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The Diagnostic Value of MRI for Preoperative Staging in Patients with Endometrial Cancer: A Meta-Analysis
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Original Investigation
The Diagnostic Value of MRI for Preoperative Staging in Patients with Endometrial Cancer: A Meta-Analysis Qiu Bi, MD1, Yuhui Chen, MD1, Kunhua Wu, MD, Junna Wang, MD, Ying Zhao, MD, Bo Wang, MD, Ji Du, BD Abbreviations MRI magnetic resonance imaging QUADAS-2 Quality Assessment of Diagnostic Accuracy Studies-2 sROC summary receiver-operating characteristics T2WI T2-weighted image DCE-MRI dynamic contrast-enhanced MRI DWI diffusion weighted imaging FIGO International Federation of Gynecology and Obstetrics PET-CT positron emission tomography-computed tomography
Objectives: To assess the diagnostic accuracy of magnetic resonance imaging (MRI) for detecting myometrial invasion, cervical invasion, and lymph node metastases in endometrial cancer. Materials and Methods: A systematic literature search was performed in PubMed, Embase, Cochrane Library, Web of Science, and Clinical trials. The methodological quality of each study was assessed by using the standard Quality Assessment of Diagnostic Accuracy Studies-2. Statistical analysis included evaluating publication bias, assessing threshold effect, exploring heterogeneity, pooling data, metaregression, forest plot, and summary receiver-operating characteristics curves construction. Results: Fourteen studies could be analyzed. For detecting deep myometrial invasion, the pooled sensitivity and specificity were 0.79 and 0.81 respectively, and patients younger than 60 years old demonstrated higher sensitivity (0.84) and specificity (0.90). The diagnostic accuracy is highest by jointly using T2-weighted image, dynamic contrast-enhanced MRI, and diffusion weighted imaging to detect the deep myometrial invasion. There were low sensitivity and high specificity for the diagnosis of cervical invasion (0.53, 0.95), cervical stromal invasion (0.50, 0.95), pelvic or/and para-aortic lymph node metastases (0.59, 0.95), and pelvic lymph node metastases (0.65, 0.95). Conclusion: MRI has good diagnostic performance for assessing myometrial invasion in patients with endometrial cancer, especially in patients younger than 60 years old. Dynamic contrast-enhanced MRI and diffusion weighted imaging can help improve sensitivity and specificity for detecting myometrial invasion. MRI shows high specificity for detecting cervical invasion and lymph node metastases in endometrial cancer. Key Words: Endometrial cancer; Magnetic resonance imaging; Myometrial invasion; Cervical invasion; Lymph node metastases. © 2019 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.
PLR positive likelihood ratio NLR negative likelihood ratio DOR diagnostic odds ratios CT computed tomography
Acad Radiol 2019; &:1–9 From the Department of MRI, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming 650032, Yunnan, China (Q.B., Y.C., K.W., Y.Z., B.W., J.D.); Department of Infectious Diseases, Xi'an No. 3 Hospital, Xi'an, China (J.W.). Received August 21, 2019; revised September 14, 2019; accepted September 14, 2019. Address correspondence to: K.W. e-mail: [email protected] 1 Qiu Bi and Yuhui Chen contributed equally to this work and are considered co-first authors. © 2019 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.acra.2019.09.018
INTRODUCTION
E
ndometrial cancer is one of the most common malignancies in female reproductive system (1), which is generally staged according to the International Federation of Gynecology and Obstetrics (FIGO) system (2). Myometrial invasion, cervical invasion, and lymph node metastases are the main parts of the staging, because they are important risk factors for extrauterine disease and poor outcome (2,3). Clinical management and the prognosis of endometrial cancer is closely related to the tumor stage on account 1
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of its different treatment options (2,3). Primary treatment of endometrial cancer consists of hysterectomy and bilateral salpingo-oophorectomy, whereas bilateral pelvic-para-aortic lymphadenectomy is needed in deep myometrial invasion tumors (3). In stage II endometrial cancer (cervical invasion in 1988 FIGO stage and cervical stromal invasion in 2009 FIGO stage), the surgical approach consists of radical hysterectomy with bilateral salpingo-oophorectomy and bilateral pelvic-para-aortic lymphadenectomy (3). The presence of metastatic lymph nodes strongly influence the treatment options, and is associated with poor clinical outcome (3,4). As a consequence, It is very important to detect deep myometrial invasion, cervical invasion, and lymph node metastases preoperatively. Magnetic resonance imaging (MRI) is a kind of standard imaging protocols for staging in endometrial cancer. And many articles have studied the accuracy of MRI in local staging (5 18). T2-weighted image (T2WI) and contrastenhanced MRI are standard MRI protocol for staging in patients with endometrial cancer according to the guidelines of the European Society of Urogenital Imaging (19). Nowadays, some other imaging techniques have increasingly been applied to staging in endometrial cancer, such as three-dimensional turbo spin-echo T2WI, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion weighted imaging (DWI) (5,9,10,12 16,18). From the previous, it was different in the use of magnetic field and MR pulse sequences in previous studies. In addition, these studies incorporated a limited number of patients and reported diverse results. Some recent meta-analyses have shown the pooled sensitivity and specificity of MRI for detecting deep myometrial invasion or lymph node metastases in endometrial cancer (20 22). Nonetheless, there was no meta-analysis or systematic review of evaluating accuracy in staging of endometrial cancer. The purpose of this meta-analysis was to assess the diagnostic accuracy of MRI staging including myometrial invasion, cervical invasion, and lymph node metastases in patients with endometrial cancer.
MATERIALS AND METHODS Literature Search
A systematic literature search of studies was performed by one observer to identify articles about the accuracy of staging using MRI in endometrial cancer. The PubMed, Embase, Cochrane Library, Web of Science, and Clinical trials from January 2000 to May 2019 for English language articles on human subjects were searched. The following keywords (including subject word and random word) were used: “endometrial neoplasms”, “MRI”, “diffusion MRI”, “stage”, “myometrial”, “cervical”, and “lymph node”. The reference lists of relevant articles were manually searched for possible missing citation.
