Malignant breast tumours: Correlation of apparent
diffusion coefficient values using diffusion-weighted images
and dynamic contrast-enhancement ratio with histologic
grading
Ghada K. Gouhar
a,*
, Mona A. El-Hariri
a, Wael E. Lotfy
ba
Department of Radiodiagnosis, Faculty of Medicine, Zagazig University, Sharkia, Egypt b
Department of General Surgery, Faculty of Medicine, Zagazig University, Sharkia, Egypt
Received 4 July 2011; accepted 23 August 2011 Available online 17 September 2011
KEYWORDS
Malignant breast tumours; Apparent diffusion coeffi-cient values;
Contrast-enhancement ratio; Histologic grading
Abstract Purpose: To evaluate the correlation of the apparent diffusion coefficient (ADC) using diffusion weighted imaging (DWI) and early/delayed enhancement (E/D) ratio using dynamic con-trast enhanced magnetic resonance imaging (DCE-MRI) with histological grading in malignant breast lesions.
Material and methods: Thirty-one women with 34 histopathologically proved malignant breast lesions underwent MRI within 2 weeks prior to surgery. MRI examination included T1 and T2 W sequences, DWI and DCE-MRI. ADC values and E/D ratios are correlated with the histo-logical grades.
Results: The mean ADC of the malignant lesions was 0.85 ± 0.12· 10 3mm2/s. The mean ADC
values of grade I, II and III were 0.96 ± 0.12· 10 3
mm2/s, 0.87 ± 0.07· 10 3
mm2/s and 0.75 ± 0.12· 10 3mm2/s, respectively. Tumours with higher grade showed significantly lower
ADC value (p = 0.0001) compared with lower grade and there is an inverse correlation between ADC value and histological grade (r = 0.62, p-value = 0.0001). The mean E/D ratio for grade
* Corresponding author. Tel.: +20 0124038955.
E-mail addresses:[email protected],ghadagouhar@yahoo. com(G.K. Gouhar).
0378-603X 2011 Egyptian Society of Radiology and Nuclear
Peer review under responsibility of Egyptian Society of Radiology and Nuclear Medicine.
doi:10.1016/j.ejrnm.2011.08.003
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I, II and III tumours were 0.98 ± 0.04, 1.01 ± 0.05 and 1.07 ± 0.08, respectively. Tumours with higher grade showed significantly higher E/D ratio (p = 0.005) compared with lower grade and there was a direct correlation between E/D ratio and histological grade (r = 0.44, p = 0.008). Conclusion: DWI is a useful diagnostic parameter with significantly higher correlation with the his-tological grade of breast cancer than DCE MRI, which is an important factor for proper treatment selection.
2011 Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction
Detection of breast lesions has become more sensitive in mam-mography, ultrasound and MRI. However, the characteriza-tion of the detected lesions can be difficult (1–5). Diffusion weighted imaging has become an important technique for detecting breast tumours and distinguishing between malignant and benign breast lesions(6,7). DW MRI is based on the prin-ciple that random motion of molecules during the interval of excitation and signal measurement reduces the amplitude of the resulting signal. The application of appropriate pulse se-quences allows the measurement of the signal cancellation due to diffusion in a given direction. While normal tissue exhib-its gross signal loss, areas with restricted motion of molecules show less signal loss and become bright in diffusion weighted images. The value of diffusion of water in tissue is called the apparent diffusion coefficient (ADC)(6). DWI is sensitive to biophysical characteristics of tissue such as cell density, mem-brane integrity and microstructure(8,9). High cell proliferation in malignant tumours increases cellular density, creating more barriers to the extracellular diffusion, resulting in signal loss and reducing the ADC to be lower than that seen in benign breast lesions or normal tissues(10–17). So DWI is a useful tool for tumour detection and characterization as well as for moni-toring and predicting treatment response(18).
Dynamic contrast enhanced magnetic resonance (MR) imaging has emerged as a promising modality for the detec-tion, diagnosis and staging of breast cancer. MR imaging pro-vides important information not only on the morphology of the lesions but also on the functional aspect reflected by the temporal and spatial uptake of the contrast medium. Integra-tion of both kinetic and morphological features is important for accurate diagnosis(19–21).
