840 0.006 0.051 invasion No invasion & partial 11 1 invasion 1.07 2.92 0.19 Complete invasion (0.55-2.07) (1.37-6.23) (0.01-1.01) reliable negative test result (negative is stage≤IIA), which a reliable positive test result (positive stage ≥ stage IIB) could change their treatment decision from conservative might highly influence gynecologic oncologists to change treatment to surgery. their treatment decision to prevent unnecessary treatment For patients with FIGO stage ≤IIA, PPV is clinically after curative surgery. eTh refore, a high PPV helps reduce the most important value for treatment planning because the substantial risk of additional treatment aeft r curative 10 International Journal of Surgical Oncology Table 4: Comparison between final pathologic stage and MRI radiologic stage. Final pathologic stage MRI radiologic stage T2b (%) T2a2(%) T2a1(%) T1b2(%) T1b1(%) T0b1∗ (%) T1a (%) Total T2b 29(61.7) 0(0) 3(75) 11(29.7) 11(8.1) 0 0 54 T2a 2(4.3) 1(50) 0(0) 1(2.7) 6(4.4) 0 0 10 T1b 16(34) 1(50) 1(25) 25(67.6) 93(68.4) 3(15.8) 0 139 T0 0 0 0 0 26(19.1) 16(84.2) 15(100) 57 47 2 4 37 136 19 15 260 ∗ After a positive biopsy for infiltrating carcinoma, no tumor was found in the cervix in the surgical specimen. Table 5: Incidence of staging errors. MRI Stage Errors and incidence with a comparison of MRI stage to surgico-pathologic stage T0(57 patients) Understaged (26:46%) T1b1: Tumor confined to the cervix or microscopic lesion greater than T1a1/a2, in greatest dimension (26) T1b (139 patients) T2a1: Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina,≤4cm in greatest dimension (1) Understaged (18:13%) T2a2: Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina> 4.0 cm in greatest dimension (1) T2b: Tumor with parametrial invasion (16) T0b1: Aer ft a positive biopsy for infiltrating carcinoma, no tumor was found in the cervix in the surgical Overstaged (3:2%) specimen (3) T2a (10 patients) Understaged (2:20%) T2b: Tumor with parametrial invasion (2) T1b1: Tumor limited to cervix or microscopic lesion greater than T1a1/a2,≤ 4.0 cm in greatest dimension Overstaged (7:70%) (6) T1b2: Tumor limited to cervix or microscopic lesion greater than T1a1/a2,> 4.0cmingreat dimension(1) T2b (54 patients) T1b1: Tumor limited to cervix,≤ 4.0 cm or less in greatest dimension (11) T1b2: Tumor limited to cervix,> 4.0 cm in great dimension (11) Overstaged (25:46%) T2a1: Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina,≤4cm in greatest dimension (3) Table 6: Clinical performance of the cut-off lesion size measured on MRI to predict the effect of large tumor size for misdiagnosis (overdiagnosis and underdiagnosis) with optimal accuracy. AUC Threshold(cm) Sensitivity (%) Specificity (%) Accuracy (%) (95% CI) 0.68 Overdiagnosis MRI tumor size > 2.9 80 53 58 (0.60-0.77) 0.64 Underdiagnosis MRItumor size < 0.25 56.5 83 77 (0.54-0.75) surgery by providing information regarding the presence of radiotherapy would be preferable to surgery in cases of parametrial invasion. suspected pT2b cervical cancer to prevent the unnecessary Notably, the 3T multiparametric MRI positive predictive rejectionofcurativesurgery. value (PPV) for parametrial invasion is 54% (29/54), which In this study, furthermore, compared with surgical stag- is moderate in this patient group [25]. u Th s, 25/54 (46.2%) ing, the overall accuracy of MRI stage was 69%; underdiag- of patients were incorrectly predicted to have parametrial nosis and overdiagnosis occurred with 13-46% and 2-46% in invasion and would prefer external beam radiotherapy to each MRI stage, respectively (Table 5). Our results showed RH in cases of suspected pT2b cervical cancer to prevent that MRI staging resulted in more inaccurate diagnoses, unnecessary abolition of curative surgery and external beam particularly for MRI stage T0 and advanced stages. International Journal of Surgical Oncology 11 Figure 4: Stage IB1 squamous cervical carcinoma in a 58-year-old woman with radical hysterectomy (A) T2-weighted axial and (B) sagittal MR images show no gross cancerous lesion of uterine cervix but a tissue defect (arrow) aer ft conization. At histopathological finding, no residual tumor in uterine cervix was found. MRI stage T0 was diagnosed as final pathologic stage T0b1. Figure 5: Stage IB1 squamous cervical carcinoma in a 28-year-old woman with trachelectomy (A) T2-weighted axial and (B) sagittal MR images show no gross cancerous lesion of uterine cervix but a tissue defect (arrow) aer ft conization. At histopathological finding, 1.2 cm sized invasive squamous cell carcinoma in uterine cervix was found. MRI stage T0 was underdiagnosed as final pathologic stage T1b1. Regarding MRI stage misdiagnosis, our results demon- and3); thesesamepatientsweresurgicopathologically staged strated that underdiagnosis is aeff cted by MRI tumor size as T2a1(3), T1b2(11) (Figure 3), or T1b1(11) (Figure 2). This and histologic cell type. Overdiagnosis is also influenced by errorofMRI stageT2bwithacomparisonofMRI stageto MRI tumor size, MRI parametrial invasion, and MRI uterine surgicopathologic stage showed 46% in this study, whereas corpus invasion. previous studies reported 63-67% incidence [2, 17, 25, 27]. The primary treatment options for early cervical cancer In cases of early cervical cancer patients diagnosed as MRI are surgery or chemoradiotherapy [8, 9, 14]. However, there T2b, the substantial likelihood of overdiagnosis should be areadvantagestotheuseofsurgery insteadofradiotherapy, considered. particularly in younger women for whom ovarian preser- Although MRI measured tumor size and volume seem to vation might be important. From a clinical perspective, be strongly correlated as a predictive factor of parametrial a dilemma exists regarding the reliability of MRI results invasion in cervical cancer, but they are still controversial to guide treatment options and design. Such reliability is [15, 18]. We have described in detail and further investigated particularly germane in case of early cervical cancer patients the factors believed to