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Original Research |
1 Department of Medical Diagnostic Sciences and Special Therapies, University of
Padua-Italy, via Giustiniani 2, Padua 35100, Italy.
2 Department of Clinical and Experimental Medicine, University of Padua-Italy,
Padua, Italy.
3 Department of Oncological and Surgical Sciences, University of Padua-Italy,
Padua, Italy.
Received April 24, 2006;
accepted after revision September 12, 2006.
Address corespondence to R. Stramare
(roberto.stramare{at}unipd.it).
Abstract
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SUBJECTS AND METHODS. In 31 patients (age range, 24-86 years; mean age ± SD, 53.6 ± 14.4 years) a single lymph node per patient was evaluated on sonography after the administration of sulfur hexafluoride-filled microbubbles. The stored sonographic images were analyzed and processed into chromatic maps that had numeric values related to the amount of contrast. The lymph node regions in which the increase of signal intensity values with respect to baseline were highest (maximum signal intensity value [SImax]) and lowest (minimum signal intensity value [SImin]) were identified, and the corresponding numeric data were stored. Statistical analyses were performed by means of the Student's t test; a p value of less than 0.05 was considered to be statistically significant.
RESULTS. Histopathologic analysis revealed metastatic lesions in 12 of the 31 lymph nodes; the remaining 19 were benign (16 reactive lymph nodes, two cases of granulomatous lymphadenitis, and one case of tubercular lymphadenitis). Values obtained from the SImax regions showed no consistent difference between benign and malignant lymph nodes; on the other hand, values from the SImin regions comparing baseline and maximal contrast-enhanced values were significantly different in the two groups (p < 0.001). Confidence for characterization of malignancy was significant using the difference between values from SImax and SImin regions, with the higher disgnostic value from 24 to 31 inclusive: sensitivity, 92% (11/12); specificity, 89% (17/19); positive predictive value, 85% (11/13); and accuracy, 90% (28/31).
CONCLUSION. The software being tested proved to be useful in differentiating benign from metastatic lymph nodes on the basis of the quantitative data it provided.
Keywords: automated perfusion measurements • color Doppler sonography • contrast media • lymph nodes • oncologic imaging • software • sonography
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Gray-scale sonography and power Doppler sonography have been commonly used in the assessment of superficial lymph nodes (neck, axilla, and groin). The role of gray-scale sonography is well established [1-4], and color Doppler, power Doppler, and pulsed Doppler sonography can supply additional information about the distribution of intranodal vessels, blood flow velocity, and vascular resistance. In particular, the absence of the echogenic hilus, round shape (longitudinal diameter-to-transverse diameter ratio of < 2), and peripheral capsular vascularization are the signs regarded in the literature as being the characteristic of metastatic lymph nodes [5-12].
Contrast-enhanced sonography has been proposed for the study of lymph nodes with a view to improving the results obtained by means of conventional techniques [13, 14]. However, this technique is also subject to limitations and is particularly criticizable because interpretation of sonographic images depends on an operator whose individual skill and experience inevitably result in a subjective diagnosis.
The aim of this study was to assess experimental software intended to provide automated quantification of sonographic signal intensity properly related to the contrast enhancement of lymph node tissue to differentiate benign from malignant lymph nodes.
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Twenty-six of the 31 patients had been referred for imaging of suspected lymph node metastasis, and the remaining five presented with superficial de novo lymphadenopathy. In the cases of suspected metastasis, the primary tumor was neck squamous cell carcinoma (13 patients), cutaneous melanoma (eight patients), and breast carcinoma (five patients). Of the lymph nodes examined, 17 were cervical; five, axillary; and nine, inguinal. The diameters of the lymph nodes varied from 5 to 40 mm (mean ± SD, 18.8 ± 8 mm) (Table 1).
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Sonographic Technique
All the patients had been previously examined on gray-scale sonography, and
the lymph node that had the most suspect morphologic characteristics on the
basis of its dimensions and longitudinal diameter-to-transverse diameter ratio
was identified [1,
3].
All the lymph nodes being considered were examined by means of an apparatus (EsaTune Ultrasound System, Esaote) that was specifically designed for sonographic examinations with a contrast agent. A contrast agent composed of sulfur hexafluoride-filled microbubbles (SonoVue, Bracco International) was used.
