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Study of endorectal ultrasonography in staging of rectal cancer
Institute: Department of Ultrasound Diagnosis, Beijing Hospital of Ministry of Health,
Beijing100730, China
Corresponding author: GUO Fa-jin,
Correspondence to: Dahua
Tel:
13910813603
Fax:
01085133830
road 1, Dongdan, Beijing100730, China
Email: [email protected];
Authors: REN Jun-hong, GUO Fa-jin, DAI Wei-de, HAN Xiu-jie and MA Na.
Maximum # of words (4000): 3637
1
ABSTRACT
Background There is no consensus regarding the performance for endorectal ultrasonography
(ERUS) at every stage of rectal cancer. Thus, the purpose of our study was to further assess
the value of ERUS in the preoperative staging of rectal cancer.
Methods A retrospective study were performed for 44 consecutive patients (mean age: 63.3 ±
10.2 years) who underwent surgical treatment for endorectal carcinoma and preoperatively
evaluated using Biplane ERUS between September 2008 and December 2010. We compared
the ERUS staging with the pathology findings based on the surgical specimens.
Results
ERUS staging agreed with the histologic staging in 39of 44 (88.6%) patients, the
agreement on the depth of transmural invasion depth was good (κappa = 0.73; 95% CI:
0.60–0.86, P=0.000). The detection sensitivities of rectal cancer with ERUS were as follows:
T1 85.7%, T2 87.5%, T3 88.9%, T4 100.0% with specificity values of T1 97.3%, T2 92.9%,
T3 96.2%, T4 97.6%. ERUS correctly staged patients with T1 95.5%, T2 90.9%, T3 70.5 %,
T4 97.7%. The positive predictive value of ERUS was lowest for T4 (75%), but positive
predictive value is highest for T3 (94.1%) as followed by T2(87.5%) and T1(85.7%); the
negative predictive values of ERUS from high to low were ordered by T4(100%),
T1(97.3%),T2(92.9%) and T3(92.6%) .The total overstaged cases was 4.5%, the understaged
cases 6.8%. The extent of perirectal lymph node metastases was determined with sensitivity
of 68.4% (13/19), specificity of 80.0% (20/25), and diagnostic accuracy of 75.0% (33/44).
Conclusions Biplane ERUS has a high diagnostic accuracy for tumoral invasion of the rectal
wall at every T stage, but relatively low diagnostic accuracy for lymph node metastases.
Key words: Ultrasonography, endoscopic; Stage; Rectal cancer
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In rectal cancer, the depth of tumor infiltration and metastatic involvement of lymph nodes
are important prognostic factors1, 2. Accurate preoperative assessment of these prognostic
factors is an important first step in assigning patients to one of the available treatment
strategies. The assessment of the depth of cancer invasion (T stage) remains the primary and
most important feature in the treatment of patients with rectal cancer. Endorectal
ultrasonography (ERUS) as one noninvasive radiologic modalities has proved to be important
and widely used diagnostic tools in the assessment of depth of cancer invasion and/or lymph
node involvement.
Extensive researches on the diagnostic performance of ERUS in the staging of rectal cancer
have been performed
3-10
, yet a wide of variationes in study design, patient population,
imaging techniques, and results exist which may be related with technical developments and
different techniques employed over the years, variation in training and expertise of the
investigators, patient characteristics (disease stage, age, or sex distribution).There is no
consensus regarding the performance for ERUS at every stage of rectal cancer. Thus, the
purpose of our study was to further assess the value of ERUS in the preoperative staging of
rectal cancer at our institution.
METHODS
Study subjects
All subjects gave their written informed consent prior to the study. This study was also
approved by our Institutional Review Board. Between September 2008 and December 2010,
44 consecutive subjects with rectal cancer were admitted to our hospital. All subjects
underwent biplane ERUS and colonoscopy, preoperatively. Postoperative pathological
examinations were carried out in all subjects. There were 30 men and 14 women with mean
age of 63.3 ±10.2 years (range from 36 years old to 79 years old).
Inclusion criteria were primary invasive rectal cancer. Exclusion criteria included multiple
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primary colon cancer, synchronous or metachronous second primary malignancie,
inflammatory bowel disease, severe arrhythmia, glaucoma, intracorporeal metal parts, severe
claustrophobia, as well as pregnancy. None of the patients received neoadjuvant therapy.
Surgical procedures for these patients involved right hemicolectomy, transverse colectomy,
left hemicolectomy, sigmoidectomy, anterior resection for rectal cancer (Dixon’s operation) or
abdominal-perineal resection (Miles’ operation).
Postoperative pathological examination was consistent with adenocarcinoma in 40 cases,
carcinoid tumor in 1 case, stromal tumor (low grade) in 1 case, and canceration of an
adenoma in 2 cases.
ERUS examination
A Technos DU8 ultrasound system (Esaote, Italy) with an endoluminal biplane broad band
multi-frequency probe was applied. The frequencies of the linear array ranged from 5.5 to 10
MHz, and the frequencies of the convex array ranged from 5.5 to 8.5 MHz. Two-dimensional
ERUS was used to observe the location, size and morphology of the lesion, the degree of
tumoral invasion of the rectal wall, the relationship between the lesion and the perirectal
organs, and the extent of perirectal lymphadenopathy. High-frequency color Doppler flow
imaging (CDFI) was used to observe the distribution of blood flow within the lesion, the peak
velocity of the arterial blood flow, and the resistance index (RI). ERUS was performed
preoperatively and interpreted by one gastrointestinal radiologist and one rectal surgeon who
were blinded to the findings of the digital rectal examination.
The depth of transmural tumor invasion was assessed according to the TNM classifications
11,12
for both ERUS and histopathologic examinations, and results were compared
prospectively. The ultrasonographic staging of rectal cancer are as follows: uT1: tumor is
limited to three layers, and the submucosa is intact (Figure1A, B, C); uT2: tumor invades the
muscularis propria, but does not reach the serosa (Figure2A, B, C); uT3: tumor invades the
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rectal serosa and peripheral tissues (Fig.3 A, B, C); uT4: tumor invades adjacent organs and
tissues (Fig. 4A, B, C)13; uN0: no lymph node metastasis or obvious lymph nodes are noted
around the rectum, or the lymph node diameter is less than 5 mm; uN1: lymph node
metastasis and the lymph node diameter is equal to or greater than 5 mm (Figure 5).
Optical colonoscopy
Optical colonoscopy was performed in the standard fashion with a standard endoscope (CF-Q
140; Olympus Optical Co., Tokyo, Japan) by the same gastroenterologist with at least 10
years of experience in performing endoscopy. The gastroenterologist was blinded to the
results of ERUS. Sedatives and analgesics were used intravenously when necessary. The
locations, sizes and numbers of colorectal neoplasms were recorded.
Routine pathological examination
Immediately after surgery, resected specimens were opened on the side opposite the tumor
and fixed in 10% formalin. After fixation, we obtained serial slices through the whole tumor
in Tis–T2 cases or through more than two sections of the deepest part of the tumor in T3 or
T4 cases. The slices were embedded in paraffin, sectioned, and examined histologically after
H and E staining.
The resected specimens were histopathologically examined by pathologists who were
blinded to the findings of the preoperative evaluation of tumor extent. Pathological T stage
was identified according to the AJCC TNM (tumor-node-metastasis) Rectal Cancer Staging
System14.
Statistical Methods
The data were represented as mean ± standard deviation ( x  s ), and the count data were
presented as percent proportion. The diagnostic accuracy, sensitivity, and specificity of
biplane ERUS in the uT staging of rectal cancer were calculated in accordance with the
postoperative pathological results (the latter were considered the gold standard). SPSS 11.0
5
was used to evaluate all data. Kappa identity test was applied and a P value less than 0.05
was considered to be statistically significant.
RESULTS
Detection of rectal cancer with ERUS
The morphology of most tumors on ERUS was irregular with uneven hypoechoic signals
inside the tumor and multiple microcalcifications observed in some areas. Tumoral invasion
of various layers of the rectal wall was observed. Since malignant tumors characteristically
invade along blood vessels, CDFI blood flow distribution can identify the depth of infiltration
of tumor within the rectal wall. Hypervascularity was noted within each tumor and the arterial
blood flow was high-impedance (RI = 0.75 ± 0.08). Enlarged perirectal lymph nodes were
found in 19 cases with diameters ranging from 3.6 to 11.5 mm (mean size: 8.4 ± 0.7 mm).
Staging of rectal cancer with ERUS
Detailed results of the ERUS staging were listed in Table 1. Findings from histopathological
examinations were served as the reference standards. Using ERUS, uT1 was found in 6 cases,
uT2 in 14 cases, uT3 in 16 cases, and uT4 in 3 cases. ERUS staging agreed with the histologic
staging in 39 of 44 (88.6%) patients, the agreement on the depth of transmural invasion depth
was good (κappa = 0.73; 95% CI: 0.60–0.86, P=0.000).