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Study Selection
Two reviewers (radiologists with 20 years and 10 years of experience in pelvic imaging respectively) independently reviewed all eligible articles. Disagreements were resolved by consensus. The inclusion criteria were as follows: (a) Accuracy was assessed for complete staging (deep myometrial invasion, cervical invasion and lymph node metastases) by using MRI as the index test in endometrial cancer; (b) Histopathological examination after surgery was used as the reference standard; (c) 2 £ 2 tables for previous staging could be reconstructed; (d) When data overlapped or publications involving the same patient cohort were presented, the article with the largest number of patients was chosen; (e) Expounding MRI blinded from reference standard. We excluded studies that were focused on other imaging techniques such as positron emission tomography-computed tomography (PET-CT) and ultrasound for local staging in endometrial cancer. Data Extraction and Processing
The same two reviewers who performed the study selection extracted data on diagnostic accuracy results and additional useful information in original research. Disagreements were resolved by consensus. The following items were extracted for each study: author name, publication year, area, number of observers, sample size, design, patient recruitment, patient age, blinded, magnetic field, manufacturer, MR pulse sequences, depth of cervical infiltration, location and cut-off value of lymph nodes metastasis, imaging criteria for staging, and the number of true-positive, false-positive, true-negative and falsenegative findings for MRI staging in endometrial cancer. When the accuracy of pelvic and para-aortic lymph node metastasis was reported separately, the former was prioritized. When different MRI sequences were reported, the most contemporary MRI scan was preferred (eg, DWI before contrastenhanced imaging). In the case of different cut-off values, the most clinically appropriate one was used (23) (e.g., lymph node metastasis was diagnosed when the short-axis diameter was 10 mm or above). When the results were provided for two or more observers, the mean values were calculated and selected. Assessment of Data Quality
The standard Quality Assessment of Diagnostic Accuracy Studies-2 (24) (QUADAS-2; Bristol University, Bristol, United Kingdom) was used to evaluate the study quality by two authors independently. Any disagreements were resolved by discussion with each other. The QUADAS-2 format includes four domains: (a) patient selection; (b) index test; (c) reference standard; and (d) flow and timing. Statistical Analysis
Analyses were performed by using Stata 15.1 (StataCorp, Texas, USA), Review Manager 5.3 (The Nordic Cochrane Centre,
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THE DIAGNOSTIC VALUE OF MRI FOR PREOPERATIVE STAGING
Copenhagen, Denmark), and MetaDisc 1.4 (Ram on y Cajal Hospital, Madrid, Spain). The spearman correlation coefficient between the logit of sensitivity and the logit of (1-specificity) was calculated to assess the threshold effect (25). If P < 0.05, the threshold effect existed. Heterogeneity among studies was explored by using the Cochran's Q statistic and the inconsistency index (I2) (26). A value of p < 0.10 indicates heterogeneity (26). I2 values greater than 50.0% are considered to indicate substantial heterogeneity (27). A random-effects model was used to summarize the overall pooled diagnostic results if heterogeneity existed. Forest plots and summary receiver-operating characteristics (sROC) curves of sensitivity and specificity of all studies were plotted. To explore heterogeneity, meta-regression was performed. Several relevant covariates were as follows: area (Asia or Europe), design (prospective or retrospective), patient age ( 60y or < 60y), magnetic field (1.5 T or 3.0 T), MR pulse sequences, depth of cervical infiltration (stromal invasion or not), and location (pelvic or not) of lymph nodes metastasis. Sensitivity analyses were performed on the basis of those influencing factors of heterogeneity. Publication bias was assessed by using Deeks’funnel plot (28). A value of p < 0.05 was considered to indicate significant bias. RESULTS Literature Search
The flowchart of the literature search and study selection is provided in Figure 1. The electronic search provided a total of 1603 records from January 2000 to May 2019 for English language articles on human subjects. Eight additional records identified after manual reference checking. There are 1116 citations remained
after duplicates. After screening of titles and abstracts, 206 records remained. The full text of these studies was reviewed, then 191 articles were excluded: (a) data overlapped or publications involving the same patient cohort; (b) no complete staging accuracy reported; (c) unable to reconstruct 2 £ 2 table; (d) no detail about MRI blinded from reference standard. Ultimately, a total of 14 eligible studies were included in the meta-analysis (5 18). Quality Assessment and Publication Bias
The details of principal characteristics of the 14 studies are summarized in Table 1. The distribution of QUADAS-2 scores of the methodological quality graph and methodological quality summary of every included study is presented in Figure 2. Common weaknesses concentrated in: (1) 11 studies did not interpret that pathology was blinded from MRI (6,7,9 13,15 18); (2) eight studies did not elucidate that patient recruitment was consecutive (6,9,10,14 18); (3) all studies did not record the time interval between histologic examination and MRI (5 18). One study did not use a uniform gold standard (10). The threshold was not clearly described in two studies (7,18). The slope coefficients for the Deeks’funnel plot for MRI staging are presented in Figure 3. There was no publication bias in evaluating deep myometrial invasion (p = 0.66). Publication bias was detected in the diagnosis of cervical invasion and lymph node metastasis (p = 0.02 and 0.01 respectively). Data Analysis
Figure 4 and Figure 5 shows the forest plots of sensitivity and specificity and sROC respectively of MRI for detecting deep
Figure 1. Flowchart of study selection.
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BI ET AL
4 TABLE 1. Description of the included studies Study
Year
Country
Age (y)
Sample size
Design
Patient recruitment
Magnetic field
Manufacturer
MR Pulse Sequences
Depth of cervical invasion
Location of lymph nodes
Cut-off value of lymph nodes metastases
Manfredi
2004
Italy
58.8
37
P
C
1.5T
GE
T2+DCE
2007
UK
61
96
R
NR
1.5T
GE
T2
Undurraga
2009
Switzerland
69.5
108
R
C
1.5T
NR
T2+CE
stroma
Haldorsen
2012
Norway
66
57
P
C
1.5T
Siemens
T2+CE
stroma
Antonsen
2013
Denmark
65
227
P
C
1.5T
Philips
T2+CE
Hahn Hori Kitajima Koplay
2013 2013 2013 2014
Korea Japan Japan Turkey
53.1 57.6 62.4 58
131 71 30 58
R P R R
NR C NR C
1.5T 3.0T 1.5T 1.5T
Philips Philips GE Siemens
T2+DCE 3D-T2+DWI T2+DCE+DWI DWI
Teng
2015
China
57.9
167
R
NR
1.5T
GE
DCE
Chan Shrivastava Goel
2016 2016 2019
China India India
55.2 52.8 60.2
90 36 58
R R P
NR NR NR
1.5T 1.5T 1.5T
Siemens Philips GE
T2+DCE+DWI T2+DCE T2+DCE
Yang
2019
China
54.1
182
R
NR
3.0T
GE
T2
stroma or/ and mucosa stroma stroma stroma stroma or/ and mucosa stroma or/ and mucosa stroma stroma stroma or/ and mucosa stroma
pelvic or/and para-aortic pelvic or/and para-aortic pelvic or/and para-aortic pelvic or/and para-aortic pelvic or/and para-aortic pelvic pelvic pelvic pelvic
1cm
Rockall
stroma or/ and mucosa stroma
P, prospective; R, retrospective; C, consecutive; NR, not reported; CE, contrast-enhanced MRI; DCE, dynamic contrast-enhanced MRI; DWI, diffusion weighted imaging.
1cm 1cm 1cm 1cm 1cm 1cm 1cm or/ and signal 1cm 1cm signal 1cm
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pelvic pelvic pelvic or/and para-aortic pelvic
NR
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pelvic
1cm
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Figure 2. Histogram plot (a) and stacked bar charts (b) of QUADAS-2 scores of methodological study quality. Abbreviation: QUADAS, Quality Assessment of Diagnostic Accuracy Studies-2.
myometrial invasion, cervical invasion, and lymph node metastases. The results of pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratios (DOR) for detecting deep myometrial invasion, cervical invasion, cervical stromal invasion, lymph node metastases, and pelvic lymph node metastases are shown in Table 2. Table 3 shows the results of metaregression
of MRI for detecting deep myometrial invasion, cervical invasion, and lymph node metastases. For Detecting Deep Myometrial Invasion The threshold effect did not exist (spearman correlation coefficient = -0.23, p = 0.44), but significant evidence of heterogeneity was found for detecting deep myometrial
Figure 3. Deeks’funnel plot for evaluating deep myometrial invasion (a), cervical invasion (b), and lymph node metastasis (c). Numbers in circles represent study number. A value of p < 0.05 was considered to indicate significant publication bias.
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Figure 4. Forest plots show diagnostic performance estimates of MRI for detecting deep myometrial invasion (a, b), cervical invasion (c, d), and lymph node metastasis (e, f) of each study. Abbreviation: MRI, magnetic resonance imaging.
Figure 5. Summary receiver-operating characteristics (sROC) curves of MRI for detecting deep myometrial invasion (a), cervical invasion (b), and lymph node metastasis (c). Abbreviation: MRI, magnetic resonance imaging.
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TABLE 2. The pooled diagnostic accuracy of MRI
Deep myometrial invasion Cervical invasion Cervical stromal invasion Lymph node metastases Pelvic lymph node metastases
Number of studies
Sensitivity
Specificity
PLR
NLR
DOR
14 14 9 11 7
0.79 (0.75-0.83) 0.53 (0.46-0.60) 0.50 (0.41-0.60) 0.59 (0.48-0.69) 0.65 (0.51-0.77)
0.81 (0.78-0.83) 0.95 (0.94-0.96) 0.95 (0.93-0.97) 0.95 (0.93-0.96) 0.95 (0.93-0.97)
4.96 (3.12-7.90) 10.99 (8.25-14.65) 10.87 (7.50-15.74) 10.17 (7.12-14.55) 11.07 (6.88-17.82)
0.25 (0.17-0.37) 0.46 (0.35-0.61) 0.51 (0.38-0.70) 0.51 (0.41-0.64) 0.45 (0.30-0.66)
21.41 (10.77-42.58) 29.50 (17.61-49.43) 27.46 (15.28-49.35) 29.56 (16.31-53.59) 36.76 (16.81-80.40)
PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratios. Data in parentheses are 95% CI.
invasion (I2 = 61.3%, p = 0.00 for sensitivity and I2 = 89.8%; p = 0.00 for specificity) (Figure 4). The pooled sensitivity, specifcity, PLR, NLR, and DOR were 0.79 (95% CI: 0.75, 0.83), 0.81 (95% CI: 0.78, 0.83), 4.96 (95% CI:3.12, 7.90), 0.25 (95% CI: 0.17, 0.37), and 21.41 (95% CI: 10.77, 42.58), respectively (Table 2). The area under the sROC of deep myometrial invasion was 0.89. Metaregression showed that age and MR pulse sequences contributed to heterogeneity (P = 0.00 and 0.01) (Table 3). Subsequently, sensitivity analysis showed that patients younger than 60 years old demonstrated higher pooled sensitivity and specificity, they were 0.84 (95% CI: 0.78, 0.89) and 0.90 (95% CI: 0.88, 0.93) respectively. Using T2WI, DCE-MRI, and DWI simultaneously to observe the deep myometrial invasion with highest pooled sensitivity and specificity, they were 0.81 (95% CI: 0.62, 0.94) and 0.91 (95% CI: 0.84, 0.96) respectively.
For Detecting Cervical Invasion There was no threshold effect for detecting cervical invasion (spearman correlation coefficient = 0.52, p = 0.06). High heterogeneity was found for sensitivity (I2 = 67.8%, p = 0.00) but low heterogeneity was found for specificity (I2 = 23.1%, p = 0.12) in the diagnosis of cervical invasion (Figure 4). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting cervical invasion were 0.53 (95% CI: 0.46, 0.60), 0.95 (95% CI: 0.94, 0.96), 10.99 (95% CI: 8.25, 14.65), 0.46 (95% CI: 0.35, 0.61), and 29.50 (95% CI: 17.61, 49.43), TABLE 3. The results of meta-regression of MRI
Area Age Design Magnetic feld MR pulse sequences Depth of cervical invasion Lymph node location
P1
P2
P3
0.31 0.00* 0.25 0.15 0.01* — —
0.05 0.07 0.37 0.94 0.08 0.96 —
0.37 0.54 0.38 0.85 0.15 — 0.37
P1, P value of detecting deep myometrial invasion; P2, P value of detecting cervical invasion; P3, P value of detecting lymph node metastases; * P<0.05.
respectively (Table 2). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting cervical stromal invasion were 0.50 (95% CI: 0.41, 0.60), 0.95 (95% CI: 0.93, 0.97), 10.87 (95% CI: 7.50, 15.74), 0.51 (95% CI: 0.38, 0.70), and 27.46 (95% CI: 15.28, 49.35), respectively (Table 2). The area under the sROC of cervical invasion was 0.95. Meta-regression showed that area, design, patient age, magnetic field, MR pulse sequences, and the depth of cervical invasion could not explain heterogeneity (Table 3). For Detecting Lymph Node Metastases The threshold effect existed for detecting pelvic or/and para-aortic lymph node metastases (spearman correlation coefficient = 0.56, p = 0.04). We reviewed the original studies to find the cause of the existence of threshold effect. A lymph node metastasis was diagnosed when the short diameter was great than 1 cm in eleven studies (5,6,8 13,15 17). The rest of three studies used signal intensity or no description for diagnosing lymph node metastases (7,14,18). When the previous three studies were excluded, the threshold effect did not exist (spearman correlation coefficient = 0.50, p = 0.12), and low heterogeneity was found for sensitivity (I2 = 26.0%, p = 0.20) but significant heterogeneity was found for specificity (I2 = 58.7%, p = 0.01) (Figure 4). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting pelvic or/and para-aortic lymph node metastases were 0.59 (95% CI: 0.48, 0.69), 0.95 (95% CI: 0.93, 0.96), 10.17 (95% CI: 7.12, 14.55), 0.51 (95% CI: 0.41, 0.64), and 29.56 (95% CI: 16.31, 53.59), respectively (Table 2). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting pelvic lymph node metastases were 0.65 (95% CI: 0.51, 0.77), 0.95 (95% CI: 0.93, 0.97), 11.07 (95% CI: 6.88, 17.82), 0.45 (95% CI: 0.30, 0.66), and 36.76 (95% CI: 16.81, 80.40), respectively (Table 2). The area under the sROC of pelvic or/and para-aortic lymph node metastases was 0.95. Meta-regression showed that area, design, patient age, magnetic field, MR pulse sequences, and the location of lymph nodes metastasis could not explain heterogeneity (Table 3). DISCUSSION This meta-analysis demonstrated good pooled sensitivity and specificity of MRI for detecting deep myometrial invasion and 7
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superior specificity in the diagnosis of cervical invasion and lymph node metastases. Metaregression revealed that patient age and MR pulse sequences were helpful to explain heterogeneity of MRI for detecting deep myometrial invasion. The treatment method of endometrial cancer rests with preoperative staging (3). It will be beneficial in improving precision treatment and minimizing costs by using a noninvasive preoperative technique for accurate preoperative staging of endometrial cancer. Imaging is an important examination method for staging of endometrial cancer. MRI, ultrasound, computed tomography (CT), and PET-CT are important imaging modalities for evaluating preoperative staging of endometrial cancer (11). However, ultrasound has limited value in diagnosing lymph node metastases. CT and PET/CT have radiation burden, and the contrast resolution for different tissues is limited. MRI is considered to be optimal imaging modality for preoperative staging of endometrial cancer because of its high soft-tissue resolution (10). MRI showed good accuracy for detecting deep myometrial invasion, and high specificity for detecting cervical invasion and lymph node metastases in this meta-analysis, which makes it especially important before the therapy of endometrial cancer. Myometrial invasion often be assessed by judging an interruption of the junctional zone. Because the junctional zone shows hypointensity on T2-weighted MR images, while endometrial cancer shows hyperintensity (5). However, the myometrium may be thinned and the junctional zone may be poorly visible due to metratrophia in postmenopausal women, particularly older women. This makes it difficult to assess the depth of myometrial invasion (5). In consequence, patients older than 60 years old demonstrated lower pooled sensitivity and specificity than patients younger than 60 years old for assessing deep myometrial invasion. Some previous meta-analyses have confirmed that DCE-MRI or DWI could improve diagnostic value in the prediction of deep myometrial invasion (5,20,29). Because DCEMRI not only could improve the contrast resolution of the myometrium and tumor, but also could distinguish them according to different enhancement time of the myometrium and tumor (5,20). And DWI could quantitatively evaluate the depth of myometrial invasion by measuring apparent diffusion coefficient values (29). To overcome the limitation of metratrophia, T2WI, DCE-MRI, and DWI should be combined performed. Deng et al (30) have verified DWI combined with T2WI could improve diagnostic performance in comparison with DWI alone. Manfredi et al (5) found that there was a significant correlation between imaging and histopathologic findings in assessing myometrial infiltration by combining T2WI and DCE-MRI. The diagnostic accuracy is highest by jointly using T2WI, DCE-MRI, and DWI to detect the deep myometrial invasion in this meta-analysis. Several studies have reported that cervical invasion indicated a poor prognosis (31,32). It is important to preoperativly assess cervical involvement of endometrial cancer in planning treatment and predicting prognosis. The normal cervical stroma is rich in fibrous tissue and appears hypointense on T2WI. Which leading to high contrast resolution comparing with 8