affect the diagnostic inaccuracy of MRI diagnosed as MRI T2b stage, notably in young women. staging, particularly regarding the predictive effect of large Interestingly, 35 cases were overdiagnosed by MRI stag- tumor size on misdiagnosis. Regarding MRI tumor size, when ing,whereas25of35werestagedasT2bby MRI(Figures2 larger tumor size determined by MRI is an important factor, 12 International Journal of Surgical Oncology Figure 6: Stage IB1 squamous cervical carcinoma in a 51-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show as 2.7 cm lobulated mass (star) on posterior lip of uterine cervix with no disruption of peripheral rim. eTh maximum diameter of the lesion is measured 2.7cm (arrowhead) on the T2-weighted sagittal image. At histopathological finding, bilateral parametrial lesion was found. MRI stage T1b (≤ 4 cm) was underdiagnosed as final pathologic stage T2b. Figure 7: Stage IB2 cervical adenocarcinoma in a 48-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show a 5 cm well defined exophytic mass (star) mainly involving right post erior exocervix with no disruption of peripheral rim. The maximum diameter of the lesion is measured 5cm (arrowhead) on the T2-weighted sagittal image. At histopathological finding, bilateral parametrial lesion was found. MRI stage T1b (> 4 cm) was underdiagnosed as final pathologic stage T2b. the possibility of overdiagnosis must be considered. In this is essential (Figure 5). In previous studies, MRI was use- study, we observed that tumor size > 2.9 cm is correlated ful to detect the presence of tumor in endocervix and highly with overdiagnosis. The larger (minimally 2.9 cm, the to guide decisions regarding fertility-sparing versus non- selected cut-off value of the ROC curve) the MRI tumor fertility-sparing treatment approaches [30]. size is, the more the overdiagnoses are likely to result. In This study examined additional details; for example, addition, we observed that, for MRI tumor size, a cut-off as pertains to underdiagnosis, specific histologic cell types value of< 0.25 cm on the ROC curve correlated highly with such as adenocarcinoma and adenosquamous carcinoma of underdiagnosis [28–30]. the cervix were significant factors. We also demonstrated Regarding MRI stage misdiagnosis, particularly under- that, in cases of MRI-invisible T0 stage, adenocarcinoma, diagnosis (Figures 5, 6, and 7), a high probability exists that and adenosquamous carcinoma histology, a high possibility the surgical treatment of patients will be aeff cted negatively existed for the presence of tumor according to the surgico- because surgical treatment in underdiagnosed cases results pathologic results. in inadequate surgery. Particularly for patients who wish to Several points require further discussion. First, the most preserve fertility, weighing the reliability of an MRI-invisible contentious ndin fi g in this study, shown in Table 2, was tumor stage result before undergoing radical trachelectomy that although MRI parametrial invasion is considered as a International Journal of Surgical Oncology 13 significant factor in predicting pathologic T2b, this study [2] J. R. van Nagell Jr., J. W. Roddick Jr., and D. M. Lowin, “eTh staging of cervical cancer: Inevitable discrepancies between notably found that MRI showed low sensitivity and a mod- clinical staging and pathologic findings,” American Journal of erate PPV for parametrial invasion [17], which is a sig- Obstetrics & Gynecology,vol.110,no. 7,pp.973–978,1971. nicfi ant predictor of overdiagnosis. eTh refore, preoperative [3] H. E. Averette, J. H. Ford Jr., R. C. Dudan, R. E. Girtanner, W. decision-making based on MRI diagnosis for early cervical J. Hoskins, and M. H. 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Treatment results disease and accordingly may require adjuvant treatment. and data on the postoperative course over a minimum of 5 years Several limitations of this study should be noted. First, following uniform surgery and standardized histological exami- this study is based on a retrospective chart review, including nation of the histological material of 1092 patients at 4 university clinical cervical cancer data. Second, most of the partici- gynecology clinics,” Geburtshilfe and Frauenheilkunde,vol.44, pants underwent conization before MRI in clinical practice no. 05, pp. 279–285, 1984. [29]. Additionally, we did not assess the effects of other [6] J. Vidaurreta, A. Bermudez, ´ G. Di Paola, and J. Sardi, “Laparo- confounding factors, such as cervicitis, deep nabothian scopic staging in locally advanced cervical carcinoma: A new cysts, tunnel clusters, and endocervical hyperplasia on the possible philosophy,” Gynecologic Oncology,vol.75,no.3,pp. accuracy of MRI interpretation. 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[12] C. W. Whitney, W. Sause, B. N. Bundy et al., “Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as Conflicts of Interest an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gyneco- The authors do not report any potential conflicts of interest. logic Oncology Group and Southwest Oncology Group Study,” Journal of Clinical Oncology,vol.17,no.5,pp.1339–1348,1999. Supplementary Materials [13] P. G. Rose, B. N. Bundy, E. B. Watkins et al., “Concurrent cisplatin-based radiotherapy and chemotherapy for locally Supplementary Table 1: three-tesla multiparametric MRI advanced cervical cancer,” eTh New England Journal of Medicine , sequence parameters. Supplementary Table 2: American vol. 340, no. 15, pp. 1144–1153, 1999. Joint Committee on Cancer (AJCC)-Tumor-Node- [14] K. Togashi, K. Nishimura, T. 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Early Cervical Cancer: Predictive Relevance of Preoperative 3-Tesla Multiparametric Magnetic Resonance Imaging

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Hindawi Publishing Corporation
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Copyright © 2018 Hyun Jin Roh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2018/9120753
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Abstract

