CME

JOURNAL OF MAGNETIC RESONANCE IMAGING 35:1365–1371 (2012)

Original Research

Diffusion-Weighted MRI in Rectal Cancer: Apparent

Diffusion Coefficient as a Potential Noninvasive
Marker of Tumor Aggressiveness
Luı́s Curvo-Semedo, MD,1 Doenja M.J. Lambregts, MD,2,3 Monique Maas, MD,2,3
Geerard L. Beets, MD, PhD,2,3 Filipe Caseiro-Alves, MD, PhD,1
and Regina G.H. Beets-Tan, MD, PhD2,3*

Purpose: To assess the value of diffusion-weighted MR Key Words: MRI; diffusion-weighted imaging; apparent
imaging (DWI) as a potential noninvasive marker of tumor diffusion coefficient; rectal cancer; prognosis; biomarker
aggressiveness in rectal cancer, by analyzing the relation- J. Magn. Reson. Imaging 2012;35:1365–1371.
ship between tumoral apparent diffusion coefficient (ADC) V
C 2012 Wiley Periodicals, Inc.

values and MRI and histological prognostic parameters.

Materials and Methods: Fifty rectal cancer patients
underwent primary staging MRI including DWI before
surgery and neo-adjuvant therapy. In 47, surgery was THE PROGNOSIS OF rectal cancer depends on several
preceded by short-course radiation therapy (n ¼ 28) or factors, some of which are traditionally assessed by
long-course chemoradiation therapy (n ¼ 19). Mean tu- histopathological examination of the surgical speci-
mor ADC was measured and compared between sub- men. These include the degree of tumor invasion into
groups based on pretreatment CEA levels, MRI parame- and beyond the bowel wall (1,2), the number of lymph
ters (mesorectal fascia - MRF - status; T-stage; N-stage) nodes involved by tumor (3,4), and involvement of the
and histological parameters (differentiation grade: poorly mesorectal fascia (MRF) (5), which can also be
differentiated, poorly moderately differentiated, moder-
assessed preoperatively by MRI (6,7). Other factors
ately differentiated, moderately well differentiated, well-
with proven prognostic importance include the plas-
differentiated; lymphangiovascular invasion).
matic level of carcinoembryonic antigen (CEA) as well
Results: Mean tumor ADCs differ between MRF-free ver- as histological factors such as the tumor differentia-
sus MRF-invaded tumors (P ¼ 0.013), the groups of cN0 tion grade or the presence of lymphangiovascular
versus cNþ cancers (P ¼ 0.011), and between the several
invasion (LVI) (8–10).
groups of histological differentiation grades (P ¼ 0.025).
There was no significant difference in mean ADCs
The current trends in the management of rectal
between the various groups of CEA levels, the T stage, cancer point toward a more widespread acceptance of
and the presence of lymphangiovascular invasion. neoadjuvant therapies. These create an increasing
need for preoperative imaging methods to noninva-
Conclusion: Lower ADC values were associated with a
sively select high-risk patients who could benefit from
more aggressive tumor profile. Significant correlations
were found between mean ADC values and radiological
the more aggressive multimodality treatment
MRF status, N stage and differentiation grade. ADC has approaches (11,12). Detailed information on the
the potential to become an imaging biomarker of tumor patient’s individual tumor profile should allow optimi-
aggressiveness profile. zation of therapy and is also relevant in terms of prog-
nosis, by providing a way to determine the risk for
local and distant recurrence (13).
At present, the use of diffusion-weighted imaging
(DWI) incorporated into a standard MR protocol is
1
Universitary Clinic of Radiology, Coimbra University Hospitals, gradually increasing because of its proven benefit not
Coimbra, Portugal. only for tumor detection/characterization but also for
2
Department of Radiology, Maastricht University Medical Centre, monitoring treatment response (14–17). Diffusion-
Maastricht, The Netherlands.
3
Department of Surgery, Maastricht University Medical Centre,
weighted imaging measures water diffusion character-
Maastricht, The Netherlands. istics, which are dependent on multiple factors such
*Address reprint requests to: R.G.H.B.-T., Department of Radiology, as cell density, vascularity, viscosity of extracellular
Maastricht University Medical Center, PO Box 5800, 6202 AZ Maas- fluid, and cell membrane integrity (18). By quantifying
tricht, The Netherlands. E-mail: r.beets.tan@mumc.nl
Received March 29, 2011; Accepted December 15, 2011.
these properties and expressing them as an apparent
DOI 10.1002/jmri.23589 diffusion coefficient (ADC), DWI could potentially be
View this article online at wileyonlinelibrary.com. used as an imaging biomarker to better select patients
V
C 2012 Wiley Periodicals, Inc. 1365
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1366 Curvo-Semedo et al.

