Nuclear Oncology, 1 Ed.

CHAPTER 27

ASSESSMENT OF LYMPH NODES IN ONCOLOGY

Ansje S. Fortuin • Thomas C. Kwee • Sandip Basu • Drew A. Torigian • Babak Saboury • Willem M. Deserno • Jelle O. Barentsz • Abass Alavi

INTRODUCTION

Humans have around 450 lymph nodes.1 Knowledge about lymph node involvement in cancer is of great importance for cancer staging, treatment planning, and determination of prognosis. Lymph node excision, followed by histopathologic examination, is regarded as the gold standard for the assessment of lymph nodes.2 However, surgical removal of lymph nodes is a costly and invasive procedure with associated potential complications.35 Another limitation of surgical lymph node mapping in general is that only lymph nodes inside the surgical area are assessed and therefore, there is no information about lymph nodes outside this field.

Imaging modalities, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and lymphoscintigraphy, provide a noninvasive approach to evaluate lymph nodes in the entire body. These procedures may reduce the number of invasive procedures needed for lymph node assessment or modify surgical lymph node assessment.6

BASIC ANATOMY OF NORMAL LYMPH NODES

Lymph Circulation

High hydrostatic pressures in arterial capillaries force proteinaceous fluid into the interstitium. Lymph is derived from this interstitial fluid and originates in the interstitial spaces of most tissues. A vast system of converging lymphatic vessels, containing one-way valves, funnels lymph to the thorax. In the thorax it is returned to the venous circulation via the thoracic and right lymphatic ducts (Fig. 27.1). At sites where lymphatic vessels converge, lymph flows through lymph nodes. Lymph nodes are ovoid, round, or bean-shaped nodular formations composed of dense accumulations of lymphoid tissue. They vary in size from 2 to 20 mm, average 15 mm in longitudinal diameter, and contain large numbers of lymphocytes, macrophages, and antigen-presenting cells.1,2,6,7

Global Organization of Normal Lymph Nodes

The lymphoid lobule is the basic anatomical and functional unit of the lymph node. The smallest lymph nodes may contain only a few lobules or even just one, whereas large lymph nodes may contain a great number.1 Lobules are anchored in the hilum by their vascular roots but are otherwise separated from the capsule by the subcapsular sinus. The apex forms part of the nodal cortex (i.e., superficial cortex, which mainly contains B-cells that are arranged as follicles) and paracortex (i.e., deep cortex, which mainly contains T-cells), and the base forms part of the nodal medulla (Figs. 27.2 and 27.3).1,2,6,7

Lymphatics and Blood Supply of Normal Lymph Nodes

Afferent lymphatic vessels deliver a constant stream of lymph to the subcapsular sinus over each lobule. Lymph spreads through the subcapsular sinus over the lobule’s apex, flows down the sides of the lobule through transverse sinuses, and then flows into the medullary sinuses (Fig. 27.4). Lymph from all lobules drains into efferent lymphatic vessels that exit the node at the hilum (Fig. 27.4). The blood supply enters the lymph node by one or more arterioles at the hilum, where they branch to the capsule, and then further divide into the medulla, dividing further into capillary networks in the cortex and paracortex. Note that single arterioles reach the capsule through trabecular structures at many sites and anastomose with branches coming from the hilum. Capillaries empty into high endothelial venules that condense repeatedly in the interfollicular cortex and in the periphery of the deep cortical unit (DCU). Then they change into medullary venules at the corticomedullary junction. Merging medullary venules return centripetally to the hilar vein (Figs. 27.2 and 27.3).1,2,6,7 Although it has been reported that superficial (inguinal) lymph nodes are generally supplied by a single artery that penetrates the hilum, deep (mesenteric) lymph nodes are invariably supplied by several separate arteries that penetrate the capsule, enter the trabeculae, and run centripetally.8The lymphatic and vascular systems communicate at certain points in the lymph node. First, part of the lymph fluid enters the conduit system inside the lymphoid compartment and leaves the lymph via the blood circulation at the high endothelial venules, which are also the main site of entry of lymphocytes to the lymph node.1,2,6,7 Second, blood could possibly enter into the lymph sinuses through the lymphatic venous communications between the veins and sinuses in the node.9