Hindawi International Journal of Surgical Oncology Volume 2018, Article ID 9120753, 14 pages https://doi.org/10.1155/2018/9120753 Research Article Early Cervical Cancer: Predictive Relevance of Preoperative 3-Tesla Multiparametric Magnetic Resonance Imaging 1 2 3 4 Hyun Jin Roh, Kyung Bin Kim, Jong Hwa Lee, Hwa Jung Kim, 1 1 Yong-Soon Kwon, and Sang Hun Lee Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea Department of Pathology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea Department of Radiology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea Department of Clinical Epidemiology and Biostatics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea Correspondence should be addressed to Sang Hun Lee; shlee73@uuh.ulsan.kr Received 13 March 2018; Revised 25 June 2018; Accepted 4 July 2018; Published 1 August 2018 Academic Editor:C.H.Yip Copyright © 2018 Hyun Jin Roh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. We assess the predictive significance of preoperative 3-Tesla multiparametric MRI findings. Methods.Atotalof260 patients with FIGO IA2-IIA cervical cancer underwent primary surgical treatment between 2007 and 2016. Univariable and multivariable logistic regression analyses were used to assess the incremental prognostic significance. Results. eTh clinical predictive factors associated with pT2b disease were MRI parametrial invasion (PMI) (adjusted odds ratio (AOR) 3.77, 95% confidence interval(CI) 1.62-8.79; P=0.02) and MRI uterine corpus invasion (UCI) (AOR 9.99, 95% CI 4.11-24.32; P<0.0001). In multivariable analysis, for underdiagnoses, histologically squamous carcinoma versus adenocarcinoma and adenosquamous carcinoma (AOR 2.07, 95% CI 1.06-4.07; P=0.034) and MRI tumor size (AOR 0.76, 95% CI 0.63-0.92; P=0.005) were significant predictors; for overdiagnoses, these results were MRI tumor size (AOR 1.51, 95% CI 1.06-2.16; P=0.023), MRI PMI (AOR 71.73, 95% CI 8.89- 611.38; P<0.0001) and MRI UCI (AOR 0.19, 95% CI 0.01-1.01; P=0.051). Conclusion. PMI and UCI on T2-weighted images through preoperative 3T MRI are useful coefficients for accurate prediction of the pT2b stage; however, careful surveillance is required. Therefore, preoperative decision-making for early cervical cancer patients based on MRI diagnosis should be considered carefully, particularly in the presence of factors that are known to increase the likelihood of misdiagnosis. 1. Introduction classification as the most commonly used method, the overall errorrateofclinicalstagingforcervicalcancercomparedwith surgical staging is between 20 and 66%. Clinical staging has Currently, the International Federation of Gynecology and Obstetrics (FIGO) classification is the most commonly used revealed more inaccurate diagnoses, especially in advanced method to determine the clinical stage of cervical cancer. stages [2–6]. Furthermore, when distinguishing between The FIGO staging guidelines were most recently updated in stages IB and IIB, tumor invasion of the parametrium is one 2009 by the FIGO Committee on Gynecologic Oncology [1]. of the most important considerations. This determination Stage 0 is no longer included in the FIGO 2009 staging [1]. completely depends on the attending gynecologist’s findings The clinical FIGO classification is exclusively used because via manual palpation, which is intrinsically subjective [7]. cancer staging is a generally accepted universal stratification As complementary measures, the National Comprehensive Cancer Network (NCCN) suggests the use of imaging meth- system for communication purposes among institutions. Despite continuous studies for the accurate staging of cervical ods such as CT, MRI, and combined PET-CT in guiding cancer, the reality is that no entirely accurate method exists treatment options and individual treatment design, but this at present. Regarding the limitations of the clinical FIGO practice guideline is not generally accepted for formal and 2 International Journal of Surgical Oncology ocia ffi l staging purposes. Accurate staging of cervical cancer Patients with the following criteria were excluded: (a) is essential when making the therapeutic decision between previously treated with radiotherapy and/or chemotherapy for cervical cancer, (b) contra-indication to the MRI pro- radiation and surgery [8, 9]. For early-stage disease, such as cedure including patients unwilling to go through contrast- stage I and selected IIA, surgery or radiation therapy can enhanced MRI, (c) a previous diagnosis of vulva and vaginal be applied as treatment options [8, 9]. eTh re are various cancer, and (d) concomitant pregnancy. treatments for voluminous stage IB according to the location andsizeofthetumor. Foradvancedstages(stageIIB and 2.2. Conventional Staging Work-Up. FIGO staging was deter- greater), radiation therapy is typically chosen [8–13]. us, Th various methods for the accurate prognostic detection of mined based on findings from physical examination, such as bimanual pelvic examination, endoscopic studies (cystoscopy parametrial invasion have been proposed [14–20]. However, and sigmoidoscopy), and radiologic studies (chest radio- more information is required to formulate accurate deci- graphy, intravenous pyelogram, and barium enema) aeft r sions regarding treatment for individual patients. With the histologic confirmation of invasive cervical cancer. introduction of more sophisticated MRIs, such as “multi- parametric” imaging (the combination or morphologic and functional MRI sequences, including T2-weighted (T2W), 2.3. Surgical Technique. All 260 patients underwent surgery. diffusion-weighted (DW), and magnetic resonance spectro- Regarding the surgical procedure types, hysterectomy scopic imaging and higher field-strength capabilities (3T (laparoscopic, transabdominal, or transvaginal), radical versus 1.5T MRI)), an improvement in staging cervical cancer hysterectomy (laparoscopic, transabdominal, robotic), and radical trachelectomy for fertility preservation were is expected. A few