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1
Department of Pediatric Radiology, University Hospital of Giessen, Abteilung
Kinderradiologie, Justus-Liebig-Universität
Giessen, Feulgenstra. 12, 35392 Giessen, Germany.
2
Department of Oral and Maxillofacial Surgery, University Hospital of
Göttingen, Robert Koch Stra. 40, 37075
Göttingen, Germany.
3
Charité, Campus Virchow Hospital,
Strahlenklinik und Poliklinik, Augustenburger Platz 1, 13353 Berlin,
Germany.
Received July 27, 1999;
accepted after revision October 21, 1999.
Address correspondence to J. D. Moritz.
Abstract
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SUBJECTS AND METHODS. Ninety-four enlarged lymph nodes in 39 adult patients (32 men and seven women; age range, 30-81 years) were examined with B-mode sonography and with unenhanced and contrast-enhanced color Doppler sonography. All patients had carcinoma of the oral cavity. Histologically, lymphadenitis was found in 57 nodes and metastases in 37 nodes. Geometric dimension, texture, and margin of the node and detection and location of vessels were noted. Histology and imaging findings were correlated.
RESULTS. The transverse-to-longitudinal diameter ratio in combination with texture and margin analysis resulted in a correct diagnosis in only approximately 79% of the nodes. With contrast-enhanced color Doppler sonography, 86% of nodes showed vessels, and 28% of nodes showed vessels with this technique exclusively. Characteristic configurations were identified: hilar vessels with branching indicated lymphadenitis (sensitivity, 98%; specificity, 100%), and predominantly peripheral vessels indicated metastases (100%, 98%). These findings changed the diagnosis in 13 nodes, changed the therapy in four patients, and led to an incorrect diagnosis in one patient.
CONCLUSION. Enlarged lymph nodes can be characterized as metastatic or inflammatory with high diagnostic accuracy on the basis of their vascular architecture as seen on contrast-enhanced color Doppler sonography.
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Recently, a contrast medium for sonography has become available that enhances the signal in perfused vessels but does not leave the vascular space. It has been found to be of value in the detection of central nervous system tumor vascularization and in the analysis of carotid stenoses [11, 12]. We designed this prospective study to determine the value of contrast-enhanced color Doppler sonography in the differential diagnosis of enlarged lymph nodes in patients with head and neck disorders.
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In the first step, all patients were examined using conventional B-mode sonography. Nodes greater than 5 mm were considered to be enlarged. Echo texture, margin sharpness, and longitudinal-to-transverse nodal dimensions were used as parameters. Nodes having an inhomogeneous echo texture and blurred margins were classified as malignant, and those having a homogeneous texture and a sharp margin were classified as benign. The longitudinal-to-transverse nodal dimension was defined as the ratio between the longest measurable diameter of the node and the length of the perpendicular. A ratio of less than 2 was considered indicative of metastatic enlargement [13]. If two or all of the criteria were classified as malignant, the nodal enlargement was judged to be malignant and vice versa.
In the second step, patients were examined with color Doppler sonography using a 12-MHz multifrequency transducer of a Logiq 500 scanner (General Electric Medical Systems, Milwaukee, WI). The recognition of vessels, their arrangement in the lymph nodes, the detection of supplying vessels, and the spatial relation between lymph nodes and the surrounding vessels were evaluated. Because a full spectral analysis was technically possible in only a few patients, no effort was made to regularly determine the pulsatility and the resistance indexes. The preservation of hilar vessels was interpreted as a sign of inflammatory change, whereas the dominance of peripheral vessels was thought to be indicative of malignancy. A second assumption was made on the basis of the accumulated information of both techniques. If the vascular pattern and at least one B-mode criterion were classified as malignant, the nodal enlargement was judged to be malignant and vice versa. In those nodes in which no vessels could be identified, the criteria of B-mode sonography were used as mentioned earlier.