LYMPH NODE METASTASIS

Arrival and Spread of Tumor in the Lymph Node

Tumors generally lack a lymphatic network.10 Therefore communication of tumor cells with lymphatic channels occurs only at the tumor periphery and not within the tumor mass. In addition, tumor cells do not have to penetrate a basement membrane to enter the lymphatic system, as lymphatic vessels lack basement membranes.11 Most tumor cells reach the (sentinel) lymph node in the afferent lymph as emboli, in the form of either single cells or clumps. Within 10 to 60 minutes after initial arrest in the subcapsular sinus of the lymph node, a significant fraction of the tumor cells detach and enter efferent lymphatic vessels. These tumor cells eventually end up in the regional or systemic venous drainage because of the existence of numerous lymphaticovenous communications.12 Malignant cells first lodge in the subcapsular sinus and the cortex of the lymph node near the afferent lymphatic vessel, where neoplastic tumor growth usually starts. Subsequently, the metastatic tumor gradually spreads from peripheral sinuses to the medulla, replaces the entire lymph node, and extends into adjacent extra nodal tissue.13,14 As the lymph node is replaced by tumor, the afferent lymph will be directed into collateral vessels to fresh nodes. With increasing lymphatic obstruction, the lymph flow may be reversed (Figs. 27.5 and 27.6), with retrograde spread of tumor to distant and sometimes anomalous locations.12 Detection of lymph node metastasis with modern functional imaging techniques further increases our knowledge about distribution of lymph node metastasis in primary and recurrent diseases.1517

Role of Neoangiogenesis

It is still unclear whether the growth of metastatic tumor deposits in lymph nodes is dependent on neoangiogenesis. It has been reported that additional blood vessels may not be essential for the growth of metastatic tumor because of the rich vascularity of the lymph node. Furthermore, early in the process of lymph node metastasis, the tumor cells occupy and grow within lymph sinuses where there is no restraint on availability of nutrients. After leaving the sinuses, the rich vascularity of the lymph node can provide the required nutrients for tumor growth.18 Other researchers have speculated, however, that the degree of angiogenesis-dependent and independent growth of lymph node metastases may be determined by their growth pattern.19

FIGURE 27.1. Schematic drawing of deep lymph nodes and vessels of the thorax and abdomen, including the thoracic and right lymphatic ducts. Afferent vessels are represented by continuous lines, and efferent and internodular vessels by dotted lines.

FIGURE 27.2. Lymphoid lobule: The simplest possible lymph node containing a single lymphoid lobule is depicted in this illustration. The lobule has a bulbous apex and a base of slender medullary cords. It projects into and fills the lumen of a dilated lymphatic sac and is anchored by its blood vessels in the hilum. The lumen of the encapsulated lymphatic sac is divided into a system of sinuses that surround the lobule. Lymph from the afferent lymphatic vessel spreads over the lobule’s apical surface in the subcapsular sinus, moves down its sides through lateral transverse sinuses, and then flows through medullary sinuses surrounding the medullary cords and exits via the efferent lymphatic vessel in the hilum. The sinuses are spanned by a delicate reticular meshwork, indicated here by a lacy background texturing. The lobule contains a denser reticular meshwork, shown here by a darker, more condensed background texturing. The reticular meshwork provides a three-dimensional scaffold with spaces for lymphocytes, antigen-presenting cells, and macrophages to interact. B-lymphocytes home to follicles in the superficial cortex where they interact with follicular dendritic cells. Three follicles are depicted by small spheres. Follicles are surrounded and separated by interfollicular cortex. In the paracortex (deep cortex), T-lymphocytes home to the deep cortical unit (DCU), depicted here as a large sphere, where they interact with dendritic cells. The DCU has a center and a periphery. The peripheral DCU and the interfollicular cortex are transit corridors that convey arterioles, high endothelial venules, and paracortical sinuses. These structures are suspended in the reticular meshwork and can be seen more clearly in Figure 27.3 where the meshwork has been omitted. The follicles and central DCU do not contain these structures and their capillary beds ( purple ) and reticular meshwork are less dense than in the transit corridors. (From Willard-Mack CL. Normal structure, function, and histology of lymph nodes. Toxicol Pathol.2006;34(5):409–424; copyright © 2006; reprinted with permission of SAGE Publications.)