Dynamic contrast enhanced imaging detects changes in the vascularity, vascular permeability, interstitial pressure and extracellular space. However it provides no direct information about tumour cellularity, which is known to be an important index of tumour grade. Diffusion weighted MRI provides un-ique information about the cellularity and the state of molec-ular motion of water (15). It also has the advantages of being of short examination time and no need to inject contrast medium(22,23).
The aim of this study was to investigate the relationship be-tween histopathological grade of breast cancer and both DWI represented by ADC and the enhancement ratio (E/D ratio) on dynamic contrast enhanced MRI as the histopathological grade is one of the important factors used in selection and planning of breast cancer. Histopathological grading of the lesions is done using Nottingham grading system. The mean and the standard deviation of the ADC and E/D ratio for all lesions and for each histological grade were calculated.
2. Materials and methods 2.1. Patients
This prospective study comprised 49 women with suspicious breast lesions based on physical examination, mammography and ultrasonography. Inclusion criteria were: histopathologi-cally proved cancer patients after excisional biopsy or surgical excision. Exclusion criteria were: patients who had neoadju-vant chemotherapy or biopsy before MR examination, or had contraindication to MR imaging (e.g., pacemaker, metal-lic implant, severe claustrophobia). Institutional review board approval and informed consent was taken from all patients. Eighteen patients were excluded from the study due to previ-ous therapy (n = 5), biopsy prior to MRI examination (n = 9), and improper MRI study (n = 4). So a total of 31 patients (Age range 38–74 years; mean 47.4 years,) with 34 lesions were included in this study.
3. MR imaging protocol
Breast MR imaging was performed with the use of a 1.5-T MR (Achieva, Philips Medical Systems, Netherland B.V.) by using a standard bilateral breast coil. The patients were placed in a prone position in the breast coil and initial scout views in axial, coronal, and sagittal planes of both breasts were taken. These scout images were used for the subsequent series to cover the whole parenchyma. MRI protocol consisted of precontrast ser-ies including T1and T2WI, dynamic contrast enhanced MRI and diffusion weighted imaging. T1W sequence in axial view was taken with the following parameters (TR/TE: 415/10), NEX: 1, slice thickness/interslice gap: 3.0 mm/0.0, flip angle: 90, FOV: 360. T2W sequences in axial and sagittal or coronal views were taken with the following parameters (TR/TE: 4900/ 120), NEX: 1, slice thickness/interslice gap: 3.0 mm/0.0, flip angle: 90, FOV: 360 mm.
3.1. Diffusion weighted MR imaging
Axial DWI with single shot echo planar imaging (EPI) was performed at b values 0 and 1000 with the following parame-ters: TR/TE: 2700/72 ms, 3 mm slice thickness, 1 mm intersec-tion gap, FOV 300 mm. Apparent diffusion coefficient (ADC) maps were automatically calculated by MRI machine software and included in the sequence.
3.2. Dynamic contrast enhanced (DCE) MRI
This was obtained using a T1-weighted sequence with fat sup-pression (dynamic THRIVE protocol) with the following parameters: TR 7 ms, TE 3 ms, flip angle 12, field of view
360 mm, 2.0 mm section thickness). The dynamic imaging consisted of 6 individual dynamic series each lasting for 1:05–1:07 min; one was obtained before and five after the rapid bolus intravenous injection of gadopentetate dimeglumine at a dose of 0.1 mmol per kilogram of body weight, followed by a 20 mL saline solution flush. After the dynamic series, image subtraction was done to suppress the signal from fat, and enhancing lesions were clearly identified on the subtracted images.
4. Image interpretation and data analysis 4.1. Interpretation of MR images
MR images including DCE-MRI and DWI were evaluated independently by the two radiologists sharing in the study. 4.2. Diffusion weighted MR imaging
The visualized lesion in the dynamic scan has to be identified in the corresponding slice of the diffusion weighted images b 0 and 1000 then a region of interest (ROI) is drawn on the lesion (cystic and necrotic areas were avoided) and copied to the ADC map. The scanner software provides the mean value within the ROI which equals the ADC value (multiplied by 10 3mm2/s).
