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Original Research |
1 Department of Radiology, Division of Medical Intelligence and Informatics,
Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima,
Japan.
2 Department of Clinical Radiology, Hiroshima University Hospital, 1-2-3,
Kasumi-cho, Minami-ku, Hiroshima, 734-8551, Japan.
3 Present address: Hiroshima Atomic Bomb Casualty Council, Hiroshima,
Japan.
Received November 9, 2007;
accepted after revision February 17, 2008.
Address correspondence to J. Horiguchi
(horiguch{at}hiroshima-u.ac.jp).
Abstract
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SUBJECTS AND METHODS. Eighty-five lymph nodes (metastatic, n = 53; reactive, n = 32) from 37 patients were examined by both elastography and B-mode sonography in this prospective study. Elastographic patterns were determined on the distribution and percentage of the lymph node area with high elasticity (hard), with pattern 1 being an absent or very small hard area to pattern 5, a hard area occupying the entire lymph node. The cutoff line for reactive versus metastatic was set between patterns 2 and 3; patterns 3–5 were considered metastatic. B-mode sonographic diagnosis was based on the sum of scores for five criteria: short-axis diameter, shape, border (regular or irregular), echogenicity (homogeneous or inhomogeneous), and hilum (present or absent). The cutoff line for reactive versus metastatic was set between scores 6 and 7; scores 5 and 6 were considered reactive, and scores 7–10, metastatic.
RESULTS. Sensitivity, specificity, and accuracy of B-mode sonography were 98%, 59%, and 84%, respectively; 83%, 100%, and 89% for elastography; and 92%, 94%, and 93% for the combined evaluation.
CONCLUSION. The combination of highly specific elastography with highly sensitive conventional B-mode sonography has the potential to further improve the diagnosis of metastatic enlarged cervical lymph nodes.
Keywords: elastography • lymph nodes • metastasis • sonography
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In brief, sonographic elastography works in the following steps: first, elastography receives digitized radiofrequency echo lines from the tissue; second, it gives slight compression to the tissue by the transducer along the radiation axis to make some displacement; and third, it receives a second, postcompression digitized radiofrequency echo line from the same tissue [4]. Then the data from these two echo lines undergo processing, and ultimately an elastographic image (elastogram) appears on the monitor. There are two types of elastograms, gray-scale and color. The hard and soft areas (i.e., areas of high and low elasticity, respectively) appear in the gray-scale elastogram as dark and bright [5, 6]. In the color elastogram, increasing tissue hardness appears in ascending order as red, yellow, green, and blue. These colors represent the relative hardness of the tissues in the elastogram.
Sonographic elastography has been used to examine several organs: the breast [7, 8], thyroid [5], prostate [9], cervix [10], liver [11], and so forth. Recently, an article relating their initial experience in the diagnosis of cervical lymph node metastasis using gray-scale sonographic elastography was published by Lyshchik et al. [6]. To our knowledge, however, no English-language articles have documented the evaluation of cervical lymph nodes using color sonographic elastography.
Of the 400–450 lymph nodes in the human body, the head and neck contain 60–70. These nodes show reactive enlargement due to infection (e.g., infection of upper aerodigestive tract). They also undergo enlargement when they are secondarily involved in head and neck cancer. Sometimes metastatic cervical lymphadenopathy appears as the first symptom in patients having malignancy in the head and neck, lung, breast, and so forth. Differentiation between reactive and metastatic lymphadenopathy is vital, and one of the differentiating criteria is hardness (elasticity) of the lymph node.
The purpose of this study was to investigate the accuracy of conventional sonography, sonographic elastography, and their combined evaluation for the differentiation between reactive and metastatic enlarged cervical lymph nodes.
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Final Diagnosis
Lymph nodes were determined to be reactive on the basis of histopathologic
findings or on the basis of clinical findings such as enlarged tender lymph
node, increased C-reactive protein, leukocytosis, decreased size of the lymph
node after antibiotic treatment, and the absence of known malignancy. The
reference standard for the final diagnosis of metastatic lymph nodes was
histopathologic findings or imaging findings suggesting central
necrosis—that is, hypodensity on contrast-enhanced CT
[12] or hypointensity on
contrast-enhanced T1-weighted MRI in patients with malignancy.