FIGURE 27.3. Lymph node: An idealized midsagittal section of a small lymph node containing three lymphoid lobules. Each lobule is centered under its own afferent lymphatic vessel. Taken together, the follicles and interfollicular cortex of these lobules constitute the superficial cortex of the lymph node, their deep cortical units (DCUs) constitute the paracortex (deep cortex), and their medullary cords and medullary sinuses constitute the medulla. Left lobule: Arterioles (red ) and venules (blue) are conveyed in the medullary cords. Arterioles arborize in the paracortical cords of the peripheral DCU and interfollicular cortex and give rise to capillary beds (purple). Capillaries are present in the follicles and central DCU, but are less dense than in the other areas. They are omitted from the medullary cords for clarity. Capillaries empty into high endothelial venules, which condense repeatedly in the interfollicular cortex and peripheral DCU and then transition to medullary venules at the corticomedullary junction. Center lobule: This lobule, with the reticular meshwork superimposed on the vasculature, is shown in Figure 27.2. Note the paracortical sinuses. The center lobule is separated from the left lobule by a transverse sinus. Right lobule: A micrograph from a rat mesenteric lymph node shows a lobule as it appears in histologic section. Densely packed basophilic lymphocytes fill the lobular reticular meshwork. Five cortical follicles give the superficial cortex a lumpy appearance. Small empty paracortical sinuses are visible in the peripheral DCU. The medullary sinuses contain macrophages, lymphocytes, and erythrocytes. (From Willard-Mack CL. Normal structure, function, and histology of lymph nodes. Toxicol Pathol. 2006;34(5):409–424; copyright © 2006; reprinted with permission of SAGE Publications.)

FIGURE 27.4. The hilum of three different nodes on thin-slab maximum intensity projections (MIPs) over 2 mm of a three-dimensional T1W MR image (180-μm isotropic resolution). Solid white arrows:Afferent lymphatic vessels. Open white arrows: Efferent lymph vessels. Thin black arrow: B-cell follicle. A: An area of low signal intensity (black arrow ) is visible in the lymph node capsule. This corresponds to a B-cell follicle at pathologic examination. B and C: The MIP is oriented in such a way as to depict all efferent vessels and as many afferent vessels as possible. Not all afferent vessels can be seen in one view. (Reprinted with permission from Korteweg MA, Zwanenburg JJ, van Diest PJ, et al. Characterization of ex vivo healthy human axillary lymph nodes with high resolution 7 Tesla MRI. Eur Radiol. 2011;21(2):310–317; Springer Science + Business Media.)

FIGURE 27.5. Schematic drawings showing blood supply and lymphatics of lymph nodes in normal (healthy) and different pathologic situations, and problems that may arise when using radiotracers/contrast agents that reach the lymph nodes through the interstitium. An example of a normal (healthy) situation with two sentinel lymph nodes, second echelon nodes, arterial and venous blood flow to and from the lymph nodes, interstitium and flow of lymph from the interstitium to the sentinel lymph nodes and second echelon nodes (A). The same situation as in (A), but with cancer cells in the tissue. There are no lymph node metastases, and flow of blood and lymph to the lymph nodes is not impeded (B). The same situation as in (B), but with metastatic cancer cells in the corresponding sentinel lymph node (C). Although the metastatic cancer cells occupy a part of this sentinel lymph node, lymph flow to this node is not impeded. In addition, blood flow to this node is not impaired either. The same situation as in (C), but with progressive sentinel lymph node metastasis (D). The sentinel lymph node is entirely replaced by tumor cells, as a result of which flow of lymph to this node is obstructed and reversed to the next (sentinel) lymph node. Radiotracers and contrast agents that reach the lymph nodes through the interstitium will fail to depict this metastatic sentinel lymph node. On the other hand, vascular supply of this metastatic sentinel lymph node is not impeded, as a result of which systemically administered compounds can still reach and depict this involved node. (Reprinted with permission from Kwee TC, Basu S, Torigian DA, et al. Defining the role of modern imaging techniques in assessing lymph nodes for metastasis in cancer: Evolving contribution of PET in this setting. Eur J Nucl Med Mol Imaging.2011;38(7):1353–1366; Springer Science + Business Media.)