with poor prognosis who will truly benefit from a more phased-array body coil. The standard imaging proto-
aggressive neoadjuvant treatment (19). col consisted of standard T2-weighted (T2W) fast spin
To date, the value of ADC as a quantitative bio- echo in three orthogonal directions, which were used
marker in patients with rectal cancer is not clear yet. for clinical staging (repetition time/echo time [TR/TE]:
Data are scarce and most published data on the value 3427/150 ms; flip angle: 90 ; echo train length: 25;
of DW-MRI for prediction of response to chemoradia- NSA: 6; acquisition voxel size: 0.78
1.14
5.00
tion are conflicting (13,19–23). We hypothesize that mm; number of slices: 22; acquisition time: 5 min 08
pretreatment tumor ADC values may reflect the tumor s). In addition, axial diffusion-weighted sequence with
profile of aggressiveness. background body signal suppression (DWIBS, b-val-
As the aggressiveness of rectal tumors is expressed ues: 0, 500, 1000 s/mm2; TR/TE: 4829/70 ms; EPI
by several factors, including T stage, N stage, involve- factor: 53, NSA: 4, acquisition voxel size: 2.50
3.11
ment of the MRF, CEA levels, differentiation grade of
5.00 mm; number of slices: 50 slices; acquisition
the tumor, and the presence of LVI, (1–9,24–26) we time: 10 min 37 s) was acquired. Nodal evaluation
aim to assess the value of DW-MRI as expressed by was performed on an axial three-dimensional (3D) T1-
the quantified ADC values as a potential noninvasive weighted gradient-echo sequence (TR/TE: 9.8/4.6 ms;
imaging biomarker of tumor aggressiveness in rectal flip angle: 15 ; NSA: 1; acquisition voxel size: 1.15

cancer. 1.15
1.00 mm; number of slices: 200; acquisition
time: 6 min 30 s), acquired after intravenous adminis-
tration of gadofosveset trisodium (AblavarTM, Lan-
MATERIALS AND METHODS theus Medical Imaging, Billerica, MA). All axial
Patients sequences were angled in identical planes, perpendic-
ular to the tumor axis as identified on sagittal MRI.
Between October 2007 and November 2010, 86 con- The T2W coronal sequence was angled parallel to the
secutive patients were considered for inclusion in this tumor axis. Patients did not receive bowel prepara-
retrospective study. Inclusion criteria were (i) histolog- tion, anti-spasmodic medication, or rectal distention
ically (biopsy) proven rectal carcinoma,(ii) treatment before the MR examination.
by surgical resection with or without neoadjuvant Apparent diffusion coefficient maps in grayscale
therapy, (iii) availability of pathological reports of sur- were automatically generated at the operating system,
gical specimens mentioning tumor differentiation using a mono-exponential decay model including all
grade, and (iv) availability of primary staging MRI three b-values.
including DWI. Patients with mucinous appearing
tumors on the primary staging MRI (completely hyper-
intense on T2-weighted images without any solid tu- ADC Evaluation
mor parts) were excluded, because they are known to The MR images were analyzed by a radiological PhD
have low cellular density, exhibiting high ADC values fellow with 3 years of specific experience in reading
and as such potentially introducing a bias in the rectal MRI examinations who was blinded to the clini-
study results (27). cal patient data and pathology reports.
Clinical and imaging data were retrieved from a Mean ADC was calculated from a sample of three
patient database. The study data were retrieved from round/oval-shaped regions of interest (ROIs) that
a previous imaging study, which received approval were manually placed within solid tumor parts (as
from the local institutional ethical committee, and for identified as focal masses showing intermediate signal
which all patients provided written informed consent. intensity on the anatomical T2-weighted images) of
Thirty-six patients were excluded: 16 did not receive three independent tumor-containing slices.
surgery, 5 had predominantly mucinous tumors on The size and position of the ROIs was chosen to
the histological evaluation of the surgical specimen, include as much of the solid tumor area as possible
and in 15 patients, the histological differentiation (Fig. 1).
grade could not be derived from the pathological
reports (including 9 complete responders in whom no
residual tumor could be found). The final study popu- Prognostic Factors
lation consisted of the remaining 50 patients (37 Clinical, radiological, and histological prognostic fac-
male, 13 female). Median age was 70 years (range, tors were derived from the clinical patient database.
49–88 years). Neoadjuvant treatment consisted either The clinical factor was the plasmatic CEA level (ng/
of short-course radiation therapy (RT) (5
5 Gy) or mL) at the time of diagnosis. The following parameters
long-course chemoradiation therapy (CRT) (28
1.8 were retrieved from MRI at primary staging: the mrT
Gy on weekdays with concomitant 2
825 mg/m2/d stage (mrT1-2, T3, T4), the mrN stage (mrN0, N1, N2)
capecitabine). – both reported according to the Sixth American Joint
Committee on Cancer TNM staging system – and the
MR Imaging MRF status at MRI (free or involved). Histological
evaluation of the surgical resection specimen was the
The primary staging MRI was performed before the reference standard for the histological parameters:
neoadjuvant and surgical therapies. Patients were tumor differentiation grade and LVI. Differentiation
imaged in a 1.5 Tesla (T) MR magnet (Intera; Philips grade of the tumor was scored by the pathologist
Medical Systems, Best, The Netherlands), using a according to the following grades, used in our
 15222586, 2012, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.23589 by Cochrane Portugal, Wiley Online Library on [04/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ADC and Rectal Cancer Aggressiveness 1367