studies have reported that the accuracy of PMI by MRI is associated with the primary tumor size and permitted. All patients underwent pelvic lymph node sampling or dissection. For patients with large tumors (> uterine corpus invasion in patients with clinically localized 2 cm), para-aortic lymph node sampling was performed. cervical cancer who underwent radical hysterectomy (RH) [14–16, 18–21]. Therefore, the present study aimed to optimize the pre- 2.4. MRI Scanning dictability of staging for cervical cancer by analyzing the incremental predictive significance of preoperative 3-Tesla 2.4.1. MRI Protocol. All MRI examinations were scanned on (3T) multiparametric MRI findings for predicting pathologic a3Twhole-bodyMRIscanner(InteraAchieva3T, Philips T2b and predictive factors associated with MRI stage mis- Medical System, Best, the Netherlands) using phased-array diagnosis in patients with early cervical cancer underwent techniques involving pelvic or torso phased-array coils. Mul- radical hysterectomy. tiparametric imaging sequence parameters (Table S1 in the Supplementary Appendix) included multiplanar T2W, T1- weighted (T1W), and DW imaging with multiple b value 2. Methods and Methods (0-800 s/mm2) of the cervix. Gadopentetate dimeglumine contrast (Magnevist; Schering, Berlin, and Germany) in all 2.1. Patient Selection and Treatment. The cohort in this the patients was administered intravenously at a weight- study included 260 documented cervical cancer patients with based dosing of 0.2 ml/kg with a bolus injection rate of clinical FIGO stages IA2 and IIA who underwent primary 2 ml/sec using an automatic injector, which was followed by surgical treatment between January 2007 and December 2016 a 20-ml saline bolus injection. following a 3T MP MRI examination at Ulsan University Hospital. Patient age ranged from 24 to 75 with a mean value 2.4.2. MRI Interpretation. AllMRimageswereassessed of 49.3 years. Tissue diagnosis of cervical cancer was per- retrospectivelybasedonalltheavailableclinicaldatabya formed through biopsy specimens for all patients. Clinical gynecological radiologist with more than 10 years of expe- and MR imaging data were recorded retrospectively based rience in the field of gynecologic cancer imaging. A gyne- on the patients’ medical records and PACs system by one cological radiologist described each MRI finding including author. the presence of primary tumor; depth of stromal invasion (no Inclusion criteria were (a) biopsy-documented invasive invasion, partial invasion, and complete invasion); extension cervical cancer by a loop electrosurgical excision procedure to uterine corpus, vagina, parametrium, pelvic sidewall, (LEEP) or a cone biopsy or punch biopsy; at least 7 days urinary bladder, and rectum; and pelvic and para-aortic aer ft a biopsy, MRI was performed to prevent false-positive lymph node metastasis. At the end of the imaging evaluation findings due to biopsy inflammation, (b) clinical FIGO stage session, multiparametric MRI staging was determined by IA, IB, or IIA, (c) histology of squamous cell carcinoma or MRI T category using both FIGO and TNM stratification adenocarcinoma or adenosquamous carcinoma, (d) no med- criteria (i.e., AJCC-TNM Cancer Staging System, 7th edition) ical or surgical contraindications to radical hysterectomy with [22, 23] as shown in Table S2. When no tumor was identified pelvic lymph node dissection (PLND) with or without para- by MR imaging despite findings of malignant cells on biopsy, aortic lymph node sampling (PALS) and dissection (PLND), a radiologic stage of MRI-invisible IB1 was assigned in (f)havinganEastern CooperativeOncologyGroup (ECOG) previous study. However, in this study, MRI-invisible IB1 was performance status of 0-1, and (g) provided informed con- independently classified as MRI-invisible-T0 stage (Figures 4 sent. and5)ratherthanincludedintheMRIIB1stage. International Journal of Surgical Oncology 3 2.4.3. Histopathologic Analysis. The procedure was per- predicting parametrial invasion (PMI) was 83%. eTh sensitiv- formed and the surgical specimens of the 260 radical hys- ity, specicfi ity, positive predictive value (PPV), and negative terectomy and trachelectomy patients were prepared accord- predictive value (NPV) of 3T multiparametric MRI for ingtostandardmethods. predicting pathologic parametrial invasion were 62%, 88%, Allsurgicalspecimens were xfi ed informalin andembed- 53%, and 91%, respectively ded in paraffin. A dedicated and experienced gynecologic oncology pathologist reviewed all of the H&E-stained sec- 3.3. Logistic Regression MVA: Pathologic T2b Disease Out- tions for all patients. The overall stage was determined come. A subset of 203 women (excluding 57 with MRI T0 according to both FIGO and TNM stratification criteria. eTh stage) was stratified according to the MRI finding. Based on TNM classification based on the American Joint Committee a univariable analysis of these women that excluded those on Cancer (AJCC) staging system, 7th edition (2010), was the with MRIT0stage,MRI PMI(AOR3.77,95%CI1.62-8.79; radical hysterectomy T category [23]. P=0.002), and MRI uterine corpus invasion (UCI) (AOR 9.99, In addition to pTNM classification based on AJCC stag- 95% CI 4.11-24.32; P<0.0001) were associated with increased ing manual, if no tumor was found in the cervix in the surgical odds of having pT2b disease aer ft adjusting clinical predictive specimen aer ft positive biopsy for infiltrating carcinoma, we factorsasshownin Table2. stratified as pT0b1 stage, which was classified as a class A0 in Meigs J.V. et al. at surgical and pathologic classification of the 3.4. Logistic Regression MVA: Underdiagnosis and Overdiag- uterine cervix [3]. nosis. eTh accuracy of MRI staging with regard to the histologic specimens from 260 cervical cancer patients with 2.5. Statistical Analysis. The distributions of the study clinical FIGO stages IA-IIA was 69%, whereas the overall cohort’s clinical and pathologic characteristics were calcu- error rates varied from 15% for MRI T1b