FIGURE 27.6. Conventional planar lymphoscintigraphy and SPECT/CT lymphoscintigraphy in a 71-year-old patient with penile carcinoma with palpable left groin lymph nodes and clinically negative right groin lymph nodes. Early (A) and delayed (B) conventional anterior scintigraphic images 2 hours after peritumoral injection of 99mTc-nanocolloid show no lymphatic drainage to the left groin. Two-dimensional axial (C) and three-dimensional volume-rendered (D) fused SPECT/CT images obtained immediately after conventional images show that this blockage is caused by enlarged lymph node in left groin (solid arrows). Two sentinel nodes with uptake of radioactivity are seen in right groin (dashed arrows). (Reprinted with permission from Leijte JA, van der Ploeg IM, Valdés Olmos RA, et al. Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J Nucl Med. 2009;50:364–367.)

CONVENTIONAL IMAGING

In routine practice, size measurements using conventional MRI and CT are still the most frequently used methods to differentiate malignant from nonmalignant lymph nodes. Lymph nodes with a short-axis diameter larger than 10 mm are generally considered to be malignant (although variable cutoff values have been suggested for different anatomic areas). Imaging with size criteria is limited because lymph nodes can enlarge as a result of benign inflammatory or infectious processes, and normal-sized lymph nodes may contain (micro-) metastasis. In prostate cancer, for example, it has been reported that up to 70% of lymph node metastases can be found in normal-sized lymph nodes.17,20 Consequently, conventional MRI and CT with size measurements achieve poor sensitivity and specificity for the detection of lymph node metastasis (Table 27.1).2125 Adding morphologic criteria to MRI evaluation might improve discrimination of lymph node metastases but their value may be limited, especially in smaller nodes.26

TABLE 27.1

META-ANALYSIS OF POOLED SENSITIVITY AND POOLED SPECIFICITY IN STAGING PELVIC LYMPH NODES IN PATIENTS WITH PROSTATE CANCER

There is also a role for US in conventional lymph node imaging. With US, both the size of a node can be determined as well as additional morphologic characteristics (such as round shape, irregular border, loss of fatty hilum) and (hypo) echogenicity can be taken into account.27 However, these characteristics also lack sufficient accuracy to differentiate malignant from benign nodes and, therefore, fine needle aspiration cytology (FNAC) is frequently employed to improve sensitivity and specificity. In the head and neck, US combined with FNAC results in values of 63% to 97% and 69% to 100%, respectively.2830 A major limitation of US is that it has limited utility for the evaluation of deep lymph nodes and lymph nodes located behind bone or gas-containing structures. US can be helpful, however, for targeted image-guided FNAC of a (US accessible) lymph node that has been identified with another imaging modality.