Figure 1. Example of manual placement of an oval-shaped ROI for measurement of the ADC values for each tumor on the
ADC map (a). High b-value (b ¼ 1000 s/mm2) DWI (b) and T2W (c) images provided respectively functional and anatomical
reference.

institution: 0, poorly differentiated; 1, poorly to mod- following groups: CEA <5 ng/mL versus 5 ng/mL
erately differentiated; 2, moderately differentiated; 3, (threshold used in our institution); mrT1-2 (tumor
moderately to well differentiated; 4, well differenti- limited to the bowel wall) versus mrT3-4 (tumor
ated. LVI was reported as absent or present. beyond bowel wall); mrN0 versus mrN1-2 (Nþ); MRF-
For T3 tumors showing extramural growth, the free versus MRF-invaded; and LVI absent versus LVI
distance in millimeters from the outermost part of the present. A one-way analysis of variance (ANOVA) was
tumor to the MRF was also measured on the primary used to test differences in ADC values between the
staging MRI. five predefined differentiation grade groups, followed
by post hoc Tuckey’s test.
Correlation between pretreatment ADC values
Statistical Analysis
and the distance from the outermost part of the tumor
Statistical analyses were performed using the Statisti- to the MRF at primary staging MRI was investigated
cal Package for the Social Sciences (SPSS, version with determination of the Pearson correlation
17.0, Inc., Chicago, IL). coefficient.
Student t-tests (independent-samples t-test) were For all the above mentioned analyses, a P value of
used to assess differences between means of the less than 0.05 was considered statistically significant.
 15222586, 2012, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.23589 by Cochrane Portugal, Wiley Online Library on [04/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1368 Curvo-Semedo et al.

Table 1
Correlations Between Pretreatment ADC Values and Clinical, Radiological, and Pathological Prognostic Factors
Prognostic factors Groups No. of patients (n¼) Mean ADC (6 SD) P
Pretreatment CEA levels* <5 ng/mL 29 1.073 (60.158) 0.502a
5 ng/mL 16 1.039 (60.168)
Pretreatment cT stage cT1-2 11 1.148 (60.181) 0.064a
cT3-4 39 1.046 (60.151)
Pretreatment cN stage cN0 17 1.148 (60.159) 0.011a
cNþ 33 1.028 (60.149)
Pretreatment MRF status Free 36 1.099 (60.169) 0.013a
Invaded 14 0.991 (60.113)
Differentiation grade Poor 5 1.159 (60.185) 0.025b
Poor-moderate 9 0.981 (60.117)
Moderate 31 1.053 (60.156)
Moderate-good 3 1.177 (60.118)
Good 2 1.316 (60.016)
Lymphangiovascular invasion** LVI absent 28 1.105 (60.149) 0.159a
LVI present 10 1.029 (60.121)
CEA ¼ carcinoembryonic antigen; c ¼ clinical; MRF ¼ mesorectal fascia; LVI ¼ lymphangiovascular invasion; ADC ¼ apparent diffusion
coefficient; SD ¼ standard deviation; ADC values given in mm2/s
103.
a
Independent-samples t-test.
b
One-way analysis of variance.
*In five patients, the CEA baseline value was not determined.
**In 12 patients, the LVI could not be retrieved from the pathological reports.