Equipment and Scanning
One radiologist who had 18 years' experience with conventional sonography
and was a novice in elastography performed the sonography. The patients
underwent both B-mode and elastographic sonography in the supine position with
a digital sonography scanner (EUB 8500, Hitachi Medical) equipped with the
Real-time Tissue Elastography software (Hitachi Medical); the probe was a
conventional linear probe with a 13-MHz transducer (EUP-L65, Hitachi
Medical).
For each lymph node, B-mode images were obtained first. Then, changing the system into the elastography mode, real-time freehand elastography was performed using the same probe for an additional 1–2 minutes. For elastography, compression with light pressure followed by decompression was repeated until a stable image was obtained—that is, nearly the same size and color distribution of the target area in several consecutive images. Direction of the compression was upward and downward (along the radiation axis). Frequency of compression appeared on a scale on the monitor. Real-time elastographic and B-mode images simultaneously appeared as a two-panel image. Figure 1 shows a typical image displayed on the monitor during elastography, in which the elastogram appears in a region-of-interest (ROI) box. The size of the box was determined to be the target lymph node including surrounding tissue in almost the same proportion while avoiding tissues (bone, blood vessel) that might disturb the appropriate analysis of the relative hardness of the target lymph node. To maintain unbiased reading, 85 sets of elastograms and corresponding B-mode images without any patient information were collected into two separate slide shows (Microsoft PowerPoint, 2003) in random order.
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B-mode evaluation—B-mode images were evaluated on the
criteria of size, shape, border, echogenicity, and hilum. Size and shape were
evaluated per region. Regional distribution was determined according to the
1997 American Joint Committee on Cancer (AJCC) criteria for lymph nodes
[13], in which neck lymph
nodes are divided into seven levels. Lymph nodes in level 7 were excluded
because scanning them was not possible with sonography. For the criterion of
size, the short-axis diameter (in mm) of the lymph nodes was evaluated. For
shape, the ratio of the short-axis diameter to the long-axis diameter (S/L
axis ratio) was used. For each lymph node, we determined the cutoff values of
short-axis diameter and S/L axis ratio that gave the best accuracy. In cases
of level 4 (AJCC classification) lymph nodes in which two cutoff values had
the highest accuracy, we used receiver operating characteristic (ROC) curve
analysis to select one for our purposes. Scores were determined for five
criteria: the short-axis diameter (diameter 
cutoff value, score of 1;
diameter > cutoff value, score of 2), the S/L axis ratio (ratio 0.6,
score of 1; > 0.6, score of 2), the border (regular, 1; irregular, 2),
echogenicity (homogeneous, 1; inhomogeneous, 2), and hilum (present, 1;
absent, 2) [6,
12–21].
The score for each lymph node was determined by summing scores for all
criteria. A statistically supported cutoff line between reactive and
metastatic was set between scores 6 and 7, depending on the best accuracy.
Scores 5 and 6 were determined to be reactive, and scores 7–10,
metastatic.
Elastogram evaluation—After observing all the elastograms,
two authors together subjectively decided five patterns for the elastograms
depending on the distribution of the blue (i.e., hard) area in the lymph node.
Elastographic patterns were determined on the distribution and percentage of
the lymph node area with high elasticity (hard): pattern 1, an absent or a
very small hard (i.e., blue) area; pattern 2, hard area < 45% of the lymph
node; pattern 3, hard area 
45%; pattern 4, peripheral hard and central
soft areas; pattern 5, hard area occupying entire lymph node with or without a
soft rim. The patterns 1, 2, 3, 4, and 5 were assigned scores of 2, 4, 6, 8,
and 10, respectively. The outline of the lymph node was drawn, and the
percentage of blue area was measured on an off-line computer using image
analysis software "Image J" developed by the National Institutes
of Health [22]. On average,
approximately 1–2 minutes was required for the measurement of the blue
area of each lymph node. A statistically supported cutoff line at 45% blue
between patterns 2 and 3 was obtained from the ROC
(Table 1 and Figs.
2,
3,
4,
5,
6, and
7).
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Combined evaluation—The combined score for each lymph node was the sum of the B-mode and elastographic scores. A statistically supported cutoff line between metastatic and reactive was set between scores 12 and 13, depending on the best accuracy. Scores 7–12 were determined to be reactive, and scores 13–20, metastatic.
For B-mode, elastography, and the combined evaluations, the precision of the diagnostic parameters (sensitivity, specificity, accuracy, and positive and negative predictive values) was expressed using 95% CI. The areas under the ROC curves were calculated.
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B-Mode Sonography
Cutoff short-axis diameters according to AJCC levels were 11 mm in level 1,
13 mm in level 2, 5 mm in level 3, 9 mm in level 4, and 7 mm in level 5. The
cutoff S/L axis ratio was 0.6; 0.6 was reactive and > 0.6 was
metastatic. The accuracy for individual B-mode criteria was 84% for size, 56%
for S/L axis ratio, 67% for border, 86% for hilum, and 78% for echogenicity
(Table 2).
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Elastography
During elastography, compression at a frequency of 3 or 4 on the frequency
scale was needed to obtain stable elastographic features. In elastogram
evaluation, all 32 reactive lymph nodes showed patterns 1 and 2 (re active).
Among 53 metastatic lymph nodes, 44 (83%) had patterns 3, 4, and 5
(metastatic). Two (4%) and seven (13%) metastatic lymph nodes showed patterns
1 and 2, respectively. Concerning elasticity pattern 4 (i.e., suggestive of
central necrosis), 12 of 13 (92%) lymph nodes were metastasized from SCC and
one (8%) from an unknown origin.
Diagnostic Performance
The diagnostic performances of B-mode sonography, elastography, and the
combined test are shown in Table
3. B-mode sonography showed sensitivity of 98% (95% CI,
94–100%), specificity of 59% (42–76%), and accuracy of 84%
(76–91%). Elastography showed sensitivity of 83% (73–93%),
specificity of 100% (100–100%), and accuracy of 89% (83–96%). The
combined evaluation showed sensitivity of 92% (85–100%), specificity of
94% (85–100%), and accuracy of 93% (88–98%). The ROC curves for
B-mode, elastography, and the combined evaluation in the differentiation of
reactive and metastatic lymph nodes are shown in
Figure 8. The areas under the
curves for B-mode sonography, elastography, and the combined evaluation were
0.901, 0.873, and 0.970, respectively.
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B-Mode Sonography
Several studies have been published on the diagnosis of metastatic cervical
lymph node by B-mode sonography
[12,
14–21];
however, specific criteria for distinguishing reactive from metastatic
cervical lymph nodes are not yet clear. The cutoff short-axis diameter for
level 2 lymph nodes was two times higher than that for level 3. This suggests
that, for the evaluation of cervical lymph nodes, a common cutoff diameter
should not be set for all levels. In a study by Lyshchik et al.
[6] using the fixed cutoff
diameter of 8 mm, the accuracy of the short-axis diameter was 65%, whereas in
our study it was 84%. With respect to shape, our calculation gave the best
accuracy at S/L axis ratio 0.6 for reactive and > 0.6 for metastatic
nodes, which supports the findings of round shape for metastatic nodes in
previous studies [6,
14,
15]. Very few studies have
evaluated lymph node borders. Ying et al.
[16], Ahuja and Ying
[17], and Ying et al.
[21] evaluated lymph node
borders as sharp and unsharp. In this study, we evaluated regular and
irregular lymph node borders as a criterion of reactive and metastatic lymph
nodes, respectively, that showed 67% accuracy. The presence or absence of a
hilum has been reported to be an important criterion for lymph node diagnosis
[6,
18]. In our study also, this
showed the best accuracy (86%).
Elastography
Stiffness of cervical lymph nodes was independently assessed both
quantitatively and qualitatively by Lyshchik et al.