Finally, color Doppler sonography was performed after IV injection of air microbubbles stabilized by a granulate of galactose and palmitoleic acid (Levovist; Schering, Berlin, Germany), a contrast medium for sonography. Informed consent for the examination was obtained from all patients. A total of 2.5 g (volume of approximately 8 ml, concentration of 300 mg/ml) was administered via the cubital vein as a single bolus in 16 patients (injection duration: approximately 8 sec). In 23 patients with multiple enlarged nodes, a maximum of 4 g with a maximum volume of approximately 12 ml was given in the form of two to three smaller boluses. Evaluated parameters were identical to those in the previous examination. A final assumption was made on the basis of the same method as in unenhanced color Doppler sonography.
The observers were aware of whether contrast material was given. All three assumptions were made without knowledge of the histologic diagnosis. Subsequently, the sonographic diagnoses were tested against histologic findings after surgical removal of the nodes. Moreover, any influence on therapeutic management was noted.
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All but two examined lymph nodes were hypoechogenic in comparison with the surrounding tissue (Table 1). Two metastatic lymph nodes were hyperechogenic. Most of the benign enlarged lymph nodes (51/57) showed a homogeneous pattern, whereas most metastatic nodes were heterogeneous in texture (23/37). A hyperechogenic center or a hyperechogenic hilum was found in only 28% of benign enlarged lymph nodes and in 19% of metastatic lymph nodes. Most benign enlarged lymph nodes were well defined, though eight had hazy borders. In contrast to that, 20 (54%) of 37 lymph node metastases were poorly defined. Seventeen metastases, however, also showed sharp borders. The longitudinal-to-transverse diameter ratio was less than 2 in 40% of inflammatory nodes and greater than 2 in 30% of the metastases. On the basis of these findings, 25 lymph nodes were rated as true-positive for lymph node metastasis, eight as false-positive, 49 as true-negative, and 12 as false-negative. The sensitivity and specificity of B-mode sonography were 68% and 88% for metastases and 88% and 68% for lymphadenitis, respectively.
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Additional information could be gathered by making the vessels visible on unenhanced color Doppler sonography (Table 2). Added information in approximately 50% of examinations led to a change in diagnosis in five nodes initially classified as lymphadenitis and in one node initially classified as metastasis. Metastatic and inflammatory infiltration were eventually histologically confirmed in these nodes. Thus, on the basis of unenhanced color Doppler sonography, 30 lymph nodes were classified as true-positive for lymph node metastasis, seven as false-positive, 50 as true-negative, and seven as false-negative. The sensitivity and specificity of this second assumption were 81% and 88% for metastases and 88% and 81% for lymphadenitis, respectively.
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With contrast-enhanced color Doppler sonography, initial effects could be detected approximately 11 sec after completed bolus administration, with a subsequent effective scanning window of approximately 5 min. In 26 (28%) of 94 lymph nodes, vessels were detected exclusively after contrast administration. An additional 55 nodes showed more vessels than in the unenhanced Doppler sonography examination. Thus, in 81 (26 + 55; 86%) of 94 lymph nodes additional information could be obtained by contrast application. The surrounding vessels could be delineated better in all but one case. Table 2 shows the characteristic distribution of vessels in the lymph nodes. In all metastases with identifiable vessels, the vessels were typically arranged in the periphery of the nodes (Fig. 1A,1B). Hilumlike vessels could be additionally detected in three cases. Nearly all benign nodes in which vessels could be sonographically detected showed hilar vessels branching in the center of larger lymph nodes (Fig. 2A,2B). One enlarged lymph node (maximum diameter, 39.5 mm) with vessels predominantly located in the periphery and rated as malignant was histologically proven to be lymphadenitic. Thus, by the vascular pattern sensitivity and specificity of 100% and 98% could be obtained for metastases and of 98% and 100% for reactively enlarged lymph nodes, respectively.