RESULTS and in 10 it was present. In the remaining 12

Treatment Characteristics patients, this information could not be retrieved from
the pathological reports.
Three patients underwent immediate surgery, whereas
the remaining 47 patients underwent surgery after
neoadjuvant treatment consisting either of a short- Correlation Between ADC and Prognostic Factors
course of radiation therapy (n ¼ 28) or a long-course The mean tumor ADC for the whole patient population
chemoradiation therapy (n ¼ 19). Surgery consisted of was 1.069 6 0.162
103 mm2/s.
a low anterior resection (n ¼ 39), abdomino-perineal Table 1 presents the differences in pretreatment
resection (n ¼ 9), extended resection (n ¼ 1) or Hart- tumor ADC values between the different subgroups.
mann resection (n ¼ 1). Mean ADCs were significantly different for MRF-free
The median time interval between the primary stag- versus MRF-invaded (P ¼ 0.013), mrN0 versus mrNþ
ing MRI and surgery was 59 days (range, 7–281 days): (P ¼ 0.011), and for the different tumor differentiation
52 days for the surgery alone group, 43 days for the grades at histology (P ¼ 0.025), with lower ADC values
patients who received short-course radiation therapy, for tumors with involved MRFs, nodal-positive
and 135 days for the patients who undergone long- disease, and for cancers of less differentiated grades
course chemoradiation therapy. (Fig. 2). The relationship between ADC values and the
different histological tumor differentiation grades is
given in Figure 3.
Clinical and Radiological Findings
The mean ADC was different between the sub-
At the time of diagnosis, 29 patients had CEA levels groups based on the T stage at primary MRI, CEA
lower than 5 ng/mL and 16 patients had CEA levels levels, and LVI at histology, with poor prognostic
equal to or above 5 ng/mL. In 5 patients, this value factors (lesions growing beyond the rectal wall, CEA
was not available at baseline. levels 5 ng/mL, and tumors with LVI) showing lower
Regarding the MRI-based findings, 11 patients had ADCs, but these differences were not statistically
tumors limited to the rectal wall (T1 or T2) while significant.
the remaining 39 were considered to be T3 tumors. A significant positive correlation (r ¼ 0.374; P ¼
Seventeen patients were staged as N0, while 33 had 0.019) between ADC values and the distance from the
positive nodal disease (N1 or N2). The MRF was free in tumor to the MRF was found (Fig. 4).
36 patients and involved by tumor in the remaining 14.

DISCUSSION
Histopathological Findings
The goal of the present work was to assess the value
From the analysis of the surgical specimens, 5 of DW-MRI as a potential noninvasive imaging bio-
patients had poorly differentiated, 9 poorly to moder- marker of tumor aggressiveness in rectal cancer. The
ately differentiated, 31 moderately differentiated, 3 results of our study demonstrate statistically signifi-
moderately to well differentiated, and 2 well differenti- cant correlations between ADC values and the clinical
ated tumors. In 28 patients, LVI invasion was absent MRF status and nodal status on MR imaging and the
 15222586, 2012, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.23589 by Cochrane Portugal, Wiley Online Library on [04/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ADC and Rectal Cancer Aggressiveness 1369

Figure 2. ADC measurement in tumors of different aggressiveness. In a less aggressive lesion (a, ADC map; b, b ¼ 1000
s/mm2 image; c, T2W image), which is limited to the bowel wall, without mesorrectal lymph nodes and moderately to well dif-
ferentiated, the ADC value (1.07
103 mm2/s) is higher than in a more aggressive neoplasm (d, ADC map; e, b ¼ 1000
s/mm2 image; f, T2W image), staged as T3N2, with involved MRF and moderately to poorly differentiated (ADC value ¼ 0.94

103 mm2/s).