to 46% for MRI T2b. latedand arepresentedin Table1.Theclinicalpredictive According to our findings, the MRI stage underdiagnosed factors were analyzed by the distributions of categorical 18% of patients and overdiagnosed 14%. factors stratified by MRI T category (T0, T1b, T2a, and T2b). The underdiagnosis rates were 46%, 13%, and 20% for Continuous variables were compared using ANOVA MRI stages T0, Tb1, and T2a, respectively. The overdiagnosis or the Kruskal-Wallis test, and categorical variables were rates were 2%, 70%, and 46% for MRI stages Tb1, T2a and compared using the휒2 test or Fisher’s exact test. T2b, respectively (Tables 4, and 5). eTh factors influencing the Accuracy was calculated using the n fi al surgical pathol- accuracy of MRI staging were further investigated (Table 3). ogy examinations as the reference. A logistic regression mul- In the underdiagnosis cases (Figures 6 and 7), the tivariable analysis (MVA) (Tables 2 and 3) was used to assess predictive factors included a histology of squamous versus the clinical factors for predicting upstaging to pT2b and adenocarcinoma and adenosquamous carcinoma (AOR 2.07, the clinical factors associated with MRI stage misdiagnosis 95% CI 1.06-4,07; P=0.034) and MRI tumor size (AOR in FIGO IA-IIA cervical cancer patients underwent radical 0.76, 95% CI 0.63-0.92; P=0.005). In the overdiagnosis cases hysterectomy, adjusting for age, menopause, parity, and BMI, (Figures 2 and 3), the predictive factors included MRI tumor cesarean section, history of at least one normal delivery, size (AOR 1.51, 95% CI 1.06-2.16; P=0.023), MRI uterine menopause, SCC ag, grade, MRI stage, clinical FIGO stage, corpus invasion (AOR 0.13, 95% CI 0.03-0.49; P=0.003), and MRI tumor size, MRI Pelvic LN invasion, MRI parametrial MRI parametrial invasion (AOR 73.73, 95% CI 8.89-611.38; invasion, MRI uterine corpus invasion, MRI deep stromal P<0.0001) aer ft preoperative predictors associated with MRI invasion, and MRI vaginal invasion. stage misdiagnosis were adjusted as shown in Table 3. Unadjusted and adjusted odds ratios (UORs and AORs, The area under receiver operating characteristics curve respectively)werecalculatedforeach clinical covariate,and analysis of the cut-off lesion size measured on MRI for these values were reported with 95% confidence intervals optimal accuracy to predict the effect of large tumor size on (CIs). Area under the receiver operating characteristic (ROC) misdiagnosis (overdiagnosis and underdiagnosis) is shown in curve (A ) was used to determine the cut-off lesion size Figure 1. measured on MRI for optimal accuracy to predict the effect With overdiagnosis, a tumor cut-off size of 2.9 cm of large tumor size on misdiagnosis (overdiagnosis and (approximated on T2W images) was observed with 80% underdiagnosis). A P value<0.05 was considered statistically sensitivity and 53% specificity (AZ=0.68, 95% CI 0.60-0.77; significant. IBM SPSS 21.0 statistics software was used (IBM Table 6), in underdiagnosis, a tumor cut-off size 0.25 cm Institute, Inc., Armonk, NY, USA). (approximatedonT2W images)was observed with57% sensitivity and 83% specificity (AZ=0.64, 95% CI 0.54-0.75; 3. Results Table 6) 3.1. Description of the Study Cohort Stratified by MRI T Category. The clinical and pathologic characteristics of the 4. Discussion 260 women in this study cohort are shown in Table 1 and categorized by MRI T category (T0, T1b, T2a, and T2b). Previous studies have evaluated the ability of 1.5 T MRI to determinethepresenceofparametrialinvasionandhavecon- 3.2. Performance Characteristics of 3T Multiparametric MRI. sidered whether the information from 1.5 T MRI might mean- The overall accuracy of 3T multiparametric MRI for ingfully supplement the known predictive factors, including 4 International Journal of Surgical Oncology Table 1: Comparison of the distribution of clinical and pathologic characteristics of the 260 women in the cohort study stratified by MRI staging. MRI MRI MRI MRI Clinical characteristics P-value T0 T1b T2a T2b (n=57) (n=139) (n=10) (n=54) Age(y)∗ 0.207 47.6 49.5 47.9 52.1 Parity∗ 0.773 2.1 2.2 1.9 2.3 Operative procedure 0.01 Open modified radical hysterectomy 2(3.5) 1(0.7) 0(0) 0(0) Open radical hysterectomy 9(15.8) 47(33.8) 2(20.0) 25(46.3) Laparoscopic modified radical hysterectomy 20(35.1) 9(6.5) 0(0) 1(1.9) Laparoscopic radical hysterectomy 22(38.6) 77(55.4) 8(80.0) 28(51.9) Laparoscopic radical trachelectomy 3(5.3) 3(2.2 0(0) 0(0) Robotic radical hysterectomy 1(1.8) 1(0.7) 0(0) 0(0) Robotic trachelectomy 0(0) 1(0.7) 0(0) 0(0) Menopause 0.004 No 37(64.9) 79(56.8) 5(50) 21(38.9) Yes 20(35.1)) 60(43.2) 5(50) 33(61.1) Cesarean section 0.101 No 54(94.7) 122(87.8) 7(70) 46(85.2) Yes 3(5.3) 17(12.2) 3(30) 8(14.8) History of at least one normal delivery 0.381 No 7(12.3) 18(12.9) 5(50) 8(14.8) Yes 50(87.7) 121(87.1) 5(50) 46(85.2) BMI 0.948 24.1 23.9 24.3 23.8 SCC Ag (ng/ml) ∗ <0.0001 0.9 2.7 3.9 10.1 CEA(U/ml) ∗ 0.098 2.7 4.9 11.1 12.3 CA 125(U/ml) ∗ 0.441 18.8 15 21.4 22.8 Histology 0.166 Squamous 35(61.4) 94(67.6) 8(80.0) 41(75.9) Adenocarcinoma 21(36.8) 38(27.3) 2(20.0) 11(20.4) Adeno-squamous 1(1.8) 7(5) 0(0.0) 2(3.7) Grade 0.132 24(42.1) 20(14.4) 0(0.0) 8(14.8) 19(33.3) 77(55.4) 5(50.0) 29(53.7) 3 5(8.8) 32(23.0) 4(40.0) 13(24.1) Unknown 9(15.8) 10(7.2) 1(10.0) 4(7.4) Biopsy type <0.0001 Punch biopsy 21(36.8) 106(76.3) 8(80.0) 41(77.4) LEEP 36(63.2) 33(23.7) 2(20.0) 12(22.6) Clinical FIGO tumor stage <0.0001 IA 15(26.3) 0(0.0) 0(0.0) 0(0.0) IB1 42(73.7) 102(73.4) 4(40.0) 20(37.0) IB2 0(0.0) 23(16.5) 3(30.0) 26(48.1) IIA1 0(0.0) 6(4.3) 2(20.0) 4(7.4) IIA2 0(0.0) 8(5.8) 1(10.0) 4(7.4) RH T category (final pathologic stage ) <0.0001 T1a 15(26.3) 0(0.0) 0(0.0) 0(0.0) T0b1 16(28.1) 3(2.2) 0(0.0) 0(0.0) T1b1 26(45.6) 96(66.9) 6(60.0) 11(20.4) International Journal of Surgical Oncology 5 Table 1: Continued. MRI MRI MRI MRI Clinical characteristics P-value T0 T1b T2a T2b (n=57) (n=139) (n=10) (n=54) T1b2 0(0.0) 25(18.0) 1(10.0) 11(20.4) T2a1 0(0.0) 1(0.7) 0(0.0) 3(5.6) T2a2 0(0.0) 1(0.7) 1(10.0) 0(0.0) T2b 0(0.0) 16(11.5) 2(20.0) 29(53.7) Pathologic Tumor size <0.0001 0.601 2.93 4.24 4.68 Pathologic tumor size <0.0001 0-≤1 43(75.4) 19(13.7) 0(0.0) 0(0.0) 1-≤2 10(17.5) 21(15.1) 0(0.0) 2(3.7) 2-≤3 2(3.5) 46(33.1) 2(20.0) 9(16.7) 3-≤4 2(3.5) 21(15.1) 4(40.0) 11(20.4) 4-≤5 0(0.0) 18(12.9) 3(30.0) 14(25.9) 5-≤6 0(0.0) 13(9.4) 0(0.0) 7(13.0) 6-≤7 0(0.0) 1(0.7) 0(0.0) 7(13.0) >7 0(0.0) 0(0.0) 1(10.0) 4(7.4) LVSI <0.0001 Yes 4(7.0) 53(38.1) 7(70.0) 36(66.7) No 53(93.0) 86(61.9) 3(30.0) 18(33.3) Pathologic deep stromal invasion <0.0001 Inner 1/3 48(84.2) 27(19.4) 2(20.0) 0(0.0) Middle 1/3 6(10.5) 44(31.7) 3(30.0) 2(3.7) Outer 1/3 3(5.3) 68(48.9) 5(50.0) 52(96.3) Pathologic parametrial invasion <0.0001 No 57(100.0) 124(89.2) 8(80.0) 25(46.3) Yes 0(0.0) 15(10.8) 2(20.0) 29(53.7) Pathologic parametrial invasion laterality <0.0001 Negative 57(100.0) 124(89.2) 8(80.0) 22(40.7) Unilateral 0(0.0) 8(5.8) 1(10.0) 14(25.9) Bilateral 0(0.0) 7(5.0) 1(10.0) 18(33.3) Pathologic pelvic LN involvement <0.0001 Negative 55(96.5) 115(82.7) 6(60.0) 30(55.6) Positive 2(3.5) 24(17.3) 4(40.0) 24(44.4) Pathologic para-aortic LN involvement 0.001 Negative 51(89.5) 120(86.3) 9(90.0) 45(83.3) Positive 0(0.0) 10(7.2) 1(10.0) 8(14.8) Not done 6(10.5) 9(6.5) 0(0.0) 1(1.9) Pathological uterine involvement No 56(98.2) 125(89.9) 8(80.0) 26(48.1) Yes 1(1.8) 14(10.1) 2(20.0) 28(51.9) MRI tumor size∗ <0.0001 0.00 2.89 4.06 4.61 MRI pelvic LN involvement Negative 57(100.0) 128(92.1) 7(70.0) 36(66.7) Positive 0(0.0) 11(7.9) 3(30.0) 18(33.3) MRI para-aortic LN involvement 0.46 Negative 57(100.0) 137(98.6) 10(100.0) 53(98.1) Positive 0(0.0) 2(1.4) 0(0.0) 1(1.9) MRI uterine corpus invasion 6 International Journal of Surgical Oncology Table 1: Continued. MRI MRI MRI MRI Clinical characteristics P-value T0 T1b T2a T2b (n=57) (n=139) (n=10) (n=54) No 57(100.0) 127(91.4) 8(80.0) 27(50.0) Yes 0(0.0) 12(8.6) 2(20.0) 27(50.0) MRI deep stromal invasion No invasion 57(100.0) 2(1.4) 0(0.0) 0(0.0) Partial invasion 0(0.0) 79(56.8) 6(60.0) 3(5.6) Complete invasion 0(0.0) 58(41.7) 4(40.0) 51(94.4) eTh data are presented as the number ( %)orthemean± SD. FIGO, International Federation of Gynecology and Obstetrics; RH, radical hysterectomy; LVSI, lymphovascular stromal invasion; LN, lymph node; CA 125, carbohydrate antigen 125; CEA, carcinoembryonic antigen; CA 19-9, carbohydrate antigen 19-9; MRI, magnetic resonance imaging. Figure 1: Comparison of finial pathologic stage versus multiparametric MRI radiologic stage versus clinical FIGO stage. primary tumor size, the depth of cervical stromal invasion, FIGO stages IA-IIA2 cervical cancer underwent radical hys- and extension to the uterine corpus in patients with cervical terectomy. cancer patients [7, 15–20, 24, 25]. In 2005, Hricak et al. reported a prospective 25-center However, few studies using 1.5 T MRI have attempted clinical study of 172 patients. In the detection of advanced to identify established factors associated with upstaging stage (≥IIB), the sensitivity, specificity, NPV, and PPV for at the radical hysterectomy in patients with early cervical MRIwere53%,74%,85%,and 37%,respectively.Inourstudy, cancer IA-IIA. To determine an optimal treatment plan for the sensitivity, specificity, NPV, and PPV of 3T multipara- patients scheduled to undergo radical hysterectomy, accu- metric MRI to predict pathologic parametrial invasion were rate risk assessment is necessary because the decision to 62%, 88%, 91%, and 53%, respectively. Our results for 3T use concurrent chemoradiation therapy with radical hys- multiparametric MRI are higher than those reported in prior terectomy depends on the patient’s clinicopathologic risk studies [17]. factors. The identification of high-risk factors is essential Hicak et al. [21] indicated a strong correlation between to avoid overtreatment, which carries substantial acute and parametrial invasion and uterine corpus invasion and Peter chronic adverse effects [4, 26]. er Th efore, we assessed the de Boer’s systemic review [20] noted a high accuracy rate for predictive relevance of preoperative 3T MRI findings in MRI in detecting cancer involvement of the uterine internal predicting pathologic stage T2b and the clinical factors os in cervical cancer. This study confirmed the results of those associated with MRI stage misdiagnosis in patients with two studies of MRI parametrial invasion and MRI uterine International Journal of Surgical Oncology 7 Table 2: Adjusted odds ratios with 95% confidence intervals (CI) and ass ociated P values from the logistic regression predicting pathologic category T2b in the 203 study cohort patients. Univariable analysis Multivariable analysis No. of events(% Clinical characteristics No. of patients of patients) UOR (95% CI) P AOR (95% CI) p Age(y) 203 1.05(1.02-1.09) 0.001 1.05(1.01-1.09) 0.009 47(23.2) Parity 203 0.99(0.76-1.31) 0.992 47(23.2) BMI 203 47(23.2) 1.04(0.95-1.13) 0.424 Cesarean section No 175 1 0.476 42(24) Yes 28 0.69(0.25-1.92) 5(17.9) History of at least one normal delivery 203 0.401 No 31 1 9(29) Yes 172 0.69(0.29-1.63) 38(22.1) Menopause 203 0.007 No 105 1 16(15.2) Yes 98 2.57(1.30-5.09) 31(31.6) Histology 0.374 Squamous 143 1 31(21.7) Adenocarcinoma 51 1.51(0.73-3.09) 15(29.4) Adenosquamous 9 0.45(0.05-3.75) 1(11.1) Grade 0.45 128 1 7(25) 2 111 0.83(0.32-2.18) 24(21.6) 349 10(20.4) 0.77(0.26-2.31) Unknown 15 2.00(0.52-7.65) 6(40) SCC ag(ng/mL) 203 1.04(1.01-1.06) 0.012 47(23.2) MRI T stage <0.0001 T1b 103 1 16(11.5) T2a 10 1.92(0.38-9.86) 2(20) T2b 54 29(53.7) 8.92(4.23-18.82) Clinical FIGO stage <0.0001 IB1 126 1 20(15.8) IB2 52 19(36.5) 7.41(3.04-16.12) IIA1 12 2.67(0.65-11.03) 3(25) IIA2 13 5.00(1.44-17.41) 5(38.5) MRI tumor size 203 1.84(1.46-2.32) <0.0001 47(23.2) MRI pelvic LN involvement 0.013 Negative 171 1 34(19.9) Positive 32 2.76(1.24-6.13) 13(40.6) MRI parametrial invasion <0.0001 0.002 No 146 11 18(12.3) Yes 57 7.37(3.59-15.08) 3.77(1.62-8.79) 29(50.9) MRI parametrial invasion <0.0001 Negative 146 1 17(11.6) Unilateral 46 6.37(2.95-13.76) 21(45.7) Bilateral 