FUNCTIONAL IMAGING

Sentinel Lymph Node Mapping

The rationale for sentinel lymph node mapping and biopsy is that the sentinel lymph nodes accurately reflect the status of the lymphatic basin draining a primary tumor.6 This assumption has been proven for malignant melanoma,31early-stage breast cancer,32 and penile carcinoma.33 Sentinel lymph node mapping is usually performed with radiocolloids (e.g., 99mTc-sulfur colloid, 99mTc-antimony trisulfide colloid, or 99mTc-nanocolloid) and vital blue dyes. After injection the radioactive particles and vital blue dye become efficiently trapped in sentinel lymph nodes. Subsequently, the sentinel lymph nodes can be identified by preoperative lymphoscintigraphy, an intraoperative γ-detecting probe, and/or by the intraoperative visualization of blue-stained lymph nodes.34 Patients with a positive sentinel lymph node biopsy may benefit from early regional lymph node dissection, whereas patients without metastasis in the sentinel lymph node are spared such dissection.6 Although this method may reduce the number of unnecessary regional lymph node dissections in patients with melanoma, early-stage breast cancer, and penile carcinoma, it is still an invasive and costly procedure with associated complications.4,5,35,36 Another drawback is the fact that only lymph nodes in the vicinity of the primary tumor are assessed.6 Furthermore, the false-negative rate of this procedure (i.e., the fraction of patients with metastatic lymph nodes that are missed by the procedure and become evident later on when the metastatic lymph nodes become clinically detectable) is not negligible.6 In a study that prospectively included 1,313 consecutive patients with melanoma who had a median follow-up of 4.5 years, the false-negative rate of sentinel lymph node mapping and biopsy was reported to be 14.4%.37 In yet another study including 323 patients with penile carcinoma who had a median follow-up of 17.9 months, the false-negative rate was 7%.38 There are several explanations for the false-negative results of sentinel lymph node mapping and biopsy. First, tumor cells may only be present in afferent lymph node vessels at the time of the sentinel lymph node biopsy. Second, tumor cells may simply bypass the sentinel lymph node and travel to and lodge in the next lymph node. Third, increasing tumor growth in the sentinel lymph node may obstruct its afferent lymphatic vessels.6,12 Consequently, the flow of lymph containing the injected radiotracers and blue dyes may be diverted to neighboring unaffected lymph nodes (Figs. 27.5 and 27.6).12,3941 In this respect, clinically suspicious nodes should be removed even if there are minimal radioactive counts or no blue staining.34 It may also be of value to perform preoperative US-guided FNAC.38

Diffusion-Weighted MRI

Diffusion-weighted MRI (DW-MRI) provides information on a molecular level. It allows noninvasive visualization and quantification of the random (brownian) motion of water molecules.42 Its extra cranial oncologic applications have recently become subject of active investigation.6 Lymph nodes have a relatively long T2 relaxation time43,44 and an impeded diffusivity caused by their high cellularity.2 Therefore, lymph nodes can generally easily be identified as high signal intensity structures at DW-MRI, irrespective of their histologic composition. Furthermore, assessment of signal intensity at DW-MRI or quantification of diffusivity in lymph nodes by means of apparent diffusion coefficient (ADC) measurements may aid in the histologic characterization of lymph nodes, because different pathologic processes may lead to differences in diffusivity because of differences in cellularity, intracellular architecture, necrosis, and perfusion (Fig. 27.7).42 Several studies, for example, in patients with head and neck, lung, esophageal, colorectal, cervical and uterine, and prostate cancers,4552 found a significant difference in ADCs between metastatic and nonmetastatic lymph nodes, independent of size criteria. In all but one study,48 ADCs of metastatic lymph nodes were significantly lower than those of nonmetastatic lymph nodes. This is because malignant tissue generally exhibits hypercellularity, increased nucleus-to-cytoplasm ratios, and an increased amount of macromolecular proteins,2 resulting in decreased diffusivity in the extra- and intracellular compartments.42 On the other hand, there are other studies that report ADCs of metastatic and nonmetastatic lymph nodes that were not significantly different, for example, in cervical and uterine cancer.53,54 This may be because of different cell density of different tumors. The sensitivities and specificities from the studies with reported significant differences varied between 69% and 94% and 56% and 100% respectively (Table 27.2).4552 Another issue is the reproducibility of ADC measurements of lymph nodes. Normal-sized lymph nodes may be less reliably assessed because of the combination of image distortions (especially adjacent to air-containing organs), insufficient spatial resolution, and partial volume effects.55 It can be argued that the use of improved echo planar imaging technology, dedicated coils, and dedicated sequence optimization may improve spatial resolution and reduce susceptibility and motion artifacts, such that the reliability and reproducibility of ADC measurements may improve.6 Another important issue is that although tissue diffusivity may differ between metastatic and nonmetastatic lymph nodes, there is a considerable overlap.4554 The ADC threshold is therefore influencing the considerable variation of sensitivity and specificity reported (Table 27.2). Various nonmalignant conditions such as ischemia and inflammation also reduce ADC, potentially resulting in false positives. In addition, false-negative ADC measurements may occur in case of a low intranodal metastatic volume, because this is less likely to form sufficient tissue boundaries to impede water molecule diffusion.6Therefore, the clinical utility of ADC measurements in the assessment of lymph nodes is still questionable.