A 7.5-MHz dedicated linear transducer was used in conjunction with new continuous-mode contrast-enhanced harmonic imaging technology. During transmission, low values of mechanical index (i.e., 0.05-0.2) and of acoustic pressure allow the microbubbles to oscillate at maximum intensity without being destroyed. The acoustic pressure was set at 45 kPa in each patient, and the mechanical index was selected automatically by the sonography scanner in relation to beam-focus depth. During reception, the signal emitted by the microbubbles is received in a selective manner, thereby eliminating all signals that are not useful; this technique, developed by Esaote and Bracco in conjunction, is referred to as "Contrast Tuned Imaging technology (CnTI)." This contrast-specific technique uses the transmission of the specific resonance frequency of sulfur hexafluoride-filled microbubbles and the selective registration of harmonic frequencies. This allows a significant reduction of the insonation power with a reduction of the nonlinear harmonic behavior of the stationary tissues.
All patients gave their informed consent for the examination including IV administration of the contrast agent. A 4.8-mL bolus of contrast agent was injected into a peripheral vein and was followed by an injection of 10 mL of physiologic saline solution. Immediately after the injections, the lymph nodes were scanned in CnTI mode with a frame rate of 15 frames/s.
The transducer was placed directly on the patient's skin without interposition of any pad and was kept in a fixed position to highlight all the phases of enhancement of the lymph node being examined. The beam focus was placed at the level of the lymph node being examined or immediately below it, and beam gain was set, in all cases, at the minimum level.
The apparatus in question affords the recording and filing of the images in digital format, and all the dynamic phases of the examinations performed during 25 seconds were saved using this system.
Quantitative Analysis
The digital recordings were sent from the sonography scanner to a PC and
were then processed by means of experimental software (Qontraxt, Amid). This
software is able to analyze the signal intensity of each single pixel of each
frame and thereby to generate chromatic maps that allow immediate evaluation
of the perfusion properties of the entire organ under examination or of
regions of interest (ROIs), irrespective of shape or dimensions, as selected
by the operator (Figs. 1A,
1B,
1C,
1D,
1E,
1F and
2A,
2B,
2C,
2D,
2E,
2F). On the basis of this
analysis, the software enables numeric values to be obtained for each point in
the region under examination as the final result; these values are correlated
to the quantity of contrast medium that reached the sector in question. In
practice, a virtual image is obtained of the lymph node composed of a scale of
primary colors varying from red (maximum signal intensity) to blue (minimum
signal intensity). By moving a cursor over the image, it is possible to
explore the various color zones and obtain, at every point therein, the
numeric value of signal intensity expressed as a percentage (maximum intensity
= 100%).
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Our preliminary experience gained with this technique has shown that the level of enhancement is not uniform over the entire lymph node volume: Generally, the normal hilar region or areas of inflammation tend to give high signal intensity, whereas signal intensity corresponding to fatty infiltration or areas of necrosis is lower. For these reasons, the position and dimensions of the ROIs were chosen on the basis of the chromatic maps obtained. The ROIs were manually drawn, and their shape and dimensions were adapted to delimit the darkest red regions (highest increase of signal intensity) and the darkest blue regions (lowest increase of signal intensity).
Each lymph node was evaluated to determine the following values: the numeric value assigned by the software to the area of maximum signal intensity (Figs. 1A and 2A) (SImax); the numeric value assigned by the software to the area of minimum signal intensity (Figs. 1B and 2B) (SImin); and the difference between those two values. These values were then compared with the characteristics of enhancement in benign and malignant lymph nodes.
Statistical Analysis
Statistical analysis of the data obtained was performed by means of the
Student's t test; a p value of less than 0.05 was considered
to be statistically significant.
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The longitudinal diameter-to-transverse diameter ratio was less than 2 in 67% (8/12) of the malignant lymph nodes and in 47.3% (9/19) of the benign lymph nodes (Table 1).
The numeric values obtained for the area corresponding to maximum increase of signal intensity (SImax) after injection of the contrast medium are reported in Figure 3. In this case, there exists ample overlapping of values between benign and metastatic lymph nodes to such an extent that any possibility of differentiating between the two groups is eliminated.
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Another limitation of sonography, but also of the other imaging techniques, lies in its inability to depict partial metastases—that is, cases in which only part of the node has been replaced by tumor without alteration of the actual morphology of the lymph node, a finding frequently present in clinically N0 tumors of the neck. Detection of these partial lymph node lesions is one of the objectives of all imaging techniques and will be attainable only by an increase in the spatial resolution and contrast of current methods.
In an attempt to overcome these limitations, contrast-enhanced harmonic imaging has been used for the study of superficial lymph nodes [13, 14]. This technique has yielded interesting results that show a significant increase in the differentiation between benign and malignant lymph nodes as compared with conventional techniques [14]. In particular, it has been shown that lymph node metastases are characterized by hypoperfuse areas due to necrosis or to the presence of metastatic tissue that is less vascularized with respect to healthy parenchyma.