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tumors. Therefore, T2WI is well suited for assessing cervical invasion (5). And there was no difference between the T2WI and the DCE-MRI for predicting cervical invasion (6). As a result, MR pulse sequences could not explain heterogeneity. There was high specificity in the diagnosis of cervical invasion and cervical stromal invasion in this meta-analysis. The high specificity of MRI in detecting cervical invasion might be of vital value in deciding the extent of surgery, that is to say, it could help to consider a simple hysterectomy or a more radical surgery (3,6). Nevertheless, only macroscopic cervical invasion could be observed by using MRI, microscopic stromal infiltration or cervical mucosa involvement might be ignored. Which was probably why the sensitivity for detecting cervical invasion or cervical stromal invasion was low. Lymph node metastasis is also an important prognostic factor in endometrial cancer (22). MRI has a good capability to directly depict lymph nodes, especially on DWI sequence, appearing hyperintensity because of their parenchymal structure (5). In gynecologic malignancies, metastatic and non-metastatic lymph nodes are usually differentiated by a size criterion of the short diameter was great than 1 cm on imaging examination (33). There were low sensitivity and high specificity for detecting pelvic or/and para-aortic lymph node metastases and pelvic lymph node metastases in endometrial cancer in this meta-analysis, as in other studies (5,6,8,10 12,15 17). On account of some features such as central necrosis, irregular nodal contour, and so on might suggest a metastatic lymph node (33). Only using size to detect lymph node metastasis might lead to a high false negative rate. In this meta-analysis, six studies combined para-aortic and pelvic lymph nodes evaluation, which leading to a lower pooled sensitivity than the pooled sensitivity that evaluated pelvic lymph nodes only (34). In order to allow a more reliable results in staging of endometrial cancer, we only included studies in which myometrial invasion, cervical invasion, and lymph node metastases were detected at the same time with the same set of patients. Hence, the number of included studies were small, did not allow us to perform separate subgroup analyses and to investigate all potential causes of heterogeneity. This was the main limitation of this meta-analysis. A second limitation was the existence of publication bias. Searches were performed from 2000 to 2019 and restricted to publish in English. Several relevant studies published in other languages may be missed, possibly introducing publication bias. Another possible reason for bias was that the sensitivity for detecting cervical invasion or lymph node metastases was low. Perhaps some articles of negative results were not published. In conclusion, this meta-analysis shows MRI has good diagnostic performance for detecting deep myometrial invasion, and has high specificity for detecting cervical invasion and lymph node metastases in endometrial cancer. Patients younger than 60 years old demonstrated higher sensitivity and specificity for detecting the deep myometrial invasion. Using T2WI, DCE-MRI, and DWI simultaneously to detect the deep myometrial invasion with highest pooled sensitivity and specificity.
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15. Chan C, Shek S, Kwok S, et al. Diagnostic accuracy of preoperative magnetic resonance imaging in staging endometrial cancer: a five-year experience. Hong Kong J Radiol 2016; 19(4):249–255. 16. Shrivastava S, Barmon D, Kataki AC, et al. Magnetic resonance imaging in pre-operative staging of endometrial cancer. Indian J Cancer 2016; 53 (1):181–185. 17. Yang T, Tian S, Li Y, et al. Magnetic Resonance Imaging (MRI) and threedimensional transvaginal ultrasonography scanning for preoperative assessment of high risk in women with endometrial cancer. Med Sci Monit 2019; 25:2024–2031. 18. Goel G, Rajanbabu A, Sandhya CJ, et al. A prospective observational study evaluating the accuracy of MRI in predicting the extent of disease in endometrial cancer. Indian J Surgl Oncol 2019; 10(1):220–224. 19. Kinkel K, Forstner R, Danza FM, et al. Staging of endometrial cancer with MRI: guidelines of the European Society of Urogenital Imaging. Eur Radiol 2009; 19(7):1565–1574. 20. Wu LM, Xu JR, Gu HY, et al. Predictive value of T2-weighted imaging and contrast-enhanced MR imaging in assessing myometrial invasion in endometrial cancer: a pooled analysis of prospective studies. Eur Radiol 2013; 23(2):435–449. 21. Andreano A, Rechichi G, Rebora P, et al. MR diffusion imaging for preoperative staging of myometrial invasion in patients with endometrial cancer: a systematic review and meta-analysis. Eur Radiol 2014; 24 (6):1327–1338. 22. Zhou M, Lu B, Lv G, et al. Differential diagnosis between metastatic and non-metastatic lymph nodes using DW-MRI: a meta-analysis of diagnostic accuracy studies. J Cancer Res Clin Oncol 2015; 141(6):1119–1130. 23. Huang L, Kong Q, Liu Z, et al. The diagnostic value of MR imaging in differentiating T staging of bladder cancer: a meta-analysis. Radiology 2018; 286(2):502–511. 24. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011; 155(8):529–536. 25. Zamora J, Abraira V, Muriel A, et al. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol 2006; 6:31. 26. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11):1539–1558. 27. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414):557–560. 28. Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 2005; 58(9):882–893. 29. Das SK, Niu XK, Wang JL, et al. Usefulness of DWI in preoperative assessment of deep myometrial invasion in patients with endometrial carcinoma: a systematic review and meta-analysis. Cancer Imaging 2014; 14:32. 30. Deng L, Wang QP, Chen X, et al. The combination of diffusion- and T2weighted imaging in predicting deep myometrial invasion of endometrial cancer: a systematic review and meta-analysis. J Comput Assist Tomogr 2015; 39(5):661–673. 31. Rubin SC, Hoskins WJ, Saigo PE, et al. Management of endometrial adenocarcinoma with cervical involvement. Gynecol Oncol 1992; 45(3):294–298. 32. Elia G, Garfinkel DA, Goldberg GL, et al. Surgical management of patients with endometrial cancer and cervical involvement. Eur J Gynaecol Oncol 1995; 16(3):169–173. 33. Narayanan P, Iyngkaran T, Sohaib SA, et al. Pearls and pitfalls of MR lymphography in gynecologic malignancy. Radiographics 2009; 29 (4):1057–1069. discussion 1069-71. 34. Klerkx WM, Bax L, Veldhuis WB, et al. Detection of lymph node metastases by gadolinium-enhanced magnetic resonance imaging: systematic review and meta-analysis. J Natl Cancer Inst 2010; 102(4):244–253.
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Original Investigation
The Diagnostic Value of MRI for Preoperative Staging in Patients with Endometrial Cancer: A Meta-Analysis Qiu Bi, MD1, Yuhui Chen, MD1, Kunhua Wu, MD, Junna Wang, MD, Ying Zhao, MD, Bo Wang, MD, Ji Du, BD Abbreviations MRI magnetic resonance imaging QUADAS-2 Quality Assessment of Diagnostic Accuracy Studies-2 sROC summary receiver-operating characteristics T2WI T2-weighted image DCE-MRI dynamic contrast-enhanced MRI DWI diffusion weighted imaging FIGO International Federation of Gynecology and Obstetrics PET-CT positron emission tomography-computed tomography
Objectives: To assess the diagnostic accuracy of magnetic resonance imaging (MRI) for detecting myometrial invasion, cervical invasion, and lymph node metastases in endometrial cancer. Materials and Methods: A systematic literature search was performed in PubMed, Embase, Cochrane Library, Web of Science, and Clinical trials. The methodological quality of each study was assessed by using the standard Quality Assessment of Diagnostic Accuracy Studies-2. Statistical analysis included evaluating publication bias, assessing threshold effect, exploring heterogeneity, pooling data, metaregression, forest plot, and summary receiver-operating characteristics curves construction. Results: Fourteen studies could be analyzed. For detecting deep myometrial invasion, the pooled sensitivity and specificity were 0.79 and 0.81 respectively, and patients younger than 60 years old demonstrated higher sensitivity (0.84) and specificity (0.90). The diagnostic accuracy is highest by jointly using T2-weighted image, dynamic contrast-enhanced MRI, and diffusion weighted imaging to detect the deep myometrial invasion. There were low sensitivity and high specificity for the diagnosis of cervical invasion (0.53, 0.95), cervical stromal invasion (0.50, 0.95), pelvic or/and para-aortic lymph node metastases (0.59, 0.95), and pelvic lymph node metastases (0.65, 0.95). Conclusion: MRI has good diagnostic performance for assessing myometrial invasion in patients with endometrial cancer, especially in patients younger than 60 years old. Dynamic contrast-enhanced MRI and diffusion weighted imaging can help improve sensitivity and specificity for detecting myometrial invasion. MRI shows high specificity for detecting cervical invasion and lymph node metastases in endometrial cancer. Key Words: Endometrial cancer; Magnetic resonance imaging; Myometrial invasion; Cervical invasion; Lymph node metastases. © 2019 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.
PLR positive likelihood ratio NLR negative likelihood ratio DOR diagnostic odds ratios CT computed tomography
Acad Radiol 2019; &:1–9 From the Department of MRI, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming 650032, Yunnan, China (Q.B., Y.C., K.W., Y.Z., B.W., J.D.); Department of Infectious Diseases, Xi'an No. 3 Hospital, Xi'an, China (J.W.). Received August 21, 2019; revised September 14, 2019; accepted September 14, 2019. Address correspondence to: K.W. e-mail: [email protected] 1 Qiu Bi and Yuhui Chen contributed equally to this work and are considered co-first authors. © 2019 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.acra.2019.09.018
INTRODUCTION
E
ndometrial cancer is one of the most common malignancies in female reproductive system (1), which is generally staged according to the International Federation of Gynecology and Obstetrics (FIGO) system (2). Myometrial invasion, cervical invasion, and lymph node metastases are the main parts of the staging, because they are important risk factors for extrauterine disease and poor outcome (2,3). Clinical management and the prognosis of endometrial cancer is closely related to the tumor stage on account 1
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of its different treatment options (2,3). Primary treatment of endometrial cancer consists of hysterectomy and bilateral salpingo-oophorectomy, whereas bilateral pelvic-para-aortic lymphadenectomy is needed in deep myometrial invasion tumors (3). In stage II endometrial cancer (cervical invasion in 1988 FIGO stage and cervical stromal invasion in 2009 FIGO stage), the surgical approach consists of radical hysterectomy with bilateral salpingo-oophorectomy and bilateral pelvic-para-aortic lymphadenectomy (3). The presence of metastatic lymph nodes strongly influence the treatment options, and is associated with poor clinical outcome (3,4). As a consequence, It is very important to detect deep myometrial invasion, cervical invasion, and lymph node metastases preoperatively. Magnetic resonance imaging (MRI) is a kind of standard imaging protocols for staging in endometrial cancer. And many articles have studied the accuracy of MRI in local staging (5 18). T2-weighted image (T2WI) and contrastenhanced MRI are standard MRI protocol for staging in patients with endometrial cancer according to the guidelines of the European Society of Urogenital Imaging (19). Nowadays, some other imaging techniques have increasingly been applied to staging in endometrial cancer, such as three-dimensional turbo spin-echo T2WI, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion weighted imaging (DWI) (5,9,10,12 16,18). From the previous, it was different in the use of magnetic field and MR pulse sequences in previous studies. In addition, these studies incorporated a limited number of patients and reported diverse results. Some recent meta-analyses have shown the pooled sensitivity and specificity of MRI for detecting deep myometrial invasion or lymph node metastases in endometrial cancer (20 22). Nonetheless, there was no meta-analysis or systematic review of evaluating accuracy in staging of endometrial cancer. The purpose of this meta-analysis was to assess the diagnostic accuracy of MRI staging including myometrial invasion, cervical invasion, and lymph node metastases in patients with endometrial cancer.