Ultrasmall Superparamagnetic Iron Oxide–Enhanced MRI

Ultrasmall superparamagnetic iron oxide (USPIO)–enhanced MRI was introduced in the beginning of the 1990s as a new method for nodal staging, independent of size criteria.56 After intravenous administration, USPIO particles reach lymph nodes by two pathways. The first pathway is via direct transcapillary passage through the high endothelial venules within individual lymph nodes. The second pathway is via nonselective endothelial transcytosis across permeable capillaries throughout the body into the interstitium. USPIO particles are subsequently taken up from the interstitium by afferent lymphatic vessels and transported to regional lymph nodes. Macrophages within both normal and hyperplastic lymph nodes phagocytize mainly the USPIO particles that arrive by this second pathway. The intracellular iron particles cause changes in magnetic properties.57 The result is that benign lymph nodes will lose signal on T1-weighted gradient echo, T2-weighted, and T2*-weighted images.57,58 On the other hand, metastatic deposits in lymph nodes do not change signal intensity since they fail to take up the USPIO particles (Figs. 27.8 and 27.9). Failure of metastatic lymph nodes to take up USPIO particles can be explained by obstruction of afferent lymphatic vessels (Fig. 27.5), replacement and displacement of intranodal macrophages by metastatic tumor deposits that do not phagocytize the contrast agent (Fig. 27.8), and tumor-induced changes in lymph node physiology causing macrophages to fail to phagocytize the contrast agent.57 A noniron sensitive sequence is useful to identify the fatty hilum of a lymph node and therefore to discriminate the hilar fat from nodal metastases. This sequence is useful also for initial anatomic localization and node detection (Fig. 27.9). Optimal uptake in the lymph nodes is reached after 24 to 36 hours.59 A meta-analysis of 34 studies investigated the diagnostic performance of USPIO-enhanced MRI for nodal staging in various tumors, and reported that overall (node-by-node base) sensitivity and specificity of USPIO-enhanced MRI (90% and 96%, respectively) were higher than those of unenhanced MRI (39% and 90%, respectively) (Table 27.3).60

FIGURE 27.7. Diffusion-weighted MRI (DW-MRI) in a 67-year-old female with grade I follicular lymphoma and cervical lymph node involvement. Coronal T1-weighted (A), T2-weighted short-inversion time inversion recovery (B), DW-MRI (acquired using a b-value of 1,000 s/mm2(C), and apparent diffusion coefficient (ADC) map (created using b-values of 0 and 1,000 s/mm2(D) show an enlarged cervical lymph node (arrows). A region of interest (ROI) was placed in the lymph node on the DW-MRI in (C) and copied and pasted onto the corresponding ADC map. The ADC of the lymph node was relatively low ([0.62 ± 0.21] × 103 mm2/s), which may suggest lymphomatous involvement. The size of the lymph node decreased after chemotherapy. (Reprinted with permission from Kwee TC, Basu S, Torigian DA, et al. Defining the role of modern imaging techniques in assessing lymph nodes for metastasis in cancer: Evolving contribution of PET in this setting. Eur J Nucl Med Mol Imaging; Springer Science + Business Media. 2011;38(7):1353–1366.)

TABLE 27.2

CHARACTERISTICS AND REPORTED SENSITIVITY AND SPECIFICITY IN DIFFUSION-WEIGHTED MRI

FIGURE 27.8. Uptake scheme for ultrasmall superparamagnetic iron oxide (USPIO) particles. USPIO particles are intravenously injected. They are transported to the interstitial space and via lymph vessels into the lymph nodes. There is accumulation of USPIO particles in macrophages in normal nodal tissue but not in metastases. Therefore, normal nodal tissue will have a low signal intensity 24 to 36 hours after contrast injection, whereas metastases will have unchanged or slightly higher signal intensity. Thus normal and metastatic nodes can be differentiated. (Reprinted with permission from Deserno W.M.L.L.G, Harisinghani MG, Taupitz M, et al. Urinary bladder cancer: preoperative nodal Staging with ferumoxtran-10-enhanced MR imaging. Radiology. 2004; 233:449–456.)

