22 Lymph Nodes
Leopoldo Rubaltelli, Alberto Tregnaghi, and Roberto Stramare
L. Rubaltelli, MD; A. Tregnaghi, MD; R. Stramare, MD Department of Medical Diagnostic Sciences and Special Ther- apies, University of Padua, Via Giustiniani 2, 35128 Padua, Italy
The latest acquisition in this field consists in the capability of studying lymph node perfusion in real time by means of microbubble-based contrast agents in combination with gray-scale tissue harmonic imaging techniques. Consequently, it is possible to assess lymph node vascularity in greater detail than Doppler US techniques and with a degree of defi- nition that is comparable with high-resolution US probes.
22.2
Conventional Baseline US
High frequency (10–13 MHz) and high-resolution transducers still represent the fundamental basis for the evaluation of the superficial lymph nodes.
Normal, or reactive, lymph nodes appear as oval or fusiform shapes with a hyperechoic central part, defined as the hilus, surrounded by the hypoechoic and homogeneous cortex. The echogenic hilus is, in reality, the representation of the lymph node medulla where numerous interfaces produced by the blood vessels, lymphatic sinuses and fatty tissue are present (Marchal et al. 1985; Perin et al. 1987;
Rubaltelli et al. 1990; Vassallo et al. 1993; Ahuja and Ying 2002, 2003; Ying and Ahuja 2003).
The morphological and structural parameters useful for distinguishing between benign and malig- nant lymph nodes are: the dimensions, the shape, the presence or absence of the echogenic hilus, the thick- ness and structure of cortex (Vassallo et al. 1992).
The absence of the echogenic hilus and the round shape (longitudinal to transverse ratio <2) are the most characteristic signs of metastatic lymph nodes (Vassallo et al. 1992; Ahuja and Ying 2003), and they were found in, respectively, 88.1% and 87.1% of the metastatic lymph nodes investigated during a recent study on cervical lymph nodes (Ahuja and Ying 2002).
These parameters are employed only in superficial lymph nodes, whereas the study of abdominal lymph
CONTENTS22.1 Introduction 315
22.2 Conventional Baseline US 315 22.3 Color and Power Doppler US 316
22.4 Computed Tomography and Magnetic Resonance Imaging 316
22.5 Contrast-Enhanced Color Doppler 317 22.6 Evaluation of Lymph Node Perfusion 317 22.6.1 Qualitative Study 317
22.6.2 Quantitative Study 321
22.7 Sentinel Lymph Node – Lymphosonography 321 22.8 Conclusions 321
References 322
22.1
Introduction
The role of imaging to evaluate lymphadenopathies is of fundamental importance. The presence or absence of lymph node metastases directly influ- ences not only the prognosis of oncologic patients, but also the appropriate therapeutic approach. Simi- larly, the characterization of enlarged lymph nodes in patients without a previous history of neoplastic disease is of primary importance.
Baseline ultrasound (US) is commonly employed to assess lymph nodes in the superficial anatomical regions (cervical, axillary, and inguinal) and the role of high-resolution US is well established (Marchal et al. 1985; Rubaltelli et al. 1990; Vassallo et al.
1992, 1993; Adibelli et al. 1998; Ahuja and Ying
2002, 2003). Besides the information supplied by
gray-scale US, nowadays additional data on lymph
node vascularity may be provided by color and power
Doppler US, which is even more sensitive (Ahuja et
al. 2001; Giovagnorio et al. 1997, 2002; Yang and
Metreweli 1998; Ying et al. 2000, 2001).
nodes requires US transducers with both lower fre- quency and resolution. Moreover, the obesity and meteorism represent still further limitations, and when the visualization of abdominal lymph nodes is possible, baseline US is generally limited to the dimensional evaluation without any possibility to assess lymph node structural parameters.
22.3
Color and Power Doppler US
At color or power Doppler US, normal lymph nodes reveal hilar vascularization since the principal vessels are found in the hilus while no peripheral vessels are identified at the boundary of the cap- sule (Steinkamp et al. 1998; Tschammler et al.
1998; Ahuja et al. 2001; Ahuja and Ying 2002).