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The additional information after contrast-enhanced color Doppler sonography (Table 3) altered diagnoses obtained with the first two techniques in six cases of lymphadenitis (initially classified as metastasis; maximum diameters, 10.3-14.8 mm; mean, 12.3 mm) and in seven cases of metastasis (initially classified as lymphadenitis; maximum diameters, 6-11.6 mm; mean, 8.7 mm) (Fig. 3A,3B,3C,3D). On the basis of contrast-enhanced color Doppler sonography, 37 lymph nodes were rated as true-positive for lymph node metastasis, one as false-positive, and 56 as true-negative. No lymph nodes were classified as false-negative. The resulting sensitivity and specificity were 100% and 98% for lymph node metastases and 98% and 100% for reactively enlarged lymph nodes.
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The increase in correct results was tested step by step using the McNemar test for paired dichotomous samples. This increase was significant (p = 0.03) when unenhanced color Doppler sonography was tested against B-mode sonography. The test showed that contrast-enhanced color Doppler sonography was significantly better than unenhanced color Doppler sonography (p = 0.0002). The highest significance level of p < 0.0001 was achieved in a test between contrast-enhanced color Doppler sonography and B-mode sonography.
In three patients, the diagnosis of metastasis based on B-mode sonography and unenhanced color Doppler sonography was changed to lymphadenitis after contrast administration, with a subsequent change of therapy (Table 3). Instead of the initially planned radical neck dissection, a submandibular block resection was performed. In one patient with a metastasis, only after contrast enhancement was the close relationship of the enlarged node to the large cervical vessels fully appreciated. Radiation therapy instead of a surgical excision was initiated.
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Established imaging techniques are significantly better than palpation in differentiating benign from malignant nodal enlargements [1, 2, 21], but their efficacy remains a matter of discussion.
The shape of nodes as determined by the longitudinal-to-transverse diameter ratio has been proposed to yield a specificity and sensitivity of 96% in sonography [22], 94% in MR imaging [23], and 97% in contrast-enhanced CT [24]. In lymph nodes larger than 8 mm, a ratio greater than 2 was suggested to indicate lymphadenitis with a sensitivity of 97% and a specificity of 97%. Metastases were said to show a ratio of less than 2 with a sensitivity of 87% and a specificity of 89% [24]. However, these statements have not been supported by other studies. In our study, only 76% of lymph nodes with a ratio greater than 2 were reactively enlarged, whereas 24% were metastases (sensitivity, 60%; specificity, 70%). Metastases were found in 53% of lymph nodes with a ratio of less than 2; however, reactively enlarged lymph nodes were diagnosed in 47% (sensitivity, 70%; specificity, 60%). Our data agree with a sonography study by van-dan-Brekel et al. [25]. In a histopathologic analysis of 2719 nodes by most of the same researchers, shape was not found to be a valuable criterion [20].
The echogenicity of the node has been said to contribute to the differential diagnosis [26]. However, in our study nearly all examined lymph nodes were hypoechogenic regardless of histology. The texture of the lymph nodes and their delineation against the surrounding tissue as seen on sonography are of limited value. Reactively enlarged lymph nodes do tend to be homogeneous and well defined, whereas metastatic lymph nodes are frequently heterogeneous in echo texture and poorly defined. But in our study as well as in others [2], considerable overlap exists. The infiltration of the surrounding structures is well seen on sonography and CT [27], with direct impact on the therapeutic strategy, but poor echographic delineation of nodes does not correlate with malignant involvement according to our findings and the findings of other authors [2].
The density of nodes as seen on contrast-enhanced CT has been scrutinized for its value in differentiating benign from malignant nodal enlargement. Nodal density was found to correlate with disease-free survival but showed no relationship to N stage and no response to neoadjuvant chemotherapy [28]. Central necroses greater than 3 mm have been found to predict malignant enlargement with a sensitivity and specificity of 74% and 100% [20], respectively, for CT. However, hilar fat, an indicator of benign disease [20], should be difficult to differentiate from central necrosis in some nodes with this technique. In MR imaging, necroses were best depicted on gadopentetate dimeglumine-enhanced T1-weighted gradient-echo images and were also found to be the most specific criterion for lymph node metastasis [29]. However, the value of gadopentetate dimeglumine in the detection of necroses could not be replicated by Yousem et al. [27] with T1-weighted fat-suppressed techniques.
The pulsatility index and the resistance index in Doppler sonography spectral analysis of lymph node vessels have also been evaluated as parameters in the differential diagnosis. Tumor angiogenesis alters the vascular architecture in metastatic lymph nodes. Color Doppler sonography is an established method for the noninvasive documentation and quantification of intravascular blood flow. The pulsatility index and the resistance index in Doppler sonography spectral analysis have been found to be significantly higher in nodes with metastasis than in inflammatory nodes [30], with adequate thresholds resulting in a sensitivity of 53% and a specificity of 97% [31]. However, of all suspicious nodes only 78% showed perfused vessels, and the pulsatility index could be measured in only 65% and the resistance index in 73% [31]. The percentage of enlarged nodes with vessels identifiable on color Doppler sonography was even lower (59%) in our study, and a reliable analysis of the Doppler sonography spectrum was successful in only a small number of cases. In those nodes that can be examined on Doppler sonography spectral analysis, a large overlap between benign and malignant nodal enlargement with regard to the resistance index has been noted in a patient population [10].
IV injection of sonographic contrast media has been shown to improve the Doppler sonography signal in perfused vessels in the neck and intracranial region [11, 12]. The application of the signal enhancer in our study made significantly more and smaller vessels identifiable in most lymph nodes. Thus, a more exact delineation of the vascular architecture became possible. Only in 13 lymph nodes were no vessels detected. A typical pattern of vascular distribution could be derived. Reactively enlarged nodes characteristically showed hilar vessels branching in the center of larger lymph nodes. This distribution has also been found in superficial benign hyperplastic lymph nodes exhibiting flow on unenhanced Doppler sonography of other locations [32]. However, in lymph node metastases, vessels were found predominantly in the periphery, without typical hilar vessels in 35 of 37 cases. In two metastatic nodes no vessels at all could be identified. In one reactively enlarged lymph node the vessels ran predominantly in the periphery, causing a false diagnosis. A similar vascular pattern has been described by Giovagnorio et al. [33]; however, a differentiation between acute inflammation and metastasis was apparently not attempted in that study.
In our study, 13 enlarged lymph nodes were avascular even on
contrast-enhanced color Doppler sonography. Histology revealed metastasis in
two of them and lymphadenitis in 11. Both metastases were small round lymph
nodes (diameter of 
10 mm) of heterogeneous echo texture. Both were found
in the vicinity of larger metastases with predominantly peripheral vessels.
The relatively small reactively enlarged lymph nodes without identifiable
vessels were oval and homogeneous and were detected near reactively enlarged
lymph nodes with typical hilar vessels. Thus, in this small subgroup the
identification of similar lymph nodes with a typical vascular pattern was
helpful.
On the basis of our parameters, the correct diagnosis was achieved in 99% of the lymph nodes with contrast-enhanced color Doppler sonography. Contrast-enhanced imaging changed the diagnosis in 14% of the examined lymph nodes. This change occurred predominantly in smaller nodes with a maximum diameter of approximately 10 mm (range, 6-15 mm). Thus, contrast-enhanced color Doppler sonography seemed to be of special value in lymph nodes of borderline size [20]. These preliminary results in a small number of patients encourage us to conduct a larger study. Such a study is of special importance because some of the results in the literature on this topic have been difficult or impossible to reproduce. Also, as with any technique using contrast media, the additional costs and risks must be weighed against the additional relevant information. The relevance of the additional findings in our study is illustrated by the change in diagnosis and therapy in a substantial number of patients.
Our results are comparable to the accuracy of 89% that van-den-Brekel et al. [25] achieved with sonographically guided aspiration cytology in patients who were not clinically suspected of having lymph node metastases. Obviously, the combination of a good imaging technique with fine-needle biopsy of suspect nodes should be the ultimate in preoperative staging [21]. If a basically noninvasive study such as ours reaches a similar accuracy, a comparative study of both approaches is certainly warranted to determine which of these techniques will prevail for nodal staging of head and neck neoplasms.
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