TABLE 27.3

META-ANALYSIS OF POOLED SENSITIVITY AND SPECIFICITY FOR ULTRASMALL SUPERPARAMAGNETIC IRON OXIDE (USPIO)-ENHANCED MRIa

FIGURE 27.9. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI in a 62-year-old patient with prostate cancer and pelvic lymph node metastases. The MRI examination was performed because of rising prostate-specific antigen levels after prostatectomy. Coronal T1-weighted (A), T2*-weighted (B), and diffusion-weighted (acquired using a b-value of 600 s/mm2(C) images of the pelvis 24 hours after the administration of USPIO particles show that several right-sided metastatic lymph nodes appear “white” (i.e., hypersignal intensity) (solid arrows) whereas a left-sided nonmetastatic lymph node appears “black” (i.e., hyposignal intensity) (dashed arrows). Note that diffusion-weighted imaging suppresses vascular structures (C), which may facilitate image interpretation. Reprinted with permission from Kwee TC, Basu S, Torigian DA, et al. Defining the role of modern imaging techniques in assessing lymph nodes for metastasis in cancer: Evolving contribution of PET in this setting. Eur J Nucl Med Mol Imaging; Springer Science + Business Media. 2011;38:1353–1366.)

A notable development in USPIO-enhanced MRI is the addition of postcontrast DW-MRI.61 As mentioned previously, DW-MRI is a very effective method to highlight lymph nodes, irrespective of their histopathologic composition. Furthermore, DW-MRI (acquired using echo planar imaging) is very susceptible to magnetic field in homogeneities that are caused by the USPIO particles. Thus, theoretically, in USPIO-enhanced DW-MRI, only malignant lymph nodes are highlighted; the high metastatic lymph node-to-background contrast will reduce image interpretation time and may increase sensitivity for the detection of small metastatic lymph nodes (Fig. 27.9).6 The feasibility of this new concept has recently been demonstrated in a study involving 28 patients with urinary bladder and prostate cancer.61 In this study, patient-based and pelvis side-based diagnostic accuracies for the detection of lymph node metastasis were comparable between USPIO-enhanced DW-MRI and conventional USPIO-enhanced MRI (both 90%), but interpretation time of the former (median: 13 minutes; range: 5 to 90 minutes) was significantly shorter (p < 0.0001) than that of the latter (median, 80 minutes; range, 45 to 180 minutes).61

Although a potentially useful method for nodal staging, USPIO-enhanced MRI has disadvantages and drawbacks. First, USPIO acts as a negative contrast agent. That is, the absence of contrast agent uptake is used as evidence for neoplastic involvement. The specificity of this method may be suboptimal because the uptake of USPIO particles is also impaired in nonneoplastic disease processes such as reactive hyperplasia.62 A second disadvantage of the current generation of USPIO particles is that they need to be injected 24 hours before scanning, which places an additional burden on the patient and on financial and logistical resources.6 Third, metastatic deposits in lymph nodes may be missed when the applied dose of USPIO particles is too high (i.e., oversaturation).6 Fourth, the iron sensitive sequence has to be compared to a noniron sensitive sequence (or a precontrast sequence). Consequently, image interpretation is complicated and time consuming. Adding DW-MRI, as described above, might reduce this disadvantage.6

USPIO contrast agents have not yet been approved for human use, neither by the Food and Drug Administration (FDA) nor by the European Medicines Agency (EMA).

PET and PET/CT

Important advantages of PET are its high tumor-to-background contrast. The combination of PET with anatomical imaging, in particular CT, allows precise localization of foci with increased PET radiotracer uptake and provides information on structural lymph node abnormalities, thereby increasing the diagnostic yield of PET alone. Another important issue is that PET radiotracer, which is systemically administered, arrives in the lymph node through its arterial blood supply. Therefore, lymphatic obstruction and the subsequent reversal of lymph flow will not affect the performance of PET in diagnosing metastatic lymph nodes (in contrast to sentinel lymph node mapping [Fig. 27.5]).