4.3. DCE-MRI analysis
Time–signal intensity plots of dynamic images were generated using computer assisted diagnosis (CAD) software as percent-age enhancement (y-axis) versus time (x-axis) of a region of interest (ROI) placed in the detected lesion. ROI was selec-tively placed on the areas of the most rapid and strongest enhancement.
The enhancement kinetics were divided into two phases: the early enhancement phase (E), defined as enhancement patterns before the curve starts to change (within the first 2 and 1/ 2 min), and the delayed phase (D), defined as enhancement pattern around 6 min after the curve starts to change. The enhancement ratio in the early to the delayed phase was calcu-lated by dividing E/D for each lesion.
5. Histopathological analysis
Histopathological grading was analysed by a pathologist with experience in the breast pathology. The examined samples were stained with haematoxylin-eosin for evaluation of mor-phologic features, then histological grades were assessed using the Nottingham grading system (Elston–Ellis modification of the Scarff–Bloom–Richardson (SBR) grading system) (24) (Table 1), in which a score of I–III was assigned for tubule for-mation, pleomorphism and mitotic count. The total score
could range from 3 to 9, with a total of 3–5 representing grade I, a total of 6 or 7 representing grade II, and a total of 8 or 9 representing grade III.
6. Statistical analysis
Statistical analysis was performed by using statistical software SPSS version 10. Our patients were divided into three groups according to the histological grading; Grade I, II and III. The mean and the standard deviation of the ADC and E/D ra-tio for all lesions and for each histological grade were calcu-lated. One way analysis of variants (ANOVA) and post-Hoc (lsd) analysis were used to test the difference in ADC and E/ Dratio means between the different histological grades. The Spearman Rank correlation was used to correlate the ADC va-lue and E/D ratio with the histological grade. The correlation coefficient (r) and the p-value were calculated. The p 6 0.05 va-lue was considered statistically significant.
7. Results
Thirty one female patients are included in this study (age range 38–74 years; mean 47.4 years,) with a total of 34 lesions. Histo-pathological analysis revealed 25 invasive ductal carcinomas, 5 ductal carcinomas in situ, 3 invasive lobular carcinomas and 1 invasive tubular carcinoma. The size of the breast cancer var-ied from 0.9 to 9 cm (mean 3.6 ± 1.8). Seven lesions (20.6%) were grade I, 17 lesions (50%) grade II and 10 lesions (29.4%) grade III.
The mean ADC value (Fig. 1) of the malignant lesions was 0.85 ± 0.12· 10 3mm2/s (range 0.51–1.11· 10 3mm2/s). The mean ADC value of grade I was 0.96 ± 0.12· 10 3mm2/s, of grade II was 0.87 ± 0.07· 10 3mm2/s and of grade III was 0.75 ± 0.12· 10 3
mm2/s (Table 2). Tumours with higher grade showed significantly lower ADC value (p = 0.0001) compared with lower grade. There was significant difference in the mean ADC value of tumours of grade I and III (p = 0.0001) and grade II and III (p = 0.003), however, there was no significant difference between grade I and II (p = 0.054) (Table 3).
The mean E/D ratio (Fig. 1) for the malignant lesions was 1.02 ± 0.06. The mean E/D ratio for grade I, II and III tu-mours were 0.98 ± 0.04, 1.01 ± 0.05 and 1.07 ± 0.08, respec-tively (Table 2). Tumours with higher grade showed significantly higher E/D ratio (p = 0.005) compared with low-er grade. Thlow-ere was significant difflow-erence in E/D ratio of tu-mours of grade I and III (p = 0.003) and grade II and III (p = 0.006) but there was no significant difference between tu-mours grade I and II (p = 0.385) (Table 3). Illustrative cases are shown in (Figs. 2–5).
Using Spearman rank correlation test, there were a better correlation between the histological grade and ADC
Table 1 Elston–Ellis modification of the Scarff–Bloom–Richardson (SBR) grading system(24).