MATERIALS AND METHODS Literature Search
A systematic literature search of studies was performed by one observer to identify articles about the accuracy of staging using MRI in endometrial cancer. The PubMed, Embase, Cochrane Library, Web of Science, and Clinical trials from January 2000 to May 2019 for English language articles on human subjects were searched. The following keywords (including subject word and random word) were used: “endometrial neoplasms”, “MRI”, “diffusion MRI”, “stage”, “myometrial”, “cervical”, and “lymph node”. The reference lists of relevant articles were manually searched for possible missing citation.
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Study Selection
Two reviewers (radiologists with 20 years and 10 years of experience in pelvic imaging respectively) independently reviewed all eligible articles. Disagreements were resolved by consensus. The inclusion criteria were as follows: (a) Accuracy was assessed for complete staging (deep myometrial invasion, cervical invasion and lymph node metastases) by using MRI as the index test in endometrial cancer; (b) Histopathological examination after surgery was used as the reference standard; (c) 2 £ 2 tables for previous staging could be reconstructed; (d) When data overlapped or publications involving the same patient cohort were presented, the article with the largest number of patients was chosen; (e) Expounding MRI blinded from reference standard. We excluded studies that were focused on other imaging techniques such as positron emission tomography-computed tomography (PET-CT) and ultrasound for local staging in endometrial cancer. Data Extraction and Processing
The same two reviewers who performed the study selection extracted data on diagnostic accuracy results and additional useful information in original research. Disagreements were resolved by consensus. The following items were extracted for each study: author name, publication year, area, number of observers, sample size, design, patient recruitment, patient age, blinded, magnetic field, manufacturer, MR pulse sequences, depth of cervical infiltration, location and cut-off value of lymph nodes metastasis, imaging criteria for staging, and the number of true-positive, false-positive, true-negative and falsenegative findings for MRI staging in endometrial cancer. When the accuracy of pelvic and para-aortic lymph node metastasis was reported separately, the former was prioritized. When different MRI sequences were reported, the most contemporary MRI scan was preferred (eg, DWI before contrastenhanced imaging). In the case of different cut-off values, the most clinically appropriate one was used (23) (e.g., lymph node metastasis was diagnosed when the short-axis diameter was 10 mm or above). When the results were provided for two or more observers, the mean values were calculated and selected. Assessment of Data Quality
The standard Quality Assessment of Diagnostic Accuracy Studies-2 (24) (QUADAS-2; Bristol University, Bristol, United Kingdom) was used to evaluate the study quality by two authors independently. Any disagreements were resolved by discussion with each other. The QUADAS-2 format includes four domains: (a) patient selection; (b) index test; (c) reference standard; and (d) flow and timing. Statistical Analysis
Analyses were performed by using Stata 15.1 (StataCorp, Texas, USA), Review Manager 5.3 (The Nordic Cochrane Centre,
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Copenhagen, Denmark), and MetaDisc 1.4 (Ram on y Cajal Hospital, Madrid, Spain). The spearman correlation coefficient between the logit of sensitivity and the logit of (1-specificity) was calculated to assess the threshold effect (25). If P < 0.05, the threshold effect existed. Heterogeneity among studies was explored by using the Cochran's Q statistic and the inconsistency index (I2) (26). A value of p < 0.10 indicates heterogeneity (26). I2 values greater than 50.0% are considered to indicate substantial heterogeneity (27). A random-effects model was used to summarize the overall pooled diagnostic results if heterogeneity existed. Forest plots and summary receiver-operating characteristics (sROC) curves of sensitivity and specificity of all studies were plotted. To explore heterogeneity, meta-regression was performed. Several relevant covariates were as follows: area (Asia or Europe), design (prospective or retrospective), patient age ( 60y or < 60y), magnetic field (1.5 T or 3.0 T), MR pulse sequences, depth of cervical infiltration (stromal invasion or not), and location (pelvic or not) of lymph nodes metastasis. Sensitivity analyses were performed on the basis of those influencing factors of heterogeneity. Publication bias was assessed by using Deeks’funnel plot (28). A value of p < 0.05 was considered to indicate significant bias. RESULTS Literature Search
The flowchart of the literature search and study selection is provided in Figure 1. The electronic search provided a total of 1603 records from January 2000 to May 2019 for English language articles on human subjects. Eight additional records identified after manual reference checking. There are 1116 citations remained
after duplicates. After screening of titles and abstracts, 206 records remained. The full text of these studies was reviewed, then 191 articles were excluded: (a) data overlapped or publications involving the same patient cohort; (b) no complete staging accuracy reported; (c) unable to reconstruct 2 £ 2 table; (d) no detail about MRI blinded from reference standard. Ultimately, a total of 14 eligible studies were included in the meta-analysis (5 18). Quality Assessment and Publication Bias
The details of principal characteristics of the 14 studies are summarized in Table 1. The distribution of QUADAS-2 scores of the methodological quality graph and methodological quality summary of every included study is presented in Figure 2. Common weaknesses concentrated in: (1) 11 studies did not interpret that pathology was blinded from MRI (6,7,9 13,15 18); (2) eight studies did not elucidate that patient recruitment was consecutive (6,9,10,14 18); (3) all studies did not record the time interval between histologic examination and MRI (5 18). One study did not use a uniform gold standard (10). The threshold was not clearly described in two studies (7,18). The slope coefficients for the Deeks’funnel plot for MRI staging are presented in Figure 3. There was no publication bias in evaluating deep myometrial invasion (p = 0.66). Publication bias was detected in the diagnosis of cervical invasion and lymph node metastasis (p = 0.02 and 0.01 respectively). Data Analysis
Figure 4 and Figure 5 shows the forest plots of sensitivity and specificity and sROC respectively of MRI for detecting deep
Figure 1. Flowchart of study selection.
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BI ET AL
4 TABLE 1. Description of the included studies Study
Year
Country
Age (y)
Sample size
Design
Patient recruitment
Magnetic field
Manufacturer
MR Pulse Sequences
Depth of cervical invasion
Location of lymph nodes
Cut-off value of lymph nodes metastases
Manfredi
2004
Italy
58.8
37
P
C
1.5T
GE
T2+DCE
2007
UK
61
96
R
NR
1.5T
GE
T2
Undurraga
2009
Switzerland
69.5
108
R
C
1.5T
NR
T2+CE
stroma
Haldorsen
2012
Norway
66
57
P
C
1.5T
Siemens
T2+CE
stroma
Antonsen
2013
Denmark
65
227
P
C
1.5T
Philips
T2+CE
Hahn Hori Kitajima Koplay
2013 2013 2013 2014
Korea Japan Japan Turkey
53.1 57.6 62.4 58
131 71 30 58
R P R R
NR C NR C
1.5T 3.0T 1.5T 1.5T
Philips Philips GE Siemens
T2+DCE 3D-T2+DWI T2+DCE+DWI DWI
Teng
2015
China
57.9
167
R
NR
1.5T
GE
DCE
Chan Shrivastava Goel
2016 2016 2019
China India India
55.2 52.8 60.2
90 36 58
R R P
NR NR NR
1.5T 1.5T 1.5T
Siemens Philips GE
T2+DCE+DWI T2+DCE T2+DCE
Yang
2019
China
54.1
182
R
NR
3.0T
GE
T2
stroma or/ and mucosa stroma stroma stroma stroma or/ and mucosa stroma or/ and mucosa stroma stroma stroma or/ and mucosa stroma
pelvic or/and para-aortic pelvic or/and para-aortic pelvic or/and para-aortic pelvic or/and para-aortic pelvic or/and para-aortic pelvic pelvic pelvic pelvic
1cm
Rockall
stroma or/ and mucosa stroma
P, prospective; R, retrospective; C, consecutive; NR, not reported; CE, contrast-enhanced MRI; DCE, dynamic contrast-enhanced MRI; DWI, diffusion weighted imaging.
