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The Role of Contrast Enhanced Ultrasound in the Assessment of Superficial Lymph Nodes
LAURA POANT1, S. POP2, M. COSGAREA2, DANIELA FODOR1 2 Internal Medicine Clinic, 2ENT Department Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
1 nd

Evaluation of superficial lymphadenopathy is important for patients with pathologies like head and neck cancers or breast cancer, as it helps the assessment of patient prognosis and the selection of treatment method. Cervical lymph nodes are also common sites of involvement in lymphoma. Lymphomatous nodes are usually difficult to differentiate from metastatic nodes in clinical examinations. As the treatment for lymphoma and metastases is different, accurate differential diagnosis between the two conditions is important. Ultrasound is a useful imaging modality in evaluation of superficial lymphadenopathy because of its high sensitivity and specificity, especially when combined histopathology. With the use of power Doppler sonography, the vasculature of the lymph nodes can also be evaluated, which provides additional information in the sonographic examination of superficial lymph nodes. But there are still nodes that cannot be examined by Doppler or their vasculature cannot be visualized. So, in the last decade, contrast-enhanced ultrasound was more and more discussed as a non-invasive method for a more accurate differential diagnosis of cervical lymphadenopathy. Key words: contrast enhanced ultrasound, superficial lymph node.

Lymph nodes are involved in a wide number of pathologies, ranging from infectious diseases and benign reactive enlargements to neoplastic diseases. Assessing lymph node characteristics continues to be a challenge even in modern medicine. Imagistic techniques available today have led to a profound revolution in lymphatic imaging (such as ultrasonography [US], magnetic resonance imaging [MRI] and computer tomography [CT]). The detection or the exclusion of lymph node metastasis in patients with various tumor locations (such as breast cancer or head and neck cancer) is of special importance because both the patients prognosis and the therapeutic concept are directly influenced by the nodal status. Conventional B-mode sonography is a wellknown established technique. It has been shown to have a higher sensitivity in the detection of enlarged lymph nodes than palpation [1, 2] and even CT [3]. This is most likely the result of the real-time and multiplanar depiction of the soft-tissue anatomy. For the same reasons, the determination of nodal size is also more accurate with sonography than with CT. Discussion continues, however, whether differentiation of benign and malignant enlarged lymph nodes on morphologic grounds is possible and whether color Doppler sonography is helpful in this context [4]. Malignant tumors exceeding a
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certain size secrete angiogenic factors [5] that stimulate the growth of de novo vessels. These vessels differ from preexisting vessels in that they lack a muscular layer and tend to form shunts, which have been shown on Doppler sonography in a number of different types of cancer. However, in metastatic as well as benign enlarged lymph nodes, a Doppler signal is not always detectable [6]. The preoperative assessment of cervical lymph nodes is important in the management of head and neck tumors. Patient survival correlates with nodal status, and the regional and distal control as well as the ultimate radiation dose depend on the N stage at the time of diagnosis. The decision to proceed to neck dissection is also frequently based on the nodal findings at the end of radiotherapy [7]. The preoperative diagnosis rate of axillary nodal metastases by both conventional ultrasound and subsequent needle sampling was also assesed in many studies [8-10]. Approximately half of nodes with abnormal morphology on US prove to be metastatic at surgery [8]. But, one-third of nodes with normal morphology on US contain, in fact, metastasis. Unnecessary sentinel lymph node biopsies and delayed node dissections in patients with breast cancer may be reduced by improving the preoperative differential diagnosis between benign and malignant [8][11].

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But inflammatory or reactive nodal enlargements can be reliably differentiated from metastatic manifestations? Histopathological data [12] indicate that the cause of enlargement may be inflammation in up to 50% of nodes. These data imply that a redefined nodal staging taking into account only nodes with truly metastatic enlargement could significantly improve the prognostic evaluation and change the therapeutic protocols. Established imaging techniques are significantly better than palpation in differentiating benign from malignant nodal enlargements [3], but their efficacy remains a matter of discussion. The shape of nodes as determined by the longitudinal-totransverse diameter ratio has been proposed to yield a specificity and sensitivity of 96% in sonography, 94% in MR imaging, and 97% in contrast-enhanced CT [1][2]. 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% [12]. However, these statements have not been supported by all the studies. In a histo-pathological analysis of 2719 nodes by most of the same researchers, shape was not found to be a valuable criterion [6]. The echogenicity of the node has been said to contribute to the differential diagnosis. Hypo-echogenity seems to be a good sign of nodal involvement by macro-metastases, along with loss of central hilum, round shape and irregular contour [13]. The texture of the lymph nodes and their delineation against the surrounding tissue as seen on sonography are also of limited value. Reactively enlarged lymph nodes tend to be homogeneous and well defined, whereas metastatic lymph nodes are frequently heterogeneous in echo texture and poorly defined. But the results are still heterogeneous, considerable overlap exists in many studies, and such morphologic characteristics are not sufficient to describe a metastatic lymph node (Fig. 1).

Fig. 1. Gray scale ultrasound of an enlarged lymph node.

Recent studies have shown, as we already said, that Doppler-US can improve the situation [13][14]. Color Doppler sonography is an established method for the noninvasive documentation and quantification of intravascular blood flow. Metastatic nodes tend to show a peripheral vascularrization compared to reactive or benign nodes, in which the distribution of vessel is predominant hilar. The sensibility and specificity range between 85% and 88% respectively [13][15][16].

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. They have been found to be significantly higher in nodes with metastasis than in inflammatory nodes [1], with adequate thresholds resulting in a sensitivity of 53% and a specificity of 97% [2][3]. They also play a major role in tuberculosis enlarged nodes, where the vascular pattern mimics malignant nodes

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[17]. However, not all the nodes can be examined in Doppler sonography and a large overlap between benign and malignant nodal enlargement with regard to the resistance index has been noted in literature [3]. Administration of sonographic contrast agents has been shown to improve the Doppler sonography signal in perfused vessels of enlarged lymph nodes [4]. In the last decade, the use of contrast-enhanced ultrasound sonography (CEUS) gained more and more space in clinical practice, especially in liver lesions; the use of CEUS in description of lymph nodes is infrequent, although its efficacy was well established in differentiating benign from malignant nodes, but here are still few studies on this subject. Ultrasound contrast agents are based on two major concepts: microbubbles with air or gas, and colloid suspensions that increase the resonance of blood and the vascularization visualization [18]. Thus, CEUS shows tissue vascularization similar to that shown on contrast-enhanced CT or MRI. The actual performance of CEUS requires contrastspecific software on the US device. Liver mass characterization is still the most established and successful indication for CEUS [6]. Most of the studies showed the success of CEUS in characterization of liver tumors, as it can differentiate benign from malignant, even in smaller masses [6]. CEUS applications continued to grow for focal pathology in the kidney, pancreas, spleen, breast, ovary,

prostate and lymph nodes [19-21]. The main obstacle in using CEUS is the practice pattern, as CEUS is a dynamic examination that depends highly on the skill of the sonographer, it is time consumer and still not included in most of the protocols for mass diagnosis [6]. The application of the signal enhancer made significantly more and smaller vessels identifiable in most lymph nodes. Thus, a more exact delineation of the vascular architecture became possible. A typical pattern of vascular distribution could be derived. Reactively enlarged nodes characteristically showed hilar vessels in the center of lymph nodes (Fig. 2). This distribution has also been found in superficial benign hyperplastic lymph nodes exhibiting flow on un-enhanced Doppler sonography of various locations [3]. However, in lymph node metastases, vessels were found predominantly in the periphery, without typical hilar vessels. The correct diagnosis was achieved in more than 90% of the lymph nodes with contrast-enhanced color Doppler sonography and seemed to be of special value in lymph nodes of borderline size [7]. Of course, there are some limitations with this procedure, too. Vessel distribution characterization is often satisfactorily exact when the whole node is involved. But if there are focal lesions or necrosis the results are not so good. Patients with lymphoma are to be regarded as a special group, as the vascular pattern of lymph nodes in these patients is more like the pattern in benign/reactive nodes [22].

Fig. 2. CEUS of the same lymph node showing hilar pattern of vasculature.

According to recent (2011) guidelines of EFSUMB, CEUS seems to provide good information about malignant versus benign superficial lymph node enlargement, but only in special clinical settings; so, more studies are needed in the future, in order to find the right place for this modern imaging technique in routine clinical practice [22].

Altogether, CEUS is an imaging technique full of hope for analyzing superficial lymph nodes, it is cost-effective, easy to perform for the patient (can be performed at the bedside), it has no nephrotoxicity and it uses no ionizing radiation; so, the use of CEUS should be encouraged in more clinical applications, including lymph node assessment.

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Evaluarea unei limfadenopatii superficiale este important pentru pacienii cu patologii precum cancerele de cap/gt sau de sn, deoarece ajut la evaluarea prognosticului pacientului i la alegerea metodei de tratament. Ganglionii limfatici cervicali sunt, de asemenea, frecvent implicai n limfoame. Adenopatiile limfomatoase sunt de obicei greu de difereniat de cele metastatice, la examenul clinic. Avnd n vedere c tratamentul pentru limfom i metastazele cu diferite puncte de plecare este diferit, diagnosticul diferenial precis ntre cele dou condiii este crucial. Ecografia este o modalitate de imagistic util n evaluarea unei limfadenopatii superficiale datorit sensibilitii i specificitii sale crescute, n special atunci cnd este combinat cu histopatologia. O dat cu folosirea ecografiei Doppler, vascularizaia ganglionilor limfatici a putut fi, de asemenea, evaluat, oferind informaii suplimentare n cadrul examinrii ecografice a ganglionilor limfatici superficiali. Dar exist i ganglioni ce nu pot fi examinai Doppler sau a cror vascularizaie nu poate fi apreciat. Astfel, n ultimul deceniu, ecografia cu substan de contrast a fost apreciat din ce n ce mai mult ca o metod non-invaziv pentru diagnosticul diferenial mai precis al adenopatiilor superficiale.
Corresponding author: Daniela Fodor, MD, PhD 2nd Internal Medicine Department Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania 2-4 Clinicilor street, 400006 Cluj-Napoca, Romania Email: dfodor@umfcluj.ro Phone: 004 0264591942/442 REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. OMOTO K, MATSUNAGA H, TAKE N, HOZUMI Y, TAKEHARA M, OMOTO Y, SHIOZAWA M, MIZUNUMA H, HARASHIMA H, TANIGUCHI N, KAWANO M. Sentinel node detection method using contrast-enhanced ultrasonography with sonazoid in breast cancer: preliminary clinical study. Ultrasound Med Biol., 2009 Aug; 35(8):1249-56. Epub 2009 Jun 10. MOSTBECK G. Real-time ultrasound (US) and contrast-enhanced US for suspicious axillary lymph nodes in breast cancer - a love and hate relationship? Ultraschall Med. 2010 Feb; 31(1):4-7. Epub 2010 Feb 15. SEVER AR, MILLS P, JONES SE, COX K, WEEKS J, FISH D, JONES PA. Preoperative sentinel node identification with ultrasound, using microbubbles, in patients with breast cancer. Am. J. Roentgenol, 2011 Feb; 196 (2):251-6. YANG WT, GOLDBERG BB. Microbubble Contrast-Enhanced Ultrasound for Sentinel Lymph Node Detection: Ready. Am. J. Roentgenol 2011; 196: 249-250. RUBALTELLI L et al. Contrast-Enhanced Ultrasound for Characterizing Lymph Nodes With Focal Cortical Thickening in Patients With Cutaneous Melanoma. Am. J. Roentgenol2011; 196:W8-W12. WILSON SR, GREENBAUM LD, GOLDBERG BB. Contrast-Enhanced Ultrasound: What Is the Evidence and What Are the Obstacles? Am. J. Roentgenol 2009; 193:5560. FISCHER T, PASCHEN CF, SLOWINSKI T, et al. Differentiation of parotid gland tumors with contrast-enhanced ultrasound. Fortschr Rntgenstr 2010; 182: 155-162. TAYLOR K, OKEEFFE S, BRITTON PD et al. Ultrasound elastography as an adjuvant to conventional ultrasound in the preoperative assessment of axillary lymph nodes in suspected breast cancer: A pilot study. Clinical Radiology 66 (2011) 10641071. GUISEPPETTI G, MARTEGANI A, DI C, et al. Elastosonography in the diagnosis of the nodular breast lesions: a preliminary report. Radiol Med 2005;110: 69-76. National Institute for Health and Clinical Excellence CG80. Early and locally advanced breast cancer, full guideline, http://www.nice.org.uk/guidance/index; 2009. BRITTON P, GOUD A, GODWARD S, et al. Use of ultrasound guided axillary node core biopsy in staging of early breast cancer. Eur J Radiol 2009;19:561-9. ANAYE A, PERRENOUD G, ROGNIN N, et al. Differentiation of Focal Liver Lesions: Usefulness of Parametric Imaging with Contrast-enhanced US. Radiology, 2011 Jul 11. [Epub ahead of print]. LUCIANI A, ITTI E, RAHMOUNI A, et al. Lymph node imaging: basic principles. Eur J Radiol 2006; 58:338-44. MORITZ JD, LUDWIG A, OESTMAN JW. Contrast-enhanced color Doppler sonography for evaluation of enlarged cervical lymph nodes in head and neck tumors. AJR Am J Roentgenol 2000; 174: 1279-84. YANG WT, METREWELI C, LAM PK, CHANG J. Benign and malignant breast masses and axillary nodes: evaluation with echo-enhanced color power Doppler US. Radiology 2001; 220: 795-802.

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