Tubular formation Mitotic count Nuclear pleomorphism 1. Majority of tumour (>75%) 0–9 mitosis/HPF Small regular uniform cells 2. Moderate degree (10–75%) 10–19 mitosis/HPF Moderate nuclear size and variation 3. Little or none (<10%) 20 or more mitosis/HPF Marked nuclear variation
(r = 0.62, p-value = 0.0001), than that between the histolog-ical grade and E/D ratio (r = 0.44, p = 0.008).
8. Discussion
Breast cancer has a variable biological behaviour and the mor-phological and cytological pattern of the tumour correlates with the degree of malignancy. The proper identification of the type of breast cancer can improve the selection of proper treatment and defines the patient’s outcome. The histological type and the tumour stage are indices for the degree of malig-nancy of the breast cancer(24–26).
Magnetic resonance imaging became an important modal-ity in characterizing the type and evaluating the extent of the breast lesions. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been a useful technique for the detec-tion, diagnosis and staging of breast cancer(27–29)and gives information about the morphology and kinetics of the lesions and can identify additional lesions and determine the extent of the tumour before surgery(30).
DWI can provide information about the tumour biology and physiology and differentiate benign from malignant tu-mours with progressive decrease in ADC value from benign le-sions to non invasive and invasive carcinoma and there is a relationship between ADC and tumour cellularity(31–34).
In this study, the mean ADC of the malignant cases was 0.85 ± 0.12· 10 3
mm2/s with the highest value being 1.15· 10 3mm2/s. This is similar to the mean ADC values reported by other previous studies; 0.89 ± 0.18· 10 3
mm2/s reported by Park et al. (35), 0.97 ± 0.20· 10 3mm2/s by Guo et al. (6), 1.02 ± 0.23· 10 3
mm2/s by Kuroki et al. (33), 1.03 ± 0.27· 10 3
mm2/s by Costantini et al. (36), 1.04 ± 0.15· 10 3mm2/s by Abdel Razek et al. (37) and 1.09 ± 0.27· 10 3
mm2/s by Kim et al.(38).
In agreement with the previous studies (6,12,17,31, 32,34,39)where the cut off value of ADC for diagnosing breast cancer ranged from 1.13· 10 3mm2/s to 1.6· 10 3mm2/s, all our ADC values did not exceed the cut off value that differen-tiates benign and malignant breast lesions in these studies.
The mean ADC values of grade I, II and III were 0.96 ± 0.12· 10 3
mm2/s, 0.87 ± 0.07· 10 3
mm2/s and 0.75 ± 0.12· 10 3mm2/s, respectively. Tumours with higher grade showed significantly lower ADC value (p = 0.0001) compared with lower grade. There was significant difference in the ADC value of tumours of grade I and III (p = 0.0001) and grade II and III (p = 0.003) but there was no significant difference between grade I and II (p = 0.054). This is consistent with Abdel Razek et al. (37)who reported that there was a significant difference between grade I and III and grade II and III and insignificant difference between grade I and II. There was an inverse correlation between ADC value and histological grade (r = 0.62, p -value = 0.0001) in this study, and this agreed with the previous studies (6,12,36,37) where a significant inverse correlation between ADC value and tumour grading was detected. Kim et al. (38)found that the mean ADC in grade III is lower than that
Table 2 The mean ADC and mean E/D ratio in the different histological grades.
All lesions Grade I Grade II Grade III Mean ADC (mean ± SD)· 10 3mm2/s 0.85 ± 0.12 0.96 ± 0.12 0.87 ± 0.07 0.75 ± 0.12
Mean E/D ratio (mean ± SD) 1.02 ± 0.06 0.98 ± 0.04 1.01 ± 0.05 1.07 ± 0.08
Figure 1 The first box plots show the mean E/D ratios of the different histological grades. The mean E/D ratio for grade I was 0.98 ± 0.04, grade II 1.01 ± 0.05 and grade III 1.07 ± 0.08. The second box plots show the mean ADC values of the different histological grades. The mean ADC value of grade I was 0.96 ± 0.12· 10 3
mm2/s, of grade II was 0.87 ± 0.07· 10 3
mm2/s and of grade III was 0.75 ± 0.12· 10 3mm2/s.