The smallest lymph nodes, with a maximum trans- verse diameter of less than 5 mm, can be apparently avascular at color or power Doppler US (Ying et al.
2001). This aspect is more frequently identified in cervical rather than in axillary or inguinal lymph nodes, especially in the posterior triangle (Ying et al. 2000), and the avascular appearance is highly frequent in the elderly. Among cervical lymph nodes the greatest extent of vascularization is found in the sub-mandibular region (Ying et al. 2000, 2001), and it may be related to inflammation of the upper respiratory tract which, although asymptomatic, is nevertheless able to activate regional lymph nodes.
Metastatic lymph nodes tend to have either periph- eral vascularization along the boundary of the cap- sule with the presence of numerous vascular poles, or a mixed, peripheral, and hilar vascularization (Giovagnorio et al. 1997; Na et al. 1997; Steinkamp et al. 1998; Tschammler et al. 1998). This frame- work of peripheral vascularization is determined by the fact that the neoplastic cells arrive at the lymph node from the lymphatic afferents, perforate the capsule on its convexity, and colonize the outer part to invade the inner part of the lymph node reaching the medulla and hilus.
The presence of hypertrophic vessels, branch- ing away from the hilus and associated to periph- eral vessels, is frequently observed in lymphomas (Giovagnorio et al. 1997). However, peripheral vessels are less frequently observed then in metas- tases, since lymphoma originate in the context of lymph node cortex and later invade the central part, while the lymph node periphery may remain normal (Giovagnorio et al. 2002).
The vascular pattern at color Doppler US of lymph nodes in lymphomas may appear similar to inflammatory lymph nodes (Adibelli et al. 1998), especially in low-grade lymphomas.
However, the most significant finding to differen- tiate benign from malignant lymph nodes is the evi- dence of peripheral vascularization, which should always induce one to perform some further diag- nostic investigations. Lastly, it should be underlined that lymph nodes which appear avascular at color Doppler US, but are morphologically altered at gray- scale US, can be metastatic with extensive areas of necrosis and obliteration of the newly-formed ves- sels.
The complete absence of visible vessels at color Doppler US has also been reported in tubercular lymphadenopathies in relation to necrosis and fibro- sis. The dislocation of intranodal vessels, reported both in metastases (Steinkamp et al. 1998) and in tuberculosis (Ahuja and Ying 2003), is not consid- ered a frequent aspect.
The resistivity (RI) and pulsatility indices (PI), calculated from the Doppler interrogation of lymph node arterial vessels, are lower in reactive lymph nodes than in metastatic lymph nodes (Choi et al.
1995; Na et al. 1997; Ho et al. 2000), although there is no consensus on the optimal cut-off to obtain an accurate differentiation (Adibelli et al. 1998).
Furthermore, if one considers the differential diag- nosis between benign and malignant lymph nodes (metastases and lymphomas), the role of RI and PI becomes even less significant since lymphomas tend to have lower RI and PI than metastases (Ferrari et al. 1997; Adibelli et al. 1998).
22.4
Computed Tomography and Magnetic Resonance Imaging
The panoramic aspect and high spatial resolution of computed tomography (CT) and magnetic reso- nance (MR) imaging guarantee notable sensitivity in the recognition of even small and deep lymph nodes.
However, such sensitivity is not accompanied by an equally high specificity since CT and MR imaging of lymph node pathology are substantially related to dimensional parameters, with variable limits of measurement in the various anatomical districts, and to recognition of areas of necrosis.
The aim of intravenously administered contrast
agents, iodinated for CT and paramagnetic for MR
imaging, is to differentiate lymph nodes from other structures (vessels, intestinal loops) and to iden- tify intranodal areas of altered vascularity. Notable improvement is expected from the employment of superparamagnetic contrast agents, composed by extremely minute corpuscular elements, capable of passing through the pulmonary circle and eventu- ally phagocytized by the lymph node cells of the reticuloendothelial system (Bellin et al. 2000;
Weimann et al. 2003).
To date, the performed studies indicate the util- ity of these contrast agents for MR imaging (Mack et al. 2002; Sigal et al. 2002), but precise evaluation of their diagnostic efficacy will only be possible in the future.
22.5
Contrast-Enhanced Color Doppler
Intravenously administered air-filled microbub- ble-based contrast agents were initially utilized to increase intranodal vascular signals at Doppler US and some studies have reported that this technique has improved diagnostic accuracy in the evalua- tion of cervical lymph nodes (Maurer et al. 1997;
Willam et al. 1998; Moritz et al. 2000). After microbubble-based agent injection, cervical lymph nodes in patients with metastatic squamous carci- noma revealed nodal vessels not identified before microbubble injection, with improvement in the assessment of vascular pattern both in benign and malignant lymph nodes (Maurer et al. 1997). The improved visualization of Doppler signals in lymph nodes after microbubble injection, was particularly significant in reactive lymph nodes. This is because baseline color Doppler US represents as avascular those lymph nodes which reveal hilar vasculariza- tion at contrast-enhanced US, which is considered a benignancy finding (Maurer et al. 1997; Willam et al. 1998).
In a more recent study, including 94 cervical lymph nodes in 39 patients with oral cavity carci- noma assessed by color Doppler US after air-filled microbubble injection, high sensitivity (100%) and specificity (98%) in differentiating benign from malignant lymph nodes were observed (Moritz et al. 2000). Such results, although brilliant, are somehow difficult to reproduce due to limitations of contrast-enhanced color Doppler US, particularly evident in lymph nodes close to pulsating structures such as the arterial vessels. Moreover, the resolution
of contrast-enhanced color Doppler US is too low to identify small intranodal lesions, even though some vascular signals are found in approximately 90% of lymph nodes having a maximum transverse diam- eter >5 mm (Yang and Metreweli 1998).
At the current state of the art, the employment of microbubble-based contrast agents to amplify Doppler signals has to be considered obsolete since microbubble-based agents are not able to improve the intrinsic limits of color and power Doppler and only information regarding lymph nodes macrovas- cularization is provided. Dedicated US contrast-spe- cific techniques are necessary to assess lymph node perfusion after microbubble injection.
22.6
Evaluation of Lymph Node Perfusion
22.6.1
Qualitative Study
The most recent contribution to advancement in US imaging lies in the possibility of evaluating lymph node perfusion by means of gray-scale harmonic imaging after intravenous administration of per- fluorocarbon or sulfur hexafluoride-filled micro- bubbles. The application of contrast-enhanced US in structures of small dimensions, and with relatively low rates of flow such as lymph nodes, is recent.
Actually, nowadays only some US equipment pro- vides good results in this field, due to the low sensi- tivity of the high frequency linear-array transducers to microbubble harmonic signals.
22.6.1.1
Methodology of scanning
After perfluorocarbon or sulfur hexafluoride-filled contrast agent injection (Solbiati et al. 2002), ded- icated contrast-specific modes selectively register the signal emitted by the microbubbles and thereby eliminate all the redundant signals. Initially, clini- cal applications utilized a 7.5-MHz linear trans- ducer equipped with continuous harmonic imaging advanced technology.
The low acoustic power (mechanical index: 0.05–
0.2) insonation produces microbubble oscillation at
maximum intensity, but without the risk of being
destroyed. A 4.8-ml dose of the contrast agent is
bolus-injected into a peripheral vein, followed by a
10-ml injection of physiological saline solution. This
technique makes it possible to achieve high resolu- tion both in the arterial (15–30 s after injection) and late-parenchymal phase (40–90 s after injection), and to identify diffuse or partial alterations of the lymph node perfusion, also in the case of lymph nodes having a maximum diameter <1 cm.
22.6.1.2
Enhancement Patterns
The experience gained in our department with this technique has led to interesting, although still pre- liminary, results. Different contrast enhancement patterns (Fig. 22.1) were identified in lymph nodes.
Reactive lymph nodes give rise to diffuse intense and homogeneous contrast enhancement (Figs. 22.2 and 22.3) due to the intense vascularization with a rich cortical capillary circulation (Gadre et al. 1994).
Nodal metastases are generally less vascularized than the adjacent normal lymph node parenchyma, and they appear as perfusion defects inside the lymph nodes after microbubble injection (Figs. 22.1 and 22.4). In metastatic lymph nodes, the presence of completely avascular areas of necrosis (Castelijns and van den Brekel 2002) is frequently observed, and contrast enhancement may be very low or totally absent due to the confluence of wide areas of necrosis extending also to the entire node. It should be under- lined that the presence of necrosis, which is consid-
ered a specific sign of metastasis under investigation with CT and MR imaging (Castelijns and van den Brekel 2002), may be the result of a phlogistic pro- cess, such as in tubercular nodes and lymphadenitis.
Contrast-enhancement patterns after microbub- ble-based agent injection in lymphomas present a more variable appearance (Fig. 22.1), which is par- tially similar to the patterns of reactive and metastatic lymph nodes. Lymphomas often present diffuse and heterogeneous contrast enhancement with a dotted appearance at arterial phase (Fig. 22.5). However, lymphomas may reveal a diffuse contrast enhance- ment pattern after microbubble injection, especially in low-grade malignity lymphomas, similarly to reac- tive or inflammatory lymph nodes. Dotted contrast enhancement at arterial phase was observed only in lymphomas, and it is probably related to the presence of hypertrophic arterial vessels larger than those present in the other forms of lymphadenopathies which appear punctiform throughout the paren- chyma (Rubaltelli et al. 2004).
22.6.1.3
Personal Experience
The study of lymph node perfusion after microbub- ble-based agent injection was performed in 56 histo- logically analyzed lymph nodes. The assessment of lymph node appearance after microbubble injection,
Fig. 22.1a–c. The different contrast enhancement patterns in lymph nodes after microbubble injection. a Normal or reac- tive lymph nodes. In normal or reactive lymph nodes con- trast enhancement appears low at arterial phase and diffusely homogeneous at late (parenchymal) phase. b Metastases.
At arterial phase contrast enhancement appears low. At late (parenchymal) phase metastases are characterized by het- erogeneous contrast enhancement due to perfusion defects from tumoral infi ltration and necrosis. c Lymphomas. In lymphomas different contrast enhancement patterns may be observed. At arterial phase contrast enhancement may appear dotted, related to the presence of tumoral vessels arising from neoangiogenesis, or diffuse as in reactive lymph nodes. At late (parenchymal) phase contrast enhancement appear diffusely heterogeneous
a
c b
Fig. 22.2a–c. Reactive lymph node. a Baseline US of reactive lymph node (arrows) of the neck with oval shape, regular margins and homogeneous hypoechoic structure. b Contrast specifi c mode (Contrast Tuned Imaging; Esaote, Genoa, Italy) before injection of contrast agent. c After injection of sulfur hexafl uoride-fi lled microbubbles, the node, in the late (paren- chymal) phase, shows diffuse contrast enhancement
a b
c
Fig. 22.3a,b. Reactive lymph node. a Baseline US shows round lymph node (arrows) without echogenic hilus. b Contrast- enhanced US shows diffuse and homogeneous contrast enhancement in the late (parenchymal) phase
a b
correctly modified nine (16%) diagnoses firstly pro- posed on baseline US and power Doppler US, whereas in three lymph nodes the diagnostic conclusion was incorrect. Only one lymph node, correctly assessed as neoplastic (non-HD lymphoma) after baseline US, was incorrectly classified as benign following micro- bubble injection (Rubaltelli et al. 2004).
In conclusion, these results show that contrast-
enhanced US provides highly accurate differentiation
between benign and malignant lymph nodes. Fur-
thermore, after detection of a perfusion defect also in
lymph nodes of smaller than 1 cm, contrast-enhanced
US may be considered a means to indicate the most
opportune site for fine-needle sampling.
Fig. 22.4a,b. Metastasis. a Baseline US before injection of contrast agent shows oval-shaped lymph node with regular margins and homogeneous structure. b Contrast-enhanced US shows diffuse contrast enhancement in the normal parenchyma and a central hypoechoic perfusion defect (arrows) due to intranodal metastasis in late (parenchymal) phase. [Reproduced with permission from Rubaltelli et al. (2004)
a b
Fig. 22.5a–c. Lymphoma. a Baseline US before injection of contrast agent shows voluminous neck node (arrows). b Contrast-enhanced US in the arterial phase shows numer- ous small echogenic spots of dotted appearance due to small vessels in the neoplastic tissue. c Parenchymal phase shows intense and diffuse contrast enhancement of the lymph node (arrows). [Reproduced with permission from Rubaltelli et al. (2004)
a b
c
22.6.2
Quantitative Study
The video sequences obtained after microbubble- based contrast agent injection and stored in digital format can be analyzed off-site by means of pro- prietary softwares, enabling objective evaluation of the quantitative parameters of perfusion. Images are processed automatically, and the video intensity of the signal is analyzed in every pixel to generate chromatic parametric maps of the various perfusion parameters such as the highest echo-signal intensity value reached in each pixel, the time to reach 50%
of the highest echo-signal intensity value, the differ- ence between the maximum and minimum value of echo-signal intensity and the slope of signal inten- sity increase. Such parametric maps permit imme- diate evaluation of the perfusion properties of the entire lymph node, according to the shape or size of the region of interest selected by the operator. The same procedure may be employed to compare the perfusion characteristics of the area of the lymph node to the other reference areas, such as the sur- rounding tissues or the large vessels.
Dedicated equipment and softwares may graphi- cally represent the relation between the echo-signal video-intensity with time. These qualitative studies are still experimental in the case of lymph nodes, even though it is also possible to obtain quantitative objective data to differentiate areas of normal tissue from perfusion defects (Fig. 22.6).
22.7
Sentinel Lymph Node – Lymphosonography
The identification and intraoperative biopsy of the sentinel lymph node is utilized in surgery for mam- mary carcinoma and cutaneous melanoma. Loca- tion is commonly achieved by lymphoscintigraphy, by means of an interstitial perilesional injection of 99-m Tc human albumin nanocolloids.
Recently, the use of contrast-enhanced US has been proposed after interstitial (subcutaneous or submucosal) injection of microbubble-based con- trast agents to identify the sentinel lymph node (Tornes et al. 2002; Goldberg et al. 2004), and this technique is named lymphosonography. It is pos- sible to trace the lymphatic channels from the injec- tion site up to the draining sentinel lymph node(s) by lymphosonography. These studies have provided encouraging results, but such techniques are still experimental and currently only applied on animals.
The advantage of lymphosonography over lympho- scintigraphy is the possibility to identify intranodal metastases (Goldberg et al. 2004).
Similar methodology has been proposed to obtain indirect US lymphography, which showed homoge- neous contrast enhancement in normal lymph nodes after microbubble-based agent injection and the pres- ence of perfusion defects or heterogeneous enhance- ment in metastatic lymph nodes (Kono et al. 2002).
22.8
Conclusions
High-resolution US and color/power Doppler US are commonly utilized for the study of superficial lymph nodes. The evaluation of morphology, echo structure, and vascularity of lymph nodes, together with the clinical and laboratory data, enables the selection of those cases to be examined either by US-guided fine- needle aspiration or by surgical biopsy.
The most recent harmonic imaging techniques combined with intravenous administration of a microbubble-based contrast agent can supply fur- ther useful information in cases where doubt has arisen with conventional techniques. The possibility to obtain data in relation to lymph node microvas- cularity represents a further step, even though the results are still preliminary and necessitate further confirmation over a wider range of cases.
Contrast-enhanced US was showed to differ- entiate benign from neoplastic lymph nodes to a
Fig. 22.6. Quantitative evaluation of perfusion in a metastaticlymph node. The maximum intensity of the signal in each pixel after microbubble-based contrast agent injection is rep- resented by the map with a color scale from dark red (maxi- mum contrast enhancement) to dark blue (absence of contrast enhancement). In this case, the map reveals the presence of a widespread perfusion defect
high degree of accuracy in comparison to baseline US, and revealed capabilities to identify perfusion defects also in lymph nodes <1 cm. In addition to the diagnostic significance, contrast-enhanced US may guide US-guided fine-needle aspiration to the most suitable lymph node portion for cytology.
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