The value of the added diffusion-weighted images to multiparametric MRI in the early diagnosis of uterine cervix cancers and nodal assessment

Cervical cancer still one of the most common causes of tumor-related death in developing countries presented in younger women. In this study, we aimed to evaluate the value of diffusion-weighted MRI in early diagnosis of malignant cervical lesions, to assess metastatic adenopathy, peritoneal dissemination, and possible tumor recurrence, and determine treatment response. This study included 60 patients with abnormal vaginal bleeding and suspected cervical lesion by US. A histopathological biopsy was done. Pelvic MR with DWI and dynamic contrast-enhanced MRI were done for all patients. According to the histopathological findings, we divided our studied 60 patents into two groups: group I, malignant lesions (46 lesions; 76.7%), and group II, benign lesions (14 lesions; 23.3%). Multiparametric MRI could detect all cervical lesions but with poor pathologic characterization, achieving 72.37% sensitivity, 37.50% specificity, 63.33% accuracy, 76.19% PPV, and 33.33% NPV. When compared with DWI with ADC value measurements at high b value (b = 800) to MRI exam, it showed a higher diagnostic accuracy with good lesion pathological characterization that achieved 95.65% sensitivity, 71.43% specificity, 90% accuracy, 91.67 PPV, and 83.33% NPV. The mean ADC value for malignant lesions was 0.86–1.1, mean = 0.92 ± 0.71 × 10−3 mm2/s, while the mean ADC value in the benign lesion group was 1.18 ± 0.1 × 10–3 mm2/s. Comparing DWI with ADC values measurements at high b value to the multiparametric MRI examination of the female pelvis increases the sensitivity, specificity, and diagnostic accuracy of characterization and early diagnosis of cervical malignant focal lesions and reduces the need for intravenous contrast administration.


Background
Cervical carcinoma is a common gynecological tumor still representing important cause of tumor-related death in younger females in developing countries [1]. The incidence rate of cervical cancer in Egypt is 6.6 cases/100, 000 populations, while prevalence of pre-invasive highgrade lesions represents 0.3%among the Egyptian females [2]. MRI could identify the anatomic origin, shape, and composition of uterine cervical masses, so a definitive diagnosis can be reached [3][4][5]. DW-MR imaging is a functional imaging technique whose contrast derives from the random motion of water molecules within tissues that allow its use in abdominal and pelvic applications [6]. DWI when combined with multiparametric MRI becomes a complementary diagnostic tool for the diagnosis of uterine lesions giving more information for the differentiation and extension of benign and malignant lesions [7,8]. DWI is not only helpful in differentiating benign from malignant lesions but also it can be used to assess metastatic adenopathy, peritoneal dissemination, and possible tumor recurrence and determine treatment response [9].
This study aimed to evaluate the value of diffusionweighted MRI in early diagnosis of malignant cervical lesions.

Methods
This study included 60 patients with history of vaginal bleedings and suspicious cervical focal lesions by ultrasound examination. The patient's age ranged from 37 to 63 years with mean age ± 44.6 years. Ethics committee approvals in addition to informed written consent were obtained from all included patients.

Study population Inclusion criteria
Patients with clinical history of abnormal vaginal bleedings with suspicious transvaginal ultrasound findings of uterine cervix focal lesion were included. The patient did not receive any treatment prior to the examination.

Exclusion criteria
Patients unfit for MRI examination (e.g., who had cardiac pacemakers/prosthetic heart valves, cochlear implants, or other metallic implants) or having a history of claustrophobia or those who could not tolerate MRI exam were excluded.

MRI examination
MR imaging was performed on a 1.5-T scanner (Achieva, Philips Medical System) using pelvic phasedarray Torso coil with the patient in the supine position. Intravenous administration of an antispasmodic drug (10 mg of [Visceralgine; Organon, Livron, France]) was given immediately before MR imaging to reduce bowel peristalsis. All cases were asked to check their renal function (creatinine level) before the examination.

MR imaging protocol inclusion
The MR imaging protocol included the following: Schering, Berlin, and Germany) was administered intravenously at weight-based dosing of 0.1 ml/kg body weight with a bolus injection rate of 2 ml/s by an automatic injector, followed by a 20 mL normal saline flushing the tube. Post-contrast T1 fat sat THRIVE (high-resolution isotropic volume examination) images were acquired instantly after administration of gadolinium. Images were acquired serially at 0, 30, 60, 90, and 120 s. -DW-MRI: using a spin echo single-shot sequence with free-breathing, with TR 2.8 s, TE 72, matrix 512 × 512, slice-thickness 3 mm with an inter-slice gap of 1 mm, and FOV of 350 mm, and b-factor of 0, 300, and 800 s/mm 2 on an axial plane for each patient prior to contrast administration. The ADC maps were automatically generated for all DW images, and ADC values were measured at b value 1000 s/mm 2 . The mean ADC value was measured by placing ROI of average 1-2 cm in the solid part of the lesion and expressed in 10 −3 mm 2 /s.

Histopathological correlation
The histopathological results were used as a gold stander reference for all lesions and correlated to the imaging findings.

Statistical analysis
All statistical calculations were done using the SPSS test for calculation of mean, standard deviation, frequencies, and percentages. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for MRI and DWI were calculated separately for each parameter.

Results
Two radiologists with 10 and 5 years' experience in gynecological MR imaging independently assessed cervical lesions of pelvic MRI examination with no available histopathological data. MRI imaging was evaluated for the following: the site, size, and extension of the cervical focal lesion, pattern of enhancement, infiltration of the related structures, and presence or absence of pelvic lymph nodes.
In the studied 60 suspicious uterine cervix focal lesions, the majority (21 patients) were complaining of abnormal vaginal bleeding, usually post-coital. Malodorous discharge and vaginal discomfort were reported in the remaining 9 patients. The patient's age ranged from 39 to 63 years with a mean age ± 44.6 years.

Histopathological results of studied 60 patients
According to the histopathological findings, we divided our studied 60 patients into two groups: group I, malignant lesions group (46 cases; 76.7%), and group II, benign lesions (14 cases; 23.3%) ( Table 1). Multiparametric MRI results in all studied uterine cervix focal lesions (number = 60 cases) Fifty-four lesions out of the studied 60 focal lesions of the uterine cervix found showed iso-to hypointense signals on T1WI and exhibited moderate hyper-intense signal on T2WI regardless of benign or malignant etiology. In the remaining 6 lesions, 4 of them were diagnosed as chronic cervicitis with nabothian cyst that showed iso-to low signal on T1WI and mixed intermediate-high signals in T2WI, and the remaining 2 cervical lesions were diagnosed to be degenerated leiomyoma which exhibits low signals on T1WI and mixed signals on T2WI (Table 2).
DW-MRI with ADC value measurement results of group I: malignant uterine cervix focal lesions (number = 46) All studied malignant uterine cervix focal lesions (46 lesions) showed restricted diffusion on DW-MRI (diffusion positive) being of hyper-intense signals at DWI with persistent high signals at high b value (b = 800) and corresponding low signal intensity at ADC map images. The ADC value of studied malignant endometrial lesions showed relatively low value averages of 0.86-1.15 × 10 -3 mm 2 /s with mean ADC value of about 0.92 ± 0.71 × 10 −3 mm 2 /s (  Table 5). The presence of lymph node metastasis in the pelvic cavity was evaluated. Metastatic lymphadenopathy was defined as any enlarged lymph nodes larger than 10 mm in the short-axis diameter on T1-weighted images [10] (Fig. 4).

Discussion
The new 2018 FIGO system promotes the value of imaging modalities especially MRI imaging to increase the accuracy of tumor staging and guide treatment/monitoring. DWI increases the staging accuracy of MRI by permitting better evaluation of tumor size, extra uterine extension, and nodal infiltration, factors that affect treatment selection and planning [11][12][13]. In this study, the age of the included patients with suspected cervical cancers ranged from 39 to 63 years, M = ± 44.6 years. The abnormal vaginal bleeding was the main complaint in 42 patients while 18 patients complained of malodorous discharge and vaginal discomfort. This was in agreement with Sherif HA et al., who studied 20 female patients age 30-75 years with a clinical picture of abnormal vaginal bleeding and vaginal discharge [14], and also with Rezvani M et al. who stated that cancer cervix typically presents in younger women with an average age around 45 years, presented by abnormal vaginal bleeding, discomfort, and malodorous discharge as the first complaints [6].
MR imaging represents the most valuable imaging modality for the detection of the primary tumor, nodal involvement, and local spread. It is also the best modality for showing recurrent disease and monitoring therapeutic response [17].
In the present work, the imaging findings revealed poor MRI signal characterization of pathologically proved different lesions as 27/30 cervical lesions showed iso-to hypointense signals on T1WI and moderate hyper-intense signals on T2WI with variable contrast  [19]. Tamai KT et al. found that degenerated leiomyomas (7 lesions) showed low SI on T1-weighted images with areas of high SI on T2-weighted images [20]. Patel et al. reported that cervical tumors tend to give iso-to high signal compared to cervical stroma on T2WI [21].
The diffusion-weighted image (DWI) visualizes the local microstructural characteristics of water diffusion. High intensity on DWI with low apparent diffusion coefficients (ADC) is suggestive for malignant polyp with hypercellular nature, whereas benign polyps tend to show higher ADC value [22]. Our results revealed that all studied malignant cervical focal lesions (n = 46) showed positive diffusion restriction at high b value (b =   . This is may be attributed to the presence of necrosis and focal signal intensity changes as well as susceptibility artifacts. These result findings matched with many other studies which concluded the reported mean ADC values for both squamous cell carcinoma and adenocarcinoma cases to be less than 1 × 10 −3 mm 2 /s, averaging 0.88-0.91 × 10 −3 mm 2 /s, 0.8827 × 10 −3 mm 2 /s, and 0.72 ± 0.168 × 10 −3 mm 2 /s, respectively [23][24][25]. Also, Mahmoud SA concluded that in the present study, the mean ADC value for malignant lesions was 0.82 × 10 −3 ± 0.1 SD mm 2 /s [18], and Sherif HA et al. stated that the mean ADC value of cervical carcinoma in our study was 0.82 × 10 −3 mm 2 /s [14]. According to these study results, multiparametric MRI could detect all cervical focal lesions but with poor pathological characterization, achieving 72.37% sensitivity, 37.50% specificity, 63.33% accuracy, 76.19% PPV, and   [26]. Mahmoud SM reported that DW-MRI revealed sensitivity, specificity, PPV, and accuracy of 100%, 50%, 97%, and 97% respectively [18]. Also, Exner M. et al. concluded that the use of DWI led to an increase in sensitivity of infiltrated adjacent tissue (from 86 to 90%) and detection of lymph node metastases (from 47 to 67%) [27].

Limitations
The main limitation of this study was the limited sample size. Further studies using a cohort study of patients with long-term follow-up are needed to establish the accuracy of this method for early detection of cervical uterine cancer.

Conclusion
Adding DWI with ADC values measurements at high b value to the multiparametric MRI examination of the female pelvis increases the sensitivity, specificity, and diagnostic accuracy for characterization and early diagnosis of cervical malignant focal lesions and appropriate planning management options. DWI may replace the contrast study especially for patients not candidates for contrast injection. It can be used in conjunction with ADC values as a standard routine protocol after application in a large number of patients aiming to decrease the diagnostic pitfalls and get higher diagnostic performance including distant metastatic infiltration.  Availability of data and materials All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics approval and consent to participate Our ethics committee guidelines are applied to all patients according to the Egyptian Network of Research Ethics Committee (ENREC). Committee reference number: not available. All patients had written informed consent.

Consent for publication
Every patient had written informed consent for publication of his medial data.