The software used in our study expresses values as a percentage of maximum recordable signal intensity. A level of saturation beyond which the signal has the same intensity of color doubtlessly exists. Although this poses a theoretic limit on the system, such values correspond to a very high concentration of contrast agent; therefore, from a practical point of view, this theoretic limit does not affect identification of hypoperfuse areas.
Recently, King et al. [17] reported that in the identification of areas of intranodal necrosis sonography has a specificity equal to that of CT and MRI, although its sensitivity is less. In that study, the researchers compared gray-scale sonography with CT and MRI performed before and after IV injection of contrast medium; it can be stated with certainty that the clinical application of sonographic contrast medium can bring the performance results of sonography still closer to those of CT and MRI, also with regard to sensitivity.
MRI with ultrasmall superparamagnetic iron oxide (USPIO) has been used for the study of both superficial and deep lymph nodes, and the results have shown that MRI with USPIO is effective in revealing even partial metastases in unenlarged lymph nodes [18, 19]. Compared with that technique, contrast-enhanced harmonic imaging is limited in that it affords the study of only superficial lymph nodes with high-resolution transducers; nevertheless, in these cases, contrast-enhanced harmonic imaging allows rapid characterization of lymphadenopathies that had previously been identified on sonography. Moreover, contrast-enhanced harmonic imaging can be indicated for patients with contraindications to MRI.
Nonetheless, contrast-enhanced harmonic imaging does have some important limitations; in particular, the results obtainable with this technique depend on the specific experience of the operator and are therefore bound to subjective evaluation. The possibility of obtaining objective and repeatable data by means of automated computer-assisted processing could at least partially overcome this limitation.
In particular, the presence of a high level of contrast enhancement can be correlated to healthy tissue, whereas values of signal increase of less than 40% were found in the pathologic areas due to neoplastic infiltration or necrosis. Areas of necrosis can be produced, although more rarely, by benign entities, as shown in our series in two cases, one that was due to granulomatous lymphadenitis and the other, to tubercular lymphadenitis.
The high sensitivity of the software used in evaluating the increase in signal intensity after injection of contrast medium also led to the detection of benign lymph nodes with relatively hypoperfuse areas, most likely attributable to physiologic variations or induced by inflammatory phenomena. However, in the inner part of the same lymph node, the hypoperfuse areas presented less difference in enhancement (SImax - SImin) with respect to metastatic lymph nodes; in fact, we found that a numeric cutoff value by the difference between SImax and SImin when ranged from 24 to 31 enabled benign lymph nodes to be characterized from malignant lymph nodes; benign lymph nodes showed values less than or equal to 24 while malignant lymph node values were equal to or superior to 31.
The intrinsic limitations of sonography remain to be considered: namely, incomplete panoramic views; impossibility of evaluating the more deep-seated lymph node groups, such as the retropharyngeal nodes; and difficulty in obtaining real-time evaluation regarding arterial phase enhancement in lymph nodes not included in the same plane or section if not administering further injections of contrast medium. On the other hand, among the advantages of contrast-enhanced harmonic imaging is the possibility of achieving dynamic real-time study of perfusion without artifacts, even in the presence of movement, whether it be respiratory, deglutitory, or pulsate, that limits traditional evaluation with color and power Doppler imaging. To these advantages is also to be added the possibility of obtaining quantitative evaluation that is repeatable and independent from subjective operator-influenced interpretations, this being achieved by means of dedicated software such as that used in the present study.
Our study does have some limitations. First, the perfusion parameters evaluated with contrast-enhanced harmonic imaging can be difficult to compare in many patients because of the high variability of the ultrasound signal with depth and the insonation technique. These limitations can, however, be partially reduced by adopting a standardized technique, especially with regard to beam gain, beam focus, acoustic pressure, and mechanical index settings.
Second, the perfusion characteristics of the lymph nodes examined were correlated with the histologic diagnoses, but no correlation was made between virtual lymph node and histologic section to match areas of major or minor enhancement with areas of different vascularization or with areas of focal necrosis or partial metastasis.
Third, our study has considered a numerically limited series of patients; therefore, the results obtained in our study necessitate further studies that include a larger number of metastases from different tumors and lymphomatous nodes.
In conclusion, notwithstanding some limitations, the results of these preliminary studies are encouraging and indicate the possibility of quantitatively evaluating lymph node perfusion with contrast-enhanced harmonic imaging, thereby obtaining a high level of diagnostic accuracy in differentiating benign from malignant lymph nodes. Moreover, in producing repeatable numeric data and information that are independent from subjective operator-influenced interpretation, the experimental software used may contribute to overcoming one of the most important limitations of sonography.
Acknowledgments
We thank Denis Swift for his much appreciated assistance in the preparation
and translation of this article.
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