European Journal of Radiology 140 (2021) 109745

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European Journal of Radiology

journal homepage: www.elsevier.com/locate/ejrad

The role of volumetric ADC histogram analysis in preoperatively evaluating

the tumour subtype and grade of endometrial cancer
Xiaoliang Ma a, Minhua Shen b, Yimeng He b, Fenghua Ma b, Jia Liu b, Guofu Zhang b, *,
Jinwei Qiang a, *
a
Department of Radiology, Jinshan Hospital, Fudan University, Longhang Road, Shanghai, 201508, People’s Republic of China
b
Department of Radiology, Obstetrics and Gynecology Hospital, Fudan University, Shenyang Road, 200090, Shanghai, People’s Republic of China

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose: To assess the value of volumetric ADC histogram metrics in evaluating the histological subtype and
Endometrial cancer grade of endometrial cancer.
Endometrioid Method: Preoperative MRI datasets of 317 patients with endometrial cancer were used to obtain volumetric ADC
Serous
histogram metrics (tumour volume; minADC, maxADC and meanADC; 10th, 25th, 50th, 75th and 90th per­
Magnetic resonance imaging
centiles of ADC; skewness; and kurtosis). The Mann-Whitney test or Student’s t-test was used to compare the
Apparent diffusion coefficient
Histogram analysis difference in ADC histogram metrics between endometrioid adenocarcinomas (EACs) and serous endometrial
cancers (SECs) and between different tumour grades (G1, G2, G3). The area under the curve (AUC) of the
receiver operating characteristic (ROC) curve was used to evaluate the performance of ADC histogram metrics or
combined models in predicting the tumour subtype and grade.
Results: SECs showed a significantly larger tumour volume (P < 0.001) and lower meanADC, 50th, 75th and 90th
percentiles of ADC than EACs (all P < 0.05). MinADC, maxADC, meanADC, 10th, 25th, 50th, 75th, 90th per­
centiles of ADC were significantly higher in G1 than in G2 and G3 EACs (all P < 0.05), while were not signif­
icantly different between G2 and G3 EACs (all P > 0.05). A tumour volume ≥ 7.752 cm3 allowed for the
prediction of SECs, with an AUC of 0.765 (0.714− 0.810). A meanADC ≥ 0.892 × 10− 3 mm2/s enabled to
discriminate G1 from G2 and G3 EACs, with an AUC of 0.818 (0.769− 0.861).
Conclusion: Volumetric ADC histogram analysis is helpful for non-invasive preoperatively predicting the subtype
of endometrial cancer and differentiating G1 from G2 and G3 EACs.

1. Introduction
Endometrial cancer is the most common gynaecological carcinoma
in the United States [1]. Its morbidity and mortality have continuously
increased since the 1970s [2]. The most important prognostic factors of
endometrial cancer are the histological subtype and grade, myometrial
invasion, and surgical FIGO stage [3]. Endometrioid adenocarcinomas
(EACs) account for 80 %–90 % of endometrial cancers, and most of them
have a favourable prognosis [4]. Non-EACs, such as serous and clear-cell
carcinomas, account for approximately 10 % of endometrial cancers but
more than 50 % of recurrences and deaths [3]. The tumour histological
grade and depth of myometrial invasion are strongly associated with the
presence of lymph node metastases and the overall survival rate [5].
These features determine the risk stratification of patients and are
associated with treatment decision-making. For example, for patients
with early-stage low-grade tumours, lymphadenectomy can be avoided
because no additional benefits are obtained and there is an increased
risk of surgery-related complications; for young nulliparous women with
grade 1 (G1) EACs confined within the endometrium,
fertility-preserving treatment may be an alternative, while for patients
with serous endometrial cancers (SECs), comprehensive surgical staging
is necessary. Therefore, an accurate preoperative evaluation of the his­
tological type and grade of endometrial cancer is crucial for treatment
planning and beneficial for patient prognosis.