11 34.15(6.80-171.43) 9(81.8) MRI vaginal involvement 0.60 No 193 1 44(22.8) Yes 10 1.45(0.36-5.85) 3(30) 8 International Journal of Surgical Oncology Table 2: Continued. No. of events(% Univariable analysis Multivariable analysis Clinical characteristics No. of patients of patients) UOR (95% CI) P AOR (95% CI) p MRI uterine corpus invasion <0.0001 <0.0001 No 162 11 19(11.7) Yes 41 16.21(7.19-36.57) 9.99(4.11-24.32) 28(68.3) Figure 2: Stage IB1 cervical adenocarcinoma in a 42-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show a moderated lobulated mass of uterine cervix with a focal disruption (arrow) of peripheral rim. The maximum diameter of the lesion is measured 3.6cm on the T2-weighted sagittal image. At histopathological finding, no parametrical lesion was found. MRI stage T2b ( ≤ 4cm) was overdiagnosed as final pathologic stage T1b1. Figure 3: Stage IB2 squamous cervical carcinoma in a 49-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show a 6cm sized lobulated concentric tumoral thickening of whole cervical stroma with an ill-defined peripheral margin (arrow) and invasion to endomyometrium(arrowhead); the maximum diameter of the lesion is measured 6cm on the T2-weighted sagittal image. At histopathological finding, no parametrial lesion was found. MRI stage T2b ( > 4 cm) was overdiagnosed as final pathologic stage T1b2. corpus invasion as credible predictive factors for predicting over RH in cases of suspected pT2b cervical cancer, whereas pT2b. clinicians are more likely concerned with the predictive It is noteworthy that radiologists have been providing values of the diagnosis than its specicfi ity or sensitivity. high specificity readings to prevent unnecessary abolition of Generally, in cases of FIGO stages≥IIB, gynecologists would curative surgery while favoring external beam radiotherapy get the greatest benetfi from tests with a high NPV for a International Journal of Surgical Oncology 9 Table 3: Univariable and multivariable analysis of factors associated with diagnostic inaccuracy of preoperative MRI staging. Under-diagnosis Over-diagnosis Univariable Multivariable Univariable Multivariable UOR 95% AOR 95% Over- all P AOR 95% CI Over- all P UOR 95% CI Over-all P Over- all P CI CI 1.02 0.99 Age(y) 0.254 0.409 (0.99-1.05) (0.95-1.02) Menopause 0.605 0.394 No 1 1 1.19 1.37 Yes (0.62-2.27) (0.66-2.83) 1.08 1.13 Parity 0.584 0.449 (0.83-1.39) (0.82-1.55) History of at least one 0.751 0.314 normal delivery No 1 1 0.86 0.62 Yes (0.35-2.15) (0.43-1.58) Histology 0.521 0.159 Squamous 1 1 2.11 0.25 Adenocarcinoma (1.07-4.16) (0.074-0.87) 1.72 1.38 Adeno-squamous (0.33-9.05) (0.27-7.17) 0.031 0.034 0.055 0.064 Squamous 1 1 1 1 Adenocarcinoma or 2.07 2.07 0.38 0.34 adenosquamos (1.07-3.99) (1.06-4.07) (0.14-1.02) (0.11-1.07) 0.96 1.01 SCC ag(ng/mL) 0.257 0.341 (0.89-1.03) (0.99-1.04) 0.76 0.76 1.46 1.51 MRI tumor size 0.004 0.005 0.001 0.023 (0.63-0.92) (0.63-0.92) (1.18-1.81) (1.06-2.16) MRI parametrial 0.029 <0.0001 <0.0001 invasion No 1 1 1 73.73 0.11 11.94 Yes (8.89- (0.14-0.79) (5.21-27.35) 611.38) MRI uterine corpus 0.347 0.363 0.003 invasion No 1 1 1 1.49 1.54 0.13 Yes (0.65-3.49) (0.61-3.90) (0.03-0.49) MRI deep stromal 0.840 0.006 0.051 invasion No invasion & partial 11 1 invasion 1.07 2.92 0.19 Complete invasion (0.55-2.07) (1.37-6.23) (0.01-1.01) reliable negative test result (negative is stage≤IIA), which a reliable positive test result (positive stage ≥ stage IIB) could change their treatment decision from conservative might highly influence gynecologic oncologists to change treatment to surgery. their treatment decision to prevent unnecessary treatment For patients with FIGO stage ≤IIA, PPV is clinically after curative surgery. eTh refore, a high PPV helps reduce the most important value for treatment planning because the substantial risk of additional treatment aeft r curative 10 International Journal of Surgical Oncology Table 4: Comparison between final pathologic stage and MRI radiologic stage. Final pathologic stage MRI radiologic stage T2b (%) T2a2(%) T2a1(%) T1b2(%) T1b1(%) T0b1∗ (%) T1a (%) Total T2b 29(61.7) 0(0) 3(75) 11(29.7) 11(8.1) 0 0 54 T2a 2(4.3) 1(50) 0(0) 1(2.7) 6(4.4) 0 0 10 T1b 16(34) 1(50) 1(25) 25(67.6) 93(68.4) 3(15.8) 0 139 T0 0 0 0 0 26(19.1) 16(84.2) 15(100) 57 47 2 4 37 136 19 15 260 ∗ After a positive biopsy for infiltrating carcinoma, no tumor was found in the cervix in the surgical specimen. Table 5: Incidence of staging errors. MRI Stage Errors and incidence with a comparison of MRI stage to surgico-pathologic stage T0(57 patients) Understaged (26:46%) T1b1: Tumor confined to the cervix or microscopic lesion greater than T1a1/a2, in greatest dimension (26) T1b (139 patients) T2a1: Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina,≤4cm in greatest dimension (1) Understaged (18:13%) T2a2: Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina> 4.0 cm in greatest dimension (1) T2b: Tumor with parametrial invasion (16) T0b1: Aer ft a positive biopsy for infiltrating carcinoma, no tumor was found in the cervix in the surgical Overstaged (3:2%) specimen (3) T2a (10 patients) Understaged (2:20%) T2b: Tumor with parametrial invasion (2) T1b1: Tumor limited to cervix or microscopic lesion greater than T1a1/a2,≤ 4.0 cm in greatest dimension Overstaged (7:70%) (6) T1b2: Tumor limited to cervix or microscopic lesion greater than T1a1/a2,> 4.0cmingreat dimension(1) T2b (54 patients) T1b1: Tumor limited to cervix,≤ 4.0 cm or less in greatest dimension (11) T1b2: Tumor limited to cervix,> 4.0 cm in great dimension (11) Overstaged (25:46%) T2a1: Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina,≤4cm in greatest dimension (3) Table 6: Clinical performance of the cut-off lesion size measured on MRI to predict the effect of large tumor size for misdiagnosis (overdiagnosis and underdiagnosis) with optimal accuracy. AUC Threshold(cm) Sensitivity (%) Specificity (%) Accuracy (%) (95% CI) 0.68 Overdiagnosis MRI tumor size > 2.9 80 53 58 (0.60-0.77) 0.64 Underdiagnosis MRItumor size < 0.25 56.5 