[6] using external sonographic
gray-scale elastography. Those authors assessed the diagnostic potential of
qualitative criteria—lymph node visibility, relative brightness, margin
regularity, and margin definition—as well as the quantitative criterion
strain index, which was obtained by comparing the absolute values of lymph
node strain with the absolute values of surrounding muscle strain. Among these
criteria, strain index greater than 1.5 was the most useful in metastatic
lymph node classification, having 98% specificity, 85% sensitivity, and 92%
accuracy. We obtained a similar level of results (100% specificity, 83%
sensitivity, and 89% accuracy) using the combination of both qualitative and
quantitative criteria. However, we propose the combined criteria, for the
following reasons: The presence of a central green area in pattern 4 was
considered to be central necrosis. Our result showing 12 of the 13 pattern 4
lymph nodes had primary SCC supports this consideration. Furthermore, we
considered a large blue area in a scattered distribution to suggest the
manifestation of focal cortical metastatic invasion and therefore categorized
this appearance as pattern 3. This criterion did not show any false-positive
results.
In endoscopic sonographic elastography of lymph nodes, Giovannini et al. [23] reported 100% sensitivity and 50% specificity without using any qualitative pattern analysis, whereas Saftoiu et al. [24] reported 91.7% sensitivity and 94.4% specificity using a pattern analysis. These facts also indicate the importance of qualitative pattern analysis. However, another pattern of elastographic lymph node analysis has been reported in which only the percentage of blue area was used as a criterion [25].
The greatest advantage of elastography is its high specificity, which has been found not only in our study but also in other studies [6, 24]. Because of this, elastography may reduce unnecessary invasive procedures for the diagnosis of cervical lymph node metastasis.
Combined Evaluation
Accuracy and area under the ROC curve showed that the diagnostic power of
the combined evaluation was higher than that of the individual evaluations.
This suggests that the examination can be best performed when B-mode
sonography, with its high sensitivity, and elastography, with its high
specificity, are complementary. The scope of our study was to test the
performance of elastography and the combined test compared with B-mode
sonography alone. In clinical practice, however, sonography practitioners
should use both methods in real time.
Gray-Scale and Color Elastography
In the gray-scale elastography study by Lyshchik et al.
[6], postprocessing of
radiofrequency images was done on an off-line computer. In our color
elastogram study, postprocessing was done in real time, which made the process
quicker. Although our study was performed on an off-line computer, in clinical
practice real-time color elastography seems to have an advantage over
gray-scale. Real-time diagnosis needs further investigation.
Limitations
This study had some limitations. First, our data sample was small; we used
the lymph node as our unit, not the patient. Second, we included only enlarged
lymph nodes, whereas elastographic findings of normal-sized lymph nodes should
also be explored. Most metastatic lymph nodes in our study were in patients
who had either primary SCC or thyroid cancer. Lymph nodes with primary
malignancy or metastases from other primary malignancies such as melanoma or
breast cancer were not included. Third, the final diagnosis of almost all
reactive lymph nodes was done based on follow-up findings instead of
histopathologic findings. Fourth, evaluation was done on an off-line computer
from single images, which would not be practical for real-time evaluation.
Although elastography is a good improvement in the field of sonography, we still need to address one limitation for the future. Our evaluation had to be done in only one section of the lymph node. Assessment of the stiffness of the whole lymph node, by volumetric measurement, may increase the diagnostic performance of elastography.
In conclusion, elastography, with its high specificity, can improve the performance of sonography for the diagnosis of enlarged metastatic cervical lymph nodes. The combined evaluation of elastography and B-mode sonography offers the strongest diagnostic power, and we recommend it in clinical practice.
Acknowledgments
We thank professors Megu Ohtaki and Keiko Otani, from the Department of
Environmetrics and Bio-Medical Informatics, Research Institute for Radiation
Biology and Medicine, for their contribution in statistical analysis.
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), and combined evaluation (
). Area
under the curve for combined evaluation (0.970) is higher than that for B-mode
sonography (0.901) or elastography (0.873).