Accuracy rate, sensitivity, specificity, positive predictive value, and negative predictive value
for detection of T2 to T4 stage were shown in Table 2. Among 5 cases in which staging errors
were encountered at T1,1 case (14.3%) were overstaged; at T2, 1 case (6.3%)overstaged and
1 case (6.3%) understaged; at T3, 1 case (5.9%) understaged ; at T4, 1 case (25%)
understaged. Histologic review of the specimens revealed that total overstaged cases( 4.5%),
the tumor invaded close to the deeper uninvolved layer and reactive changes were present in
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the connective tissue around the tumor including inflammatory. Histologic review of
understaged cases (6.8%) indicated that they had only microscopic invasion beyond the
estimated layers and that reactive changes of the connective tissue around the tumor were
slight or absent.
The extent of perirectal lymph node metastases was determined with sensitivity of 68.4%
(13/19), specificity of 80.0% (20/25), and diagnostic accuracy of 75.0% (33/44).
DISCUSSION
For a patient with rectal cancer to achieve a better prognosis and quality of life, the extent of
surgery should accurately reflect the disease status. Treatment options should be selected
according to the extent of the tumor. The evaluation of the tumor infiltration depth (T staging)
and the lymph node metastasis (N staging) is a very important part of preoperative staging. In
general, T1 tumors invading the superficial submucosa can be effectively treated by local
excision, T2 tumors invading the muscularis propria, or T3 tumors invading the perirectal fat
slightly but remaining within the mesorectal fascia can be treated by mesorectal excision.
Patients with T3 tumors invading the mesorectal fascia or T4 tumors invading the neighboring
organs require more radical surgery15. To select patients for optimal management, it is crucial
to staging of cancer before surgery, because overstaging would increase patients’ sufferings
arising from the adverse effects while understaging would deprive patients from the desired
benefits 16.
In a meta-analysis, Bipat, et al.17obtained summary estimates and ROC curves for the
diagnostic accuracy of ERUS, CT, and MR imaging in the staging of patients with rectal
cancer. ERUS was found to be the most accurate modality when compared with CT and MR
imaging for evaluation of local invasion of rectal cancer. For lymph node involvement, the
results were comparable, with low sensitivity values. However, So far, the accuracy of ERUS
7
examination is far from satisfactory, especially for N stage. A systematic review of showed
that ultrasound had an overall accuracy of 82% and was particularly useful for early localized
rectal cancers. ERUS had accuracy of 73% in the assessment of nodal metastases18.And the
accuracy was closely related with the experience of examiners. It is therefore possible that the
overall accuracy of the examinations in routine clinical practices is even worse than was
reported. In the current study, the T-stage on ERUS correlated with histopathology in 39 of 44
patients (88.6%). The N-stage on ERUS correlated with histopathology in 33 of 44 patients
(75.0%). Our finding was in concordance with the previous report which determining the
depth of infiltration of the tumor, the mean total accuracy of US for 2718 patients was
reported to be 63%-96% with a mean value of 81.8%19, 20.
Our results demonstrated that, with the reference standards of outcomes from histopathology,
detection sensitivities of rectal cancer with ERUS were as follows: T1 85.7%, T2, 87.5%,
T3 88.9%, T4 100.0% with specificity values of T1 97.3%,T2 92.9%, T3 96.2%, T497.6%.
Patients with T1 tumors were overstaged more often compared with T2 (14.3% vs. 6.3%), and
more T4 disease was understaged than T3 (25 % vs.5.9%). ERUS correctly staged patients
with T1 or T2 and T4 rectal cancers more often than T3 (95.5% or 90.9% and 97.7% v s.
70.5 %). The total overstaged cases was 4.5%, the understaged cases 6.8%. Specifity of
ERUS staged T1 to T4 almost equally, a great proportion of T4 was more sensitively to stage
than T1 to T3.The positive predictive value of ERUS was lowest for T4 (75%), but positive
predictive value was highest for T3 (94.1% ), and all most negative could be predicted at T1
to T4. The above results revealed that ERUS enabled distinction between early and advanced
rectal lesion and this technique seemed to be more precise in distinguishing between T1 and
T2, differentiation between T3 and T4 lesions remains challenging. Massari, et al21 found
overall accuracy in staging depth of infiltration by ERUS was 90.7%. Overstaging occurred in
4% of patients, whereas understaging occurred in 5.3%. In staging lymph nodal involvement,
8
overall accuracy was 76%, sensitivity was 69.8%, specifity was 84.4%. These findings were
comparable to our results.
ERUS is not able to discriminate between lymph nodes inside or outside the mesorectal fascia,
since the fascia is not identified at ERUS. The latter is also of importance in determining the
spread of stage T3 tumors considered for total mesorectal excision. In another systematic
review on the diagnostic performance of the imaging modality in the staging of rectal cancer,
Kwok and colleagues22 reported summary sensitivity values of 93% with specificity values of
78% for ERUS imaging in the determination of wall penetration (stage T3). Sensitivity of this
study was higher, and specificity was lower than ours, it might be related to ideal conditions
in experimental study.