Table 3 One way ANOVA post hoc analysis testing the difference in the mean ADC and the mean E/D between the different histological grades.
Grades I and II Grades I and III Grades II and III Mean ADC p= 0.054 p= 0.0001 p= 0.003 Mean E/D ratio p= 0.385 p= 0.003 p= 0.006
Figure 2 Forty-seven year old female patient with right breast cancer. Axial early (a) and late (b) dynamic images show the enhanced lesion at the right breast with E/D ratio 0.99. Time signal intensity curve of the lesion (c) shows type II platue curve. The lesion is hyperintense in DWI b = 1000 (d) and is of low signal intensity at ADC map (e) with ADC value equals 0.083· 10 3
mm2/s. Histopathologically the tumour proved to be grade II.
of grade II which is lower than that of grade I but it did not reach a statistical significance (p = 0.82), however, Yoshikawa et al.(40)found that the mean ADC of breast cancer did not significantly correlate with cancer cellularity.
Concerning DCE MRI we found that the mean E/D ratio for grade I, II and III tumours were 0.98 ± 0.04, 1.01 ± 0.05 and 1.07 ± 0.08, respectively. Tumours with high-er grade showed significantly highhigh-er E/D ratio (p = 0.005) compared with lower grade. There was significant difference in E/D ratio of tumours of grade I and III (p = 0.003) and
grade II and III (p = 0.006), however, there was no significant difference between tumours grade I and II (p = 0.385). A di-rect correlation between E/D ratio and histological grade (r = 0.44, p = 0.008) was present.
Our results are in agreement with previous studies(9,19,41– 46). Matsubayashi et al.(41)stated that the enhancement ra-tios of breast carcinoma on dynamic MR images closely corre-lated with cellular density and the histological and morphological features. Mussurakis et al. (42) observed a strong significant association between all automated ROI
Figure 3 Forty-four year old female patient with small right breast cancer. Axial early (a) and late (b) dynamic images show a small well defined laterally located homogenously enhanced lesion at the right breast with E/D ratio 1.01. The lesion is hyperintense at DWI b= 1000 (c) and is of low signal intensity at ADC map (d). ADC value of the lesion equals 0.092· 10 3mm2/s. Histopathologically the
enhancement ratios and histological grade (p = 0.001). Other studies (19,43–45) reported a significant correlation between the enhancement pattern and histological grade or high cellu-lar proliferation.
Radjenovic et al.(46) and Lee et al.(19) studied the rela-tionship between the histological grades of breast tumours and the pharmacokinetic parameters that reflect the capillary permeability as K trans (transfer constant representing extrav-asation of Gd-DTPA from the central plasma compartment) and K ep (the back flux of Gd-DTPA from the extravascular
extracellular compartment into the plasma compartment) and found a statistically significant variation of K trans and K ep with tumour grade (Spearman’s correlation = 0.473, p < 0.0005), it was higher in grade III tumours than grade I and II tumours but, there was no significant difference between grade I and II.
Our study has some limitations; first, it was difficult to ex-actly match a histologic specimen with the ROIs selected on DWI and DCE MRI, second is small areas of necrosis not de-tected by DCE MR images may increase the ADC value.
Figure 4 Forty-two year old female patient with left breast cancer. Axial early (a) and late (b) dynamic images show a large heterogeneously enhanced lesion at the left breast with E/D ratio 1.03. Time signal intensity curve (c) shows type III wash out curve. The lesion is hyperintense at DWI b = 1000 (d) with ADC value of 0.081· 10 3mm2/s. Histopathologically the tumour proved to be grade
Lastly, our cases had variable histological types which may af-fect the significance of the results.
9. Conclusion
DWI represented by ADC has higher correlation with the histological grade of the breast cancer than DCE MRI represented by E/D ratio which is an important factor in the treatment selection and improvement of the patient outcome.
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