1cm 1cm 1cm 1cm 1cm 1cm 1cm or/ and signal 1cm 1cm signal 1cm
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pelvic pelvic pelvic or/and para-aortic pelvic
NR
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pelvic
1cm
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Figure 2. Histogram plot (a) and stacked bar charts (b) of QUADAS-2 scores of methodological study quality. Abbreviation: QUADAS, Quality Assessment of Diagnostic Accuracy Studies-2.
myometrial invasion, cervical invasion, and lymph node metastases. The results of pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratios (DOR) for detecting deep myometrial invasion, cervical invasion, cervical stromal invasion, lymph node metastases, and pelvic lymph node metastases are shown in Table 2. Table 3 shows the results of metaregression
of MRI for detecting deep myometrial invasion, cervical invasion, and lymph node metastases. For Detecting Deep Myometrial Invasion The threshold effect did not exist (spearman correlation coefficient = -0.23, p = 0.44), but significant evidence of heterogeneity was found for detecting deep myometrial
Figure 3. Deeks’funnel plot for evaluating deep myometrial invasion (a), cervical invasion (b), and lymph node metastasis (c). Numbers in circles represent study number. A value of p < 0.05 was considered to indicate significant publication bias.
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Figure 4. Forest plots show diagnostic performance estimates of MRI for detecting deep myometrial invasion (a, b), cervical invasion (c, d), and lymph node metastasis (e, f) of each study. Abbreviation: MRI, magnetic resonance imaging.
Figure 5. Summary receiver-operating characteristics (sROC) curves of MRI for detecting deep myometrial invasion (a), cervical invasion (b), and lymph node metastasis (c). Abbreviation: MRI, magnetic resonance imaging.
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TABLE 2. The pooled diagnostic accuracy of MRI
Deep myometrial invasion Cervical invasion Cervical stromal invasion Lymph node metastases Pelvic lymph node metastases
Number of studies
Sensitivity
Specificity
PLR
NLR
DOR
14 14 9 11 7
0.79 (0.75-0.83) 0.53 (0.46-0.60) 0.50 (0.41-0.60) 0.59 (0.48-0.69) 0.65 (0.51-0.77)
0.81 (0.78-0.83) 0.95 (0.94-0.96) 0.95 (0.93-0.97) 0.95 (0.93-0.96) 0.95 (0.93-0.97)
4.96 (3.12-7.90) 10.99 (8.25-14.65) 10.87 (7.50-15.74) 10.17 (7.12-14.55) 11.07 (6.88-17.82)
0.25 (0.17-0.37) 0.46 (0.35-0.61) 0.51 (0.38-0.70) 0.51 (0.41-0.64) 0.45 (0.30-0.66)
21.41 (10.77-42.58) 29.50 (17.61-49.43) 27.46 (15.28-49.35) 29.56 (16.31-53.59) 36.76 (16.81-80.40)
PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratios. Data in parentheses are 95% CI.
invasion (I2 = 61.3%, p = 0.00 for sensitivity and I2 = 89.8%; p = 0.00 for specificity) (Figure 4). The pooled sensitivity, specifcity, PLR, NLR, and DOR were 0.79 (95% CI: 0.75, 0.83), 0.81 (95% CI: 0.78, 0.83), 4.96 (95% CI:3.12, 7.90), 0.25 (95% CI: 0.17, 0.37), and 21.41 (95% CI: 10.77, 42.58), respectively (Table 2). The area under the sROC of deep myometrial invasion was 0.89. Metaregression showed that age and MR pulse sequences contributed to heterogeneity (P = 0.00 and 0.01) (Table 3). Subsequently, sensitivity analysis showed that patients younger than 60 years old demonstrated higher pooled sensitivity and specificity, they were 0.84 (95% CI: 0.78, 0.89) and 0.90 (95% CI: 0.88, 0.93) respectively. Using T2WI, DCE-MRI, and DWI simultaneously to observe the deep myometrial invasion with highest pooled sensitivity and specificity, they were 0.81 (95% CI: 0.62, 0.94) and 0.91 (95% CI: 0.84, 0.96) respectively.
For Detecting Cervical Invasion There was no threshold effect for detecting cervical invasion (spearman correlation coefficient = 0.52, p = 0.06). High heterogeneity was found for sensitivity (I2 = 67.8%, p = 0.00) but low heterogeneity was found for specificity (I2 = 23.1%, p = 0.12) in the diagnosis of cervical invasion (Figure 4). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting cervical invasion were 0.53 (95% CI: 0.46, 0.60), 0.95 (95% CI: 0.94, 0.96), 10.99 (95% CI: 8.25, 14.65), 0.46 (95% CI: 0.35, 0.61), and 29.50 (95% CI: 17.61, 49.43), TABLE 3. The results of meta-regression of MRI
Area Age Design Magnetic feld MR pulse sequences Depth of cervical invasion Lymph node location
P1
P2
P3
0.31 0.00* 0.25 0.15 0.01* — —
0.05 0.07 0.37 0.94 0.08 0.96 —
0.37 0.54 0.38 0.85 0.15 — 0.37
P1, P value of detecting deep myometrial invasion; P2, P value of detecting cervical invasion; P3, P value of detecting lymph node metastases; * P<0.05.