Abbreviations: MRI, Magnetic resonance imaging; ROI, Region of interest; EAC, Endometrioid adenocarcinoma; SEC, Serous endometrial cancer; ROC, Receiver
operating characteristic; AUC, Area under the curve; DWI, Diffusion weighted imaging; ADC, Apparent diffusion coefficient; CI, Confidence interval; ICC, Interclass
correlation coefficient.
* Corresponding authors.
E-mail addresses: guofuzh@fudan.edu.cn (G. Zhang), dr.jinweiqiang@163.com (J. Qiang).

https://doi.org/10.1016/j.ejrad.2021.109745
Received 27 October 2020; Received in revised form 20 February 2021; Accepted 27 April 2021
Available online 30 April 2021
0720-048X/© 2021 Elsevier B.V. All rights reserved.

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X. Ma et al. European Journal of Radiology 140 (2021) 109745

Endometrial sampling biopsy with curettage or hysteroscopy is
performed for almost all of the suspected patients before surgery;
however, the accuracy of biopsy histopathology is moderate [6–8].
Therefore, additional tools or alternative methods for preoperatively
evaluating the histological features of endometrial cancer should be
taken into account. Magnetic resonance imaging (MRI) is recommended
for evaluating the extent of endometrial cancer [9]. Diffusion weighted
imaging (DWI) with quantitative apparent diffusion coefficient (ADC)
has been confirmed to be capable of noninvasively characterizing the
biological abnormalities and microstructural changes of tumours [10].
However, the potential of ADC in differentiating the subtype and grade
of endometrial cancers remains uncertain. Most of previous studies are
limited by a relatively small sample size and histological diversity.
Moreover, drawing region of interest (ROI) on a representative section
of tumours also impacts the ADC values and interobserver variability
[11,12].
Recently, volumetric ADC histogram analysis has been increasingly
used for assessing the histopathological features of a tumour by quan­
tifying the diffusion distribution and variation of all voxels to reflect
tumour heterogeneity [13,14], thereby eliminating sampling bias and
providing reproducible results [12]. Several studies have shown that
ADC histogram analysis is promising in differentiating the histological
types [15–18] and grades of tumours [15,19,20] in many organs.
However, to the best of our knowledge, no ADC histogram analysis has
focused on the differentiation of EACs and SECs, and only a few studies
have graded EACs with a relatively small sample size [19,21]. Therefore,
this study aimed to explore the value of ADC histogram metrics in
identifying the histological type and grade of endometrial cancer with a
large sample size.
2. Material and methods
2.1. Study population
This retrospective study was approved by the Institutional Review
Board, and informed consent was waived for all patients. Between June
2014 and April 2019, a total of 568 consecutive patients with endo­
metrial cancer confirmed by surgery and histopathology in our hospital
were reviewed. All patients underwent pelvic MRI examination within
two weeks before surgery and underwent total hysterectomy, bilateral
salpingo-oophorectomy, and lymph node sampling (pelvic ± para-aortic
lymphadenectomy, or sentinel lymph node biopsy). Among them, 251
patients were excluded because of EACs with squamous differentiation
(n = 34), non-EACs and non-SECs (n = 52; including 11 clear cell car­
cinomas, 15 undifferentiated or dedifferentiated carcinomas, and 26
carcinosarcomas), MRI occult tumours (n = 47), tumours that were too
small (maximum diameter less than 10 mm) to be accurately measured
(n = 77), DWI with nonstandard b values (0, 800 s/mm2) (n = 19), and
nondiagnostic image quality (n = 22). Finally, 317 patients (288 pa­
tients with EACs and 29 patients with SECs) comprised the study pop­
ulation. Among them, 296 patients (271 EACs and 25 SECs) underwent
endometrial sampling biopsy (dilatation and curettage: 232 EACs and 20
SECs; pipelle biopsy: 39 EACs and 5 SECs) before MRI examination. No
significant differences between EAC and SEC patients in biopsy rate
(P = 0.103) or biopsy method (P = 0.451) were found.
2.2. MRI protocol
MRI was performed with a 1.5-T scanner (Avanto; Siemens, Erlan­
gens, Germany) by using an eight-channel pelvic phased-array coil.
Patients lay in supine position and freely breathed. MRI sequences and
parameters are listed in Table 1. Dynamic contrast-enhanced T1-
weighted imaging (DCE-T1WI) was performed after administration of
0.2 ml/kg of body weight contrast agent (gadodiamide, 0.5 mmol/mL,
GE Healthcare, Shanghai, China) at an injection rate of 2− 3 ml/s.
2.3. MRI analysis
ADC histogram analysis was performed with Firevoxel software (v.
314A, Department of Radiology, NYUMC, https://www.firevoxel.org/).
DWI images (b = 0, 1000s/mm2) were loaded to Firevoxel as a single
document. ROIs were drawn along the border of the tumour on all slices
of DWI images (b = 1000s/mm2) to generate a volumetric ROI (mean
volume: 12.4 cm3 ± 20.0; range: 1.4–178.9) of the whole tumour. T1WI,
T2WI and DCE T1WI were used as references to avoid the necrotic,
cystic, and bleeding areas being included in the ROIs. The necrotic and
cystic areas were defined as areas with a relatively lower signal intensity
compared with the tumour on DWI images (b = 1000s/mm2), a higher
signal intensity on T2WI, and no enhancement on DCE images. The
bleeding areas were defined as areas with a higher signal intensity
compared with the tumour on T1WI and DWI, and no enhancement on
DCE images. ADC histogram metrics, including tumour volume, mini­
mum ADC (minADC), maximum ADC (maxADC), mean ADC (mean­
ADC), 10th, 25th, 50th, 75th and 90th percentiles ADC values, skewness
and kurtosis, were recorded. One radiologist (X.L.M, with 6 years of
experience in gynaecologic MRI) performed the analysis for all 317
patients (numbered 1–317) and was blinded to the specific histopatho­
logical results (ie., tumour subtype and grades, etc.). Another radiologist
(M.H.S, with 10 years of experience in gynaecologic MRI) analysed a
subset of patients (n = 63, whose last numbers were 4 and 8) to assess
interobserver repeatability.
2.4. Statistical analysis
Statistical analyses were performed with SPSS software (v. 20.0,
SPSS, Chicago, Ill, USA). Continuous variables were evaluated using the
Kolmogorov-Smirnov test and presented as the mean ± standard devi­
ation (normal distribution) or median and interquartile range (non­
normal distribution). The interobserver agreements for ADC histogram
metrics were interpreted according to the interclass correlation co­
efficients (ICCs) as follows: 0.8–1.0, excellent; 0.6− 0.8, good; 0.4− 0.6,
moderate; and < 0.4, poor. The chi-square test was used to compare the

Table 1
MR imaging protocol and paramenters in patients with endometrial cancer.
Sequences/ Parameters Axial T1WI Sagittal T1WI Axial T2WI Sagittal T2WI Coronal T2WI Axial DCE Sagittal DCE Axial DWI

Technique TSE TSE BLADE BLADE BLADE 2D VIBE 2D VIBE EPI

TR/TE (ms) 4.89/2.38 778/12 7240/83 4490/83 3840/83 4.89/2.38 439/10 4200/83
FOV (mm2) 380 × 380 300 × 300 370 × 370 270 × 270 400 × 400 400 × 400 270 × 270 300 × 300
Matrix 320 × 256 320 × 256 320 × 256 320 × 256 320 × 256 320 × 256 320 × 256 160 × 95
ST / Gap (mm) 4/1 4/1 4/1 4/1 4/1 4/1 4/1 4/1
Average (NEX) 2 1 1 1 1 2 1 5
b value (s/mm2) – – – – – – – 0,1000
AT (s) 46 120 146 100 82 172 113 98

NOTE. T1WI = T1-weighted imaging; T2WI = T2-weighted imaging; DCE = dynamic contrast enhancement; DWI = diffusion weighted imaging; TSE = turbo spin
echo; 2D VIBE = two dimensional volume interpolated breath-hold examination; EPI = echo planar imaging； TR/TE = time of repetition / time of echo; FOV = Field
of view; ST = slice thickness；NEX = number of excitation; AT = acquisition time.

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differences in biopsy rate and methods between EAC and SEC patients. Table 3
Student’s t-test (normal distribution) or Mann-Whitney U test (non­ Comparison of ADC histogram metrics between EACs and SECs.
normal distribution) was used to evaluate the differences in ADC his­ Histogram metrics EACs (n = 288) SECs (n = 29) P value
togram metrics between EACs and SECs and between different 3
Volume (cm ) 5.59 (2.79, 9.83) 14.98 (8.12, 38.50) 0.000*
histological grades (G 1 and 2, G 2 and 3, G 1 and 3 EACs). Forward MinADC 0.55 ± 0.14 0.50 ± 0.16 0.073†
stepwise multivariate logistic regression analysis was used to determine MaxADC 1.57 ± 0.27 1.62 ±0.40 0.460†
the optimal metrics or combined model in differentiating the subtypes MeanADC 0.92 ± 0.13 0.86 ± 0.14 0.032†
and grades. P < 0.05 was considered statistically significant. The Skewness 0.74 ± 0.58 0.86 ± 0.56 0.268†
Kurtosis 0.75 (-0.07, 1.82) 1.27 (0.57, 2.31) 0.068*
Hosmer-Lemeshow test was used to evaluate the overall model fitness. 10th PCT-ADC 0.72 ± 0.12 0.68 ± 0.14 0.090†
P > 0.05 was considered to be well fitted. The area under the curve 25th PCT-ADC 0.79 ± 0.12 0.75 ± 0.14 0.059†
(AUC) of the receiver operator characteristic (ROC) was calculated to 50th PCT-ADC 0.89 ± 0.13 0.84 ± 0.14 0.038†
compare the diagnostic performance of ADC histogram metrics. The 75th PCT-ADC 1.01 ± 0.15 0.95 ± 0.15 0.026†
90th PCT-ADC 1.14 ± 0.17 1.07 ± 0.17 0.022†
maximum Youden index (sensitivity + specificity–1) of ADC histogram
metrics was used to determine the optimal cut-off value and corre­ NOTE. ADC values are in units of × 10− 3 mm2/s; EAC = endometrioid adeno­
sponding sensitivity and specificity. carcinoma; SEC = serous endometrial cancer; Date are mean ± standard devi­
ation (normal distribution) or median and interquartile range (non-normal
distribution); * = Mann-Whitney U test, † = Student’s t-test.
3. Results

3.1. Histopathological findings and repeatability of ADC histogram 3.3. Diagnostic performance of ADC histogram metrics and the combined
metrics model in differentiating the tumour subtypes and grades

Among the 317 patients with endometrial cancer confirmed by sur­ In differentiating the subtypes of endometrial cancers, tumour vol­
gery and final histopathology, 288 cases were EACs (mean age, 54.2 ume was superior to the other ADC histogram metrics, with the largest
years ± 9.1; range, 25–79) and 29 cases were SECs (mean age, 57.8 years AUC of 0.765 (0.714− 0.810). A combination of tumour volume and
± 11.4; range, 25–72). Of the 288 EACs, 145 were in G1, 96 were in G2, 90th percentile of ADC was the best combined model (a good fitness by
and 47 were in G3. The ICCs for all ADC histogram metrics were Hosmer-Lemeshow test, p = 0.640), with an AUC of 0.756
excellent (0.839− 0.995, Table 2). (0.705− 0.802), which was lower than that of the tumour volume. A
tumour volume larger than 7.752 cm3 allowed for the prediction of SECs
with a sensitivity of 82.8 % and a specificity of 66.0 % (Table 5). ROC
3.2. Comparison of ADC histogram metrics between different histological curves of the significant ADC histogram metrics are shown in Fig. 2.
subtypes and grades In grading the EACs, the meanADC showed the best performance,
with the largest AUC of 0.818 (0.769− 0.861), followed by 90th, 75th,
The mean tumour volume of SECs was significantly larger than that 50th, 25th, and 10th percentiles of ADC (AUCs of 0.811, 0.810, 0.810,
of EACs (P < 0.001), whereas the meanADC, 50th, 75th and 90th per­ 0.803 and 0.788, respectively). The meanADC was an independent risk
centiles of ADC were significantly lower in SECs than in EACs (all factor for tumour grade (odds ratio = 0.881; 95 % CI, 0.854− 0.909;
P < 0.05), no significant differences were found for minADC, maxADC, p < 0.001). A meanADC value larger than 0.892 × 10− 3 mm2/s enabled
skewness, kurtosis, 10th and 25th percentiles of ADC between EACs and us to discriminate G1 from G2 and G3 EACs, with a sensitivity of 77.9 %
SECs (all P > 0.05) (Table 3). and a specificity of 70.6 % (Table 5). ROC curves of the significant ADC
No significant differences were found for mean tumour volume be­ histogram metrics are shown in Fig. 3.
tween G1 and G2, G2 and G3, or G1 and G3 EACs (P = 0.382, 0.485,
0.190, respectively). The minADC, maxADC, meanADC, 10th, 25th, 4. Discussion
50th, 75th, 90th percentiles of ADC were significantly higher in G1 than
in G2 or G3 tumours (all P < 0.05). Kurtosis was significantly lower in Our study demonstrated that volumetric ADC histogram analysis has
G1 than in G2 and G3 tumours (P = 0.013 and 0.001, respectively). the potential to be a supplementary tool for preoperatively differenti­
Skewness was significantly lower in G1 than in G2 tumours (P = 0.027) ating the tumour subtypes and grades. Tumour volume is superior to
but not significantly different between G1 and G3 tumours (P = 0.107). ADC values in distinguishing SECs from EACs, while meanADC has the
No significant differences were observed for any of the ADC histogram best performance in differentiating G1 from G2 and G3 EACs.
metrics between G2 and G3 tumours (all P > 0.05) (Table 4). ADC his­ The preoperative accurate assessment of histopathological features
tograms of different grades of EACs are shown in Fig. 1. of endometrial cancers is crucial to determine the initial staging and risk
stratification of patients, which further guides treatment decision-
Table 2 making, such as fertility sparing, surgery, or adjuvant treatment; sur­
Interclass correlation coefficients for ADC histogram metrics. gery with or without lymphadenectomy; and minimally invasive surgery
Histogram metrics ICC 95 % CI
or extensive staging surgery. Although histopathology based on preop­
erative endometrial sampling biopsy is available for almost all patients
Volume 0.9769 (0.9617, 0.9861)
(93.4 % in this study), the agreement with postoperative histopathology
MinADC 0.9767 (0.9614, 0.9860)
MaxADC 0.8628 (0.7723, 0.9173) is only 60.7%–74% [6–8]. Preoperative sampling is easily affected by
MeanADC 0.9807 (0.9680, 0.9884) various factors, such as lesion size, sampling accuracy, and operator
Skewness 0.8864 (0.8114, 0.9315) experience. In addition, for patients with cervical stenosis or lesions
Kurtosis 0.8394 (0.7335, 0.9033) located in the uterine cornua, endometrial sampling may encounter
10th PCT-ADC 0.9950 (0.9917, 0.9970)
25th PCT-ADC 0.9918 (0.9864, 0.9951)
difficulties. All these factors may adversely affect the clinical decision.
50th PCT-ADC 0.9847 (0.9746, 0.9908) Therefore, versatile and non-invasive MRI has led to great expectations
75th PCT-ADC 0.9776 (0.9629, 0.9865) for preoperatively evaluating the histological subtypes and grades of
90th PCT-ADC 0.9556 (0.9263, 0.9733) endometrial cancers.
NOTE. ADC = apparent diffusion coefficient; Min = minimum; Previous studies have demonstrated that tumour volume could
Max = maximum; PCT = percentile; ICC = interclass correlation coefficient; indicate the aggressiveness of endometrial cancers [22] and be a pre­
CI = confidence interval. dictor for the histopathological features of EACs, such as tumour grade,

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Table 4
Comparison of ADC histogram metrics between different histologicalal grades of EACs.
histologicalal grade P value
Histogram metrics
G1 (n = 145) G2 (n = 96) G3 (n = 47) P1 P2 P3

Volume (cm3) 5.42 (2.72, 8.97) 5.99 (2.80, 11.90) 7.53 (2.49, 24.62) 0.382* 0.485* 0.190*
MinADC 0.60 ± 0.12 0.52 ± 0.11 0.46± 0.16 0.000† 0.019† 0.000†
MaxADC 1.63 ± 0.24 1.50± 0.28 1.51 ± 0.31 0.000† 0.901† 0.017†
MeanADC 0.99 ± 0.12 0.85± 0.10 0.83 ± 0.10 0.000† 0.117† 0.000†
Skewness 0.66 ± 0.59 0.83 ± 0.56 0.81 ± 0.54 0.027† 0.902† 0.107†
Kurtosis 0.44 (-0.20, 1.47) 0.93 (0.05, 2.26) 1.22 (0.50, 2.46) 0.013* 0.306* 0.001*
10th PCT-ADC 0.78 ± 0.11 0.67 ± 0.09 0.65 ±0.10 0.000† 0.099† 0.000†
25th PCT-ADC 0.86 ± 0.11 0.71 ±0.10 0.74 ± 0.09 0.000† 0.064† 0.000†
50th PCT-ADC 0.96 ± 0.12 0.83 ± 0.10 0.80 ± 0.10 0.000† 0.086† 0.000†
75th PCT-ADC 1.09± 0.14 0.94 ± 0.12 0.91 ± 0.11 0.000† 0.206† 0.000†
90th PCT-ADC 1.23 ± 0.15 1.07 ± 0.14 1.04± 0.12 0.000† 0.217† 0.000†

NOTE. G = grade; P1, P2, P3 are the P values between grade 1 and grade 2 tumours, grade 2 and grade 3 tumours, grade 1 and grade 3 tumours, respectively. * = Mann-
Whitney U test, † = Student’s t-test.

Fig. 1. Apparent diffusion coefficient (ADC) histograms of grades 1, 2, and 3 endometrioid adenocarcinomas (EACs). (a - d) A 45-year-old female patient with grade
1 EAC. (e - h) A 57-year-old female patient with grade 2 EAC. (i - l) A 69-year-old female patient with grade 3 EAC. The solid parts of grades 1, 2, and 3 EACs show a
similar slightly high signal intensity on T2-weighted imaging (a, e, i), a low enhancement at the delay phase of contrast-enhanced imaging (b, f, j), and a prominent
hyperintense signal on diffusion weighted imaging (b = 1000s/mm2) (c, g, k). ADC histogram analysis shows that the meanADC values of grades 1, 2 and 3 EACs are
1006.0 × 10− 6 mm2/s, 866.2× 10− 6 mm2/s, and 824.2 × 10− 6 mm2/s, respectively. The distribution of the ADC histogram shows more frequent low ADC values in
grades 2 and 3 EACs than in grade 1 EACs.

depth of myometrial invasion, lymphovascular space invasion and
lymph node metastasis [21,23]. Conversely, Sahin H et al. [24] reported
that tumour volume was insufficient to predict myometrial invasion,
lymphovascular space invasion, tumour grade and subtype of endome­
trial cancers. In this study, we concluded a similar result that tumour
volume could not be used for grading EACs, although it gradually
increased from G1 and G2 to G3 EACs. However, contrary to Sahin H
et al. [24], our study demonstrated that tumour volume was helpful for
differentiating SECs from EACs. This inconsistency may be related to the
small sample size of non-EACs (8 cases) in their study, which may lead to
bias in the results. A reasonable interpretation for our results was that
the tumour volume is associated with its growth rate, which increases
with tumour aggressiveness. SECs are more aggressive than EACs.
Poorly aggressive tumours tend to have a polypoid growth pattern into

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Table 5
Diagnosis performance of ADC histogram metrics in differentiating SECs from EACs, and grade 1 from grade 2 and 3 EACs.
Tumour subtype (n = 317) Tumour grade (n = 288)
Histogram metrics YI CV SEN SPE AUC YI CV SEN SPE AUC
(%) (%) (95 % CI) (%) (%) (95 % CI)

Volume (cm3) 0.488 > 7.752 82.8 66.0 0.765 (0.714− 0.810) – – – – –
MinADC – – – – – 0.319 > 0.550 69.0 62.9 0.713 (0.657− 0.764)
MaxADC – – – – – 0.235 > 1.510 69.7 53.8 0.631 (0.573− 0.687)
MeanADC 0.288 ≤ 0.855 62.1 66.7 0.640 (0.584− 0.693) 0.485 > 0.892 77.9 70.6 0.818 (0.769− 0.861)
Skewness – – – – – 0.174 ≤ 0.660 53.8 63.6 0.586 (0.527− 0.644)
Kurtosis – – – – – 0.217 ≤ 0.351 49.7 72.0 0.615 (0.556− 0.671)
10th PCT-ADC – – – – – 0.464 > 0.680 82.8 63.6 0.788 (0.736− 0.834)
25th PCT-ADC – – – – – 0.491 > 0.750 86.2 62.9 0.803 (0.753− 0.848)
50th PCT-ADC 0.336 ≤ 0.800 58.6 75.0 0.639 (0.583− 0.692) 0.484 > 0.830 89.7 58.7 0.810 (0.760− 0.854)
75th PCT-ADC 0.245 ≤1.030 82.8 41.7 0.636 (0.581− 0.689) 0.470 > 0.950 84.1 62.9 0.810 (0.760− 0.854)
90th PCT-ADC 0.257 ≤ 1.020 51.7 74.0 0.625 (0.569− 0.679) 0.464 > 1.090 82.1 64.3 0.811 (0.761− 0.854)
Volume + 90th PCT-ADC 0.444 – 85.8 58.6 0.756 (0.705− 0.802) – – – – –

NOTE. YI = Youden index; CV = cutofff value; SEN = sensitivity; SPE = specificity; AUC = area under the curve.

Fig. 2. Receiver operating characteristic (ROC) curves of the significant ADC histogram metrics for differentiating serous endometrial cancers from endometrioid
adenocarcinomas. The tumour volume (blue) had the largest area under the curve (AUC) of 0.765, followed by volume + 90th PCT-ADC (AUC = 0.756).

Fig. 3. ROC curves of the significant ADC histogram metrics for differentiating grade 1 from grades 2 and 3 endometrioid adenocarcinoma. The meanADC (red) had
the largest AUC of 0.818, followed by the 90th percentile ADC (AUC = 0.811), 75th and 50th percentile ADCs (AUC = 0.810).

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X. Ma et al.
the endometrial cavity, while highly aggressive tumours are more likely
to have an infiltrative growth pattern. In addition, there are variations in
growth rates in tumours, even in the same histological subtype. These
factors affecting tumour growth may coexist and thus lead to overlap in
tumour volume. Notably, although we manually measured the tumour
volume on DWI images rather than on T2WI chosen by most previous
researchers, the choice of MR sequences for volume measurement might
have no marked impact on the tumour volume because of a high
reproducibility between different sequences and observers [21]. Our
results showed that the tumour volume had a relatively higher diag­
nostic performance in differentiating SECs from EACs compared with
other metrics or the combined model, with an AUC of 0.765, a sensitivity
of 82.8 % and a specificity of 66.0 %. Although its specificity was not
excellent, it might be an acceptable alternative indicator for those who
fail to undergo successful curettage or endometrial biopsy, owing to its
easy and non-invasive accessiblility. The tumour subtype predicted by
the tumour volume, combined with the grading and staging information
obtained from MRI, contributed to the patients’ risk stratification and
thus assisted in guiding the initial surgical planning.
A few studies have analysed the ability of ADC values to discriminate
the histological subtype of endometrial cancer. Study by Bakir VL et al.
[25] demonstrated that the meanADC value was significantly higher in
EACs than in non-EACs. Their result was supported by Tian S et al. [26]
who yielded a promising result that a meanADC higher than
1.02 × 10− 3 mm2/s can identify EACs from SECs with a sensitivity of
85.0 % and a specificity of 92.3 %. However, both studies were limited
by a small sample size (63 and 33, respectively) and with ROIs drawn on
only one representative section of the tumour, thus selection bias was
inevitable. Our study was based on a large sample size and used the
volumetric ADC histogram analysis, which enable to reduce or avoid the
selection bias of ROIs by reflecting the spatial heterogeneity of the solid
part of whole tumours. Similar to previous studies, our primary results
showed that the meanADC, 50th, 75th and 90th percentiles of ADC were
significantly higher in EACs than in SECs. However, the diagnostic
performances of these metrics were ordinary, with AUCs ranging from
0.625 to 0.640. This means that the ADC values may be insufficient for
clinical purpose, although ADC differences do exist between EACs and
SECs. It is supposed that the results may be related to the fact that G3
EACs are quite similar to SECs in histopathological structure and mo­
lecular features and subsequently compromise the diagnostic perfor­
mance of ADC values.
The value of ADC in grading endometrial cancers is controversial.
Several studies have shown that ADC values are not useful for predicting
the grade of endometrial cancer [27–29]. However, several other studies
have yielded promising results and showed an inverse relationship be­
tween ADC values and tumour grades [21,25,30,31]. These conflicting
results may be related to selection bias and the degree of necrosis within
the tumour [12,21,25]. In this study, we excluded necrotic areas to
avoid their adverse influence on ADC values. Our results demonstrated
that the minADC, maxADC, and meanADC and the 10th, 25th, 50th,
75th, and 90th percentiles of ADC were significantly lower in G3 and G2
EACs than in G1 EACs. This was mainly because high-grade tumours
were associated with increased cell density and nucleus to cytoplasm
ratio, thereby restricting diffusion movement of water molecules.
However, the difference between G2 and G3 tumours was not significant
in our study. By using the same volumetry approach, Nougaret S et al.
[21] found significantly lower ADC values in G3 than G2 and G1 tu­
mours, whereas there was no significant ADC difference between G1 and
G2 tumours. A reasonable explanation was that there were considerable
overlaps in the ADC value range between G1, G2, and G3 tumours, and
the results might be affected by the sample size and composition. In our
study, the meanADC was an independent risk factor for tumour grade,
and a value larger than 0.892 × 10− 3 mm2/s enabled us to discriminate
G1 from G2 and G3 EACs, with a sensitivity of 77.9 % and a specificity of
70.6 %. This means that meanADC might be helpful in selecting patients
suitable for fertility-preserving treatment and avoiding unnecessary
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European Journal of Radiology 140 (2021) 109745
lymphadenectomy.
There were some limitations. First, our study was a single-center
retrospective study with potential selection bias. Second, it was diffi­
cult to accurately determine the boundary between EACs and endome­
trial hyperplasia because they usually coexist and had similar signals on
DWI. The partial volume effect was another factor leading to a relatively
obscure boundary. Third, this study excluded tumours with a maximum
diameter less than 10 mm, which might have impacted the results.
Further prospective studies are required to validate our findings.
In conclusion, our study suggested that volumetric ADC histogram
analysis, with its metrics of tumour volume and meanADC values, could
be helpful for non-invasive preoperatively differentiating SECs from
EACs and G1 from G2 and G3 EACs, thereby contributing to clinical
treatment planning.
Funding
Shanghai Municipal Health Commission (No. ZK2019B01)
CRediT authorship contribution statement
Xiaoliang Ma: Conceptualization, Methodology, Validation, Formal
analysis, Investigation, Writing - original draft, Visualization. Minhua
Shen: Validation, Formal analysis, Investigation, Data curation. Yimeng
He: Methodology, Investigation, Data curation. Fenghua Ma: Method­
ology, Formal analysis, Visualization. Jia Liu: Methodology, Investiga­
tion, Visualization. Guofu Zhang: Conceptualization, Methodology,
Writing - review & editing, Supervision, Project administration. Jinwei
Qiang: Conceptualization, Methodology, Writing - review & editing,
Supervision, Project administration.
Declaration of Competing Interest
The authors declared no potential conflicts of interests associated
with this study.
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