ERUS has certain advantages in the diagnosis of rectal cancer. Biplane endorectal
ultrasonography can clearly identify the rectal wall structures and perirectal lymph nodes;the
ultrasound beam is vertical to the rectal wall and lesion, the biplane probe can reduce artifacts,
improve image resolution, and accurately locate the tumor. Biplane endorectal
ultrasonography, however, has several limitations. Tumor identification may be too deep or
too shallow on ERUS. In addition, when the degree of tumor infiltration induces only a mild
change in the rectal wall layers (as in superficial tumors) it can be misdiagnosed on ERUS as
inflammation. Tumor and lymph nodes can also be obscured by intestinal contents on ERUS.
These limitations may result in overstage or understage. Additionally, ERUS is not applicable
for stenosing tumors; further improvements are necessary for optimum tailoring of treatment
for the individual patient. Tumor and lymph nodes can also be obscured by intestinal contents
on ERUS. We defined lymph node metastasis as lymph nodes equal to or greater than 5 mm in
diameter. The size of perirectal normal lymph nodes are normally about 2-3 mm in diameter.
Pathological studies show that 20% of lymph nodes less than 3-4 mm in diameter contain
metastasis. The identification of lymph nodes with ERUS imaging remains a major point of
9
concern23.
Ongoing research technology may be helpful in improving detection accuracy of ERUS.
Recently, some newly developed techniques, such as ERUS-guided fine needle aspiration,
3D-MRI and endorectal coil MRI16
24
have been applied to improve the diagnostic accuracy
of nodal metastasis in clinical practice. Although these techniques are promising in improving
staging accuracy, they need further evaluation. In addition, they are not widely
available.Because of the limitations in the use of both MRI and ERUS for rectal cancer
staging, comprehensive evaluation should be carried out using colonoscopy, MRI, CT, and
ERUS.25-29
In summary, our findings are useful for predicting histologic diagnosis and may contribute to
treatment selection. The limitation of our preliminary study on ERUS in detection of rectal
cancer is that only 44 symptomatic patients scheduled for ERUS were recruited. These results
need to be further evaluated in a large-scale study for the population.
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TABLES
Table 1. Comparison of T staging between US and postoperative pathological
examination (cases)
Ultrasonographic
staging
Postoperative pathological staging
pT1
pT2
pT3
pT4
Total
overstage understage
uT1
6
1
0
0
7
14.3%
uT2
1
14
1
0
16
6.3%
uT3
0
1
16
0
17
5.9%
uT4
0
0
1
3
4
25.0%
Total
7
16
18
3
44
4.5%
6.3%
6.8%
Table 2. Summary estimates for US in the staging of rectal cancer (%)
pT1
pT2
pT3
pT4
Diagnostic accuracy
95.5(42/44)
90.9(40/44)
70.5(31/44)
Sensitivity
85.7(6/7)
87.5(14/16)
88.9(16/18) 100.0(3/3)
Specificity
97.3(36/37)
92.9(26/28)
96.2(25/26)
Positive predictive value
85.7 (6/7)
87.5 (14/16)
94.1 (16/17) 75.0 (3/4)
Negative predictive value
97.3(36/37)
92.9(26/28)
97.7(43/44)
97.6(40/41)
92.6(25/27) 100.0(40/40)
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FIGURES
A
B
C
Figure 1. uT1 tumor. The tumor is limited to the former three layers, and the submucosa is intact,
discontinuous mucosal echo can be observed, and the muscularis propria and serosa are intact.
A: Ultrasonographic cross sectional image of the rectal wall. B: Ultrasonographic vertical section
of the rectal wall. C: Pathological section (H&E staining, ×40)).
A
B
C
Figure 2. uT2 tumor. The tumor has invaded the muscularis propria, but the serosa is intact.
A: Ultrasonographic cross sectional image of the rectal wall. B: Ultrasonographic vertical section
of the rectal wall. C: Pathological section (H&E staining, ×40)).
A
B
C
Figure 3. uT3 tumor. The tumor has invaded the rectal serosa and peripheral tissues.
A: Ultrasonographic cross sectional image of the rectal wall. B: Ultrasonographic vertical section of
the rectal wall. C: Pathological section (HE staining, ×40)).
15
Figure 4. uT4 tumor. The tumor has penetrated the serosa and invaded the uterus (The arrow
shows the uterus).
Figure 5.
Pathological image of lymph node metastasis around the rectal
cancer (H&E staining, ×40).
16