respectively (Table 2). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting cervical stromal invasion were 0.50 (95% CI: 0.41, 0.60), 0.95 (95% CI: 0.93, 0.97), 10.87 (95% CI: 7.50, 15.74), 0.51 (95% CI: 0.38, 0.70), and 27.46 (95% CI: 15.28, 49.35), respectively (Table 2). The area under the sROC of cervical invasion was 0.95. Meta-regression showed that area, design, patient age, magnetic field, MR pulse sequences, and the depth of cervical invasion could not explain heterogeneity (Table 3). For Detecting Lymph Node Metastases The threshold effect existed for detecting pelvic or/and para-aortic lymph node metastases (spearman correlation coefficient = 0.56, p = 0.04). We reviewed the original studies to find the cause of the existence of threshold effect. A lymph node metastasis was diagnosed when the short diameter was great than 1 cm in eleven studies (5,6,8 13,15 17). The rest of three studies used signal intensity or no description for diagnosing lymph node metastases (7,14,18). When the previous three studies were excluded, the threshold effect did not exist (spearman correlation coefficient = 0.50, p = 0.12), and low heterogeneity was found for sensitivity (I2 = 26.0%, p = 0.20) but significant heterogeneity was found for specificity (I2 = 58.7%, p = 0.01) (Figure 4). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting pelvic or/and para-aortic lymph node metastases were 0.59 (95% CI: 0.48, 0.69), 0.95 (95% CI: 0.93, 0.96), 10.17 (95% CI: 7.12, 14.55), 0.51 (95% CI: 0.41, 0.64), and 29.56 (95% CI: 16.31, 53.59), respectively (Table 2). The pooled sensitivity, specificity, PLR, NLR, and DOR for detecting pelvic lymph node metastases were 0.65 (95% CI: 0.51, 0.77), 0.95 (95% CI: 0.93, 0.97), 11.07 (95% CI: 6.88, 17.82), 0.45 (95% CI: 0.30, 0.66), and 36.76 (95% CI: 16.81, 80.40), respectively (Table 2). The area under the sROC of pelvic or/and para-aortic lymph node metastases was 0.95. Meta-regression showed that area, design, patient age, magnetic field, MR pulse sequences, and the location of lymph nodes metastasis could not explain heterogeneity (Table 3). DISCUSSION This meta-analysis demonstrated good pooled sensitivity and specificity of MRI for detecting deep myometrial invasion and 7
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superior specificity in the diagnosis of cervical invasion and lymph node metastases. Metaregression revealed that patient age and MR pulse sequences were helpful to explain heterogeneity of MRI for detecting deep myometrial invasion. The treatment method of endometrial cancer rests with preoperative staging (3). It will be beneficial in improving precision treatment and minimizing costs by using a noninvasive preoperative technique for accurate preoperative staging of endometrial cancer. Imaging is an important examination method for staging of endometrial cancer. MRI, ultrasound, computed tomography (CT), and PET-CT are important imaging modalities for evaluating preoperative staging of endometrial cancer (11). However, ultrasound has limited value in diagnosing lymph node metastases. CT and PET/CT have radiation burden, and the contrast resolution for different tissues is limited. MRI is considered to be optimal imaging modality for preoperative staging of endometrial cancer because of its high soft-tissue resolution (10). MRI showed good accuracy for detecting deep myometrial invasion, and high specificity for detecting cervical invasion and lymph node metastases in this meta-analysis, which makes it especially important before the therapy of endometrial cancer. Myometrial invasion often be assessed by judging an interruption of the junctional zone. Because the junctional zone shows hypointensity on T2-weighted MR images, while endometrial cancer shows hyperintensity (5). However, the myometrium may be thinned and the junctional zone may be poorly visible due to metratrophia in postmenopausal women, particularly older women. This makes it difficult to assess the depth of myometrial invasion (5). In consequence, patients older than 60 years old demonstrated lower pooled sensitivity and specificity than patients younger than 60 years old for assessing deep myometrial invasion. Some previous meta-analyses have confirmed that DCE-MRI or DWI could improve diagnostic value in the prediction of deep myometrial invasion (5,20,29). Because DCEMRI not only could improve the contrast resolution of the myometrium and tumor, but also could distinguish them according to different enhancement time of the myometrium and tumor (5,20). And DWI could quantitatively evaluate the depth of myometrial invasion by measuring apparent diffusion coefficient values (29). To overcome the limitation of metratrophia, T2WI, DCE-MRI, and DWI should be combined performed. Deng et al (30) have verified DWI combined with T2WI could improve diagnostic performance in comparison with DWI alone. Manfredi et al (5) found that there was a significant correlation between imaging and histopathologic findings in assessing myometrial infiltration by combining T2WI and DCE-MRI. The diagnostic accuracy is highest by jointly using T2WI, DCE-MRI, and DWI to detect the deep myometrial invasion in this meta-analysis. Several studies have reported that cervical invasion indicated a poor prognosis (31,32). It is important to preoperativly assess cervical involvement of endometrial cancer in planning treatment and predicting prognosis. The normal cervical stroma is rich in fibrous tissue and appears hypointense on T2WI. Which leading to high contrast resolution comparing with 8
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tumors. Therefore, T2WI is well suited for assessing cervical invasion (5). And there was no difference between the T2WI and the DCE-MRI for predicting cervical invasion (6). As a result, MR pulse sequences could not explain heterogeneity. There was high specificity in the diagnosis of cervical invasion and cervical stromal invasion in this meta-analysis. The high specificity of MRI in detecting cervical invasion might be of vital value in deciding the extent of surgery, that is to say, it could help to consider a simple hysterectomy or a more radical surgery (3,6). Nevertheless, only macroscopic cervical invasion could be observed by using MRI, microscopic stromal infiltration or cervical mucosa involvement might be ignored. Which was probably why the sensitivity for detecting cervical invasion or cervical stromal invasion was low. Lymph node metastasis is also an important prognostic factor in endometrial cancer (22). MRI has a good capability to directly depict lymph nodes, especially on DWI sequence, appearing hyperintensity because of their parenchymal structure (5). In gynecologic malignancies, metastatic and non-metastatic lymph nodes are usually differentiated by a size criterion of the short diameter was great than 1 cm on imaging examination (33). There were low sensitivity and high specificity for detecting pelvic or/and para-aortic lymph node metastases and pelvic lymph node metastases in endometrial cancer in this meta-analysis, as in other studies (5,6,8,10 12,15 17). On account of some features such as central necrosis, irregular nodal contour, and so on might suggest a metastatic lymph node (33). Only using size to detect lymph node metastasis might lead to a high false negative rate. In this meta-analysis, six studies combined para-aortic and pelvic lymph nodes evaluation, which leading to a lower pooled sensitivity than the pooled sensitivity that evaluated pelvic lymph nodes only (34). In order to allow a more reliable results in staging of endometrial cancer, we only included studies in which myometrial invasion, cervical invasion, and lymph node metastases were detected at the same time with the same set of patients. Hence, the number of included studies were small, did not allow us to perform separate subgroup analyses and to investigate all potential causes of heterogeneity. This was the main limitation of this meta-analysis. A second limitation was the existence of publication bias. Searches were performed from 2000 to 2019 and restricted to publish in English. Several relevant studies published in other languages may be missed, possibly introducing publication bias. Another possible reason for bias was that the sensitivity for detecting cervical invasion or lymph node metastases was low. Perhaps some articles of negative results were not published. In conclusion, this meta-analysis shows MRI has good diagnostic performance for detecting deep myometrial invasion, and has high specificity for detecting cervical invasion and lymph node metastases in endometrial cancer. Patients younger than 60 years old demonstrated higher sensitivity and specificity for detecting the deep myometrial invasion. Using T2WI, DCE-MRI, and DWI simultaneously to detect the deep myometrial invasion with highest pooled sensitivity and specificity.
ARTICLE IN PRESS Academic Radiology, Vol &, No &&, && 2019
THE DIAGNOSTIC VALUE OF MRI FOR PREOPERATIVE STAGING
ETHICAL APPROVAL This article does not contain any studies with human participants or animals performed by any of the authors. FUNDING This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. REFERENCES 1. 2. 3.
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