tumor differentiation grade at histology. There was no study showed a similar trend toward low ADC values
significant correlation between ADC and the T stage for poorly differentiated tumors (9).
at primary MRI, pretreatment CEA levels, or the pres- Although not statistically significant, there was also
ence of LVI at histology. a trend toward lower ADC values for patients with
To the best of our knowledge, a correlation between tumors growing beyond the rectal wall (T3–4) as com-
clinical preoperative prognostic factors and ADC val- pared to tumors that were restricted to the bowel wall
ues in rectal cancer has not been the focus of previ- (T1–2). The lack of significance may partly be due to
ous studies. In our study pretreatment mean ADC the relatively small patient population. Another rea-
was significantly lower for tumors invading MRF or son could be that the assumption of the subgroups
tumors with positive nodal disease. This is an inter- T1–2 and T3–4 having different prognosis (good
esting finding as it is proven that both MRF involve- versus bad) may not be correct. There is a huge vari-
ment and positive lymph nodes are powerful predic- ability in prognosis within the group of T3 tumors:
tors of a local recurrence and distant metastases. The whereas large, bulky T3 tumors are associated with a
presence of any correlation between ADC and MRF or poorer prognostic outcome and would behave more
nodal status, therefore, suggests that ADC on itself closely like T4 tumors, the smaller (borderline) T3
correlates with prognosis. This could be explained by tumors are known to have a better prognosis, behav-
the fact that ADC values are indirectly derived from a ing more closely like T2 tumors. A worsening of prog-
tumor’s cellular microarchitecture and may thus nosis that is associated with a gradual increase of the
reflect the aggressiveness of the tumor tissue profile. depth of tumor extension into the surrounding meso-
This is further supported by the finding that tumors rectal fat is described (25). This is also supported by
that were less well differentiated showed relatively low our findings that showed a significant correlation
ADCs, again suggesting that low ADC values are asso- between ADC and the distance from the tumor to the
ciated with an unfavorable tumor profile. A recent MRF with lower ADC values associated with a shorter
 15222586, 2012, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.23589 by Cochrane Portugal, Wiley Online Library on [04/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1370 Curvo-Semedo et al.

Figure 3. Comparison of mean

ADC values of tumors according to
the histological differentiation grade.
The whiskers represent the stand-
ard deviation. Tuckey’s post hoc
testing showed that the mean ADCs
between poor to moderately differen-
tiated and well differentiated tumors
differ significantly (P ¼ 0.047). The
relatively high ADC value of the
poorly differentiated tumors could
partly be related to the small num-
ber of patients in this subgroup.
Another explanation could be that
they have more necrosis at a cellular
microscopical level resulting in
higher ADC values.

distance between the outermost part of the tumor and study the correlation between ADC and the primary
the fascia. tumor profile, i.e., before it was affected by any thera-
Previous studies have investigated the value of pre- peutic interventions. Hence, we did not use the final
treatment tumor ADC as a prognostic factor in terms pathological T-stage, N-stage, and MRF for correlation
of prediction of response to chemoradiation in the with ADC, as the majority of patients had undergone
specific subgroup of patients with locally advanced chemoradiation therapy before surgery, in which set-
rectal cancer. Results are conflicting, with some ting the T and N stage at histology is no longer repre-
authors demonstrating significantly lower pretreat- sentative of the initial tumor profile. After chemora-
ment ADC values for the good responders as com- diation treatment, histopathology is an indicator of
pared to the nonresponders, which suggests that pre- treatment response and the prognostic relevance of
treatment ADC can be beneficial to predict treatment the definite histological stage seems to be significant
response (19–21). Others, however, reported that pre- mainly in patients with a pathologically complete
treatment ADC values were not statistically different response (31). Third, although MRI is known to be a
for responders and nonresponders and as such may reliable modality for rectal cancer staging, its assess-
be limited in predicting treatment outcome ment is observer-dependent and under- or overstag-
(22,23,28,29). As the extent of response after chemo- ing may have occurred. Nevertheless, for the most rel-
radiation may also be dependent on the tumor profile, evant prognostic factors for which the association
it therefore seems logical to think that initial ADC val-
ues may be correlated both with response and the
overall prognostic tumor profile as assessed in this
current study. The findings of our study and the
above mentioned reports may thus be related to each
other. However, the assessment of treatment response
was not the focus of our study, and, furthermore, the
patients undergoing neoadjuvant chemoradiation con-
stituted only a small subgroup (n ¼ 19) of the patient
population, precluding any meaningful subanalyses.
Our study has some limitations. First, our ADC
measurements were obtained by measuring three
sample ROIs, which may not be fully representative
for the overall tumor profile (30). However, this
approach was chosen because outlining of the whole
tumor volume is very time-consuming and difficult to
perform in clinical practice. We aimed to reproduce
what happens in the clinical daily work, where time
constraints frequently suggest that a simpler and
quicker way to obtain ADC values will be used. Meas-
urements were obtained by one experienced reader.
We acknowledge that this does not allow for evalua-
tion of potential interobserver variations. Second, we
chose to correlate ADC with factors derived from the Figure 4. Correlation between ADC values and pretreatment
primary clinical staging MRI because we wanted to distance from tumor to MRF.
 15222586, 2012, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.23589 by Cochrane Portugal, Wiley Online Library on [04/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ADC and Rectal Cancer Aggressiveness 1371

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