83 77 (0.54-0.75) surgery by providing information regarding the presence of radiotherapy would be preferable to surgery in cases of parametrial invasion. suspected pT2b cervical cancer to prevent the unnecessary Notably, the 3T multiparametric MRI positive predictive rejectionofcurativesurgery. value (PPV) for parametrial invasion is 54% (29/54), which In this study, furthermore, compared with surgical stag- is moderate in this patient group [25]. u Th s, 25/54 (46.2%) ing, the overall accuracy of MRI stage was 69%; underdiag- of patients were incorrectly predicted to have parametrial nosis and overdiagnosis occurred with 13-46% and 2-46% in invasion and would prefer external beam radiotherapy to each MRI stage, respectively (Table 5). Our results showed RH in cases of suspected pT2b cervical cancer to prevent that MRI staging resulted in more inaccurate diagnoses, unnecessary abolition of curative surgery and external beam particularly for MRI stage T0 and advanced stages. International Journal of Surgical Oncology 11 Figure 4: Stage IB1 squamous cervical carcinoma in a 58-year-old woman with radical hysterectomy (A) T2-weighted axial and (B) sagittal MR images show no gross cancerous lesion of uterine cervix but a tissue defect (arrow) aer ft conization. At histopathological finding, no residual tumor in uterine cervix was found. MRI stage T0 was diagnosed as final pathologic stage T0b1. Figure 5: Stage IB1 squamous cervical carcinoma in a 28-year-old woman with trachelectomy (A) T2-weighted axial and (B) sagittal MR images show no gross cancerous lesion of uterine cervix but a tissue defect (arrow) aer ft conization. At histopathological finding, 1.2 cm sized invasive squamous cell carcinoma in uterine cervix was found. MRI stage T0 was underdiagnosed as final pathologic stage T1b1. Regarding MRI stage misdiagnosis, our results demon- and3); thesesamepatientsweresurgicopathologically staged strated that underdiagnosis is aeff cted by MRI tumor size as T2a1(3), T1b2(11) (Figure 3), or T1b1(11) (Figure 2). This and histologic cell type. Overdiagnosis is also influenced by errorofMRI stageT2bwithacomparisonofMRI stageto MRI tumor size, MRI parametrial invasion, and MRI uterine surgicopathologic stage showed 46% in this study, whereas corpus invasion. previous studies reported 63-67% incidence [2, 17, 25, 27]. The primary treatment options for early cervical cancer In cases of early cervical cancer patients diagnosed as MRI are surgery or chemoradiotherapy [8, 9, 14]. However, there T2b, the substantial likelihood of overdiagnosis should be areadvantagestotheuseofsurgery insteadofradiotherapy, considered. particularly in younger women for whom ovarian preser- Although MRI measured tumor size and volume seem to vation might be important. From a clinical perspective, be strongly correlated as a predictive factor of parametrial a dilemma exists regarding the reliability of MRI results invasion in cervical cancer, but they are still controversial to guide treatment options and design. Such reliability is [15, 18]. We have described in detail and further investigated particularly germane in case of early cervical cancer patients the factors believed to affect the diagnostic inaccuracy of MRI diagnosed as MRI T2b stage, notably in young women. staging, particularly regarding the predictive effect of large Interestingly, 35 cases were overdiagnosed by MRI stag- tumor size on misdiagnosis. Regarding MRI tumor size, when ing,whereas25of35werestagedasT2bby MRI(Figures2 larger tumor size determined by MRI is an important factor, 12 International Journal of Surgical Oncology Figure 6: Stage IB1 squamous cervical carcinoma in a 51-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show as 2.7 cm lobulated mass (star) on posterior lip of uterine cervix with no disruption of peripheral rim. eTh maximum diameter of the lesion is measured 2.7cm (arrowhead) on the T2-weighted sagittal image. At histopathological finding, bilateral parametrial lesion was found. MRI stage T1b (≤ 4 cm) was underdiagnosed as final pathologic stage T2b. Figure 7: Stage IB2 cervical adenocarcinoma in a 48-year-old woman with radical hysterectomy (A) T2-weighted axial MR images show a 5 cm well defined exophytic mass (star) mainly involving right post erior exocervix with no disruption of peripheral rim. The maximum diameter of the lesion is measured 5cm (arrowhead) on the T2-weighted sagittal image. At histopathological finding, bilateral parametrial lesion was found. MRI stage T1b (> 4 cm) was underdiagnosed as final pathologic stage T2b. the possibility of overdiagnosis must be considered. In this is essential (Figure 5). In previous studies, MRI was use- study, we observed that tumor size > 2.9 cm is correlated ful to detect the presence of tumor in endocervix and highly with overdiagnosis. The larger (minimally 2.9 cm, the to guide decisions regarding fertility-sparing versus non- selected cut-off value of the ROC curve) the MRI tumor fertility-sparing treatment approaches [30]. size is, the more the overdiagnoses are likely to result. In This study examined additional details; for example, addition, we observed that, for MRI tumor size, a cut-off as pertains to underdiagnosis, specific histologic cell types value of< 0.25 cm on the ROC curve correlated highly with such as adenocarcinoma and adenosquamous carcinoma of underdiagnosis [28–30]. the cervix were significant factors. We also demonstrated Regarding MRI stage misdiagnosis, particularly under- that, in cases of MRI-invisible T0 stage, adenocarcinoma, diagnosis (Figures 5, 6, and 7), a high probability exists that and adenosquamous carcinoma histology, a high possibility the surgical treatment of patients will be aeff cted negatively existed for the presence of tumor according to the surgico- because surgical treatment in underdiagnosed cases results pathologic results. in inadequate surgery. Particularly for patients who wish to Several points require further discussion. 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