The glucose analog 18F-fluoro-2-deoxy-D-glucose (FDG) is currently the most frequently used PET radiotracer in clinical practice.6 The rationale for the use of FDG for PET imaging in oncology is that the vast majority of malignant cancer phenotypes exhibit an increased glucose metabolism (i.e., the Warburg effect).63 18FDG-PET plays a pivotal role in the evaluation of many malignancies.63,64 Overall, diagnostic performance of 18FDG-PET in nodal staging is suboptimal. 18FDG-PET is reported to have a pooled sensitivity of 79% (and a pooled specificity of 86%) in patients with head and neck squamous cell carcinoma.65 Furthermore, in patients with a clinically negative neck, pooled sensitivity and specificity were only 50% and 87%, respectively. Further meta-analysis investigated the diagnostic performance of 18FDG-PET in assessing axillary lymph node status in breast cancer66 and in detecting para-aortic lymph node metastasis in patients with cervical cancer.67 18FDG-PET cannot yet reliably replace surgical biopsy of the axillary lymph nodes in patients with breast cancer. 18FDG-PET performs acceptably only in populations with a relatively high probability of para-aortic lymph node metastasis in the case of cervical cancer. In another meta-analysis in patients with nonsmall cell lung cancer (NSCLC),68 it was reported that the presence or absence of lymph node enlargement at CT influenced the diagnostic performance of 18FDG-PET in mediastinal lymph node staging. 18FDG-PET is more likely to yield both true-negative and false-negative findings in patients without lymph node enlargement because of its limitations in detecting small hypermetabolic lesions of any origin (note that current commercially available PET systems have a spatial resolution of about 4 to 7 mm for whole-body imaging). However, in patients with enlarged lymph nodes, 18FDG-PET is more likely to reveal both true-positive findings that are caused by metastasis and false-positive findings that are caused by hyperplasia, infection, inflammation, or granulomatous disease.68,69

FIGURE 27.10. CT, early FDG-PET imaging (60 minutes after radiotracer injection), and delayed FDG-PET imaging (3 hours after radiotracer injection) in a patient with lung adenocarcinoma and mediastinal lymph node metastasis (lymph node 7) in the subcarinal area. CT images (A) show a nodule in the right lung (arrows) without any significant mediastinal lymph node enlargement. Early FDG-PET imaging (B) shows strong accumulation in the lung nodule (solid arrow ) but only faint accumulation in lymph node 7 (dashed arrow ). Delayed FDG-PET imaging (C) shows increased uptake in both the lung nodule (early standardized uptake value [SUV] of 6.85, delayed SUV of 10.01) (solid arrow ) and in lymph node 7 (early SUV of 3.49, delayed SUV of 5.08) (dashed arrow ), while background SUVs decrease. (Reprinted with permission from Uesaka D, Demura Y, Ishizaki T, et al. Evaluation of dual-time-point 18F-FDG PET for staging in patients with lung cancer. J Nucl Med. 2008;49(10):1606–1612.)

Future advances in PET technology that provide a higher signal-to-noise ratio and a higher spatial resolution are likely to increase the diagnostic performance of FDG-PET in nodal staging. Additional improvements in the diagnostic yield of 18FDG-PET for nodal staging may be achieved with delayed PET imaging (i.e., 3 or 4 hours after 18FDG administration). The rationale for delayed imaging is based on the fact that several tumors exhibit a maximum 18FDG uptake well beyond 60 minutes after 18FDG administration whereas surrounding normal tissues and benign pathologies show a decline in 18FDG uptake with time.7073 This phenomenon occurs because malignant cells have substantially enhanced glucose transporters on their surface and express high levels of hexokinase and low levels of glucose-6-phosphatase, which leads to an accumulation of 18FDG in these cells. By contrast, inflammatory cells have higher levels of glucose-6-phosphatase than malignant cells, and therefore a lower ratio of hexokinase to glucose-6-phosphatase. Consequently, 18FDG-6-phosphate is rapidly dephosphorylated and cleared from the cell, leading to decreasing concentration of this metabolic product over time.7073 Therefore, malignant lymph node-to-background contrast can considerably be increased at delayed PET imaging (Fig. 27.10).7073 Figure 27.11 shows the summarized time activity curves of SUVmax in malignant lesions and in normal organs of three patients with nonsmall cell lung cancer who had undergone FDG-PET at several time points, beginning at 5 minutes and extending up to 8 hours after 18FDG administration.6 These figures well demonstrate that the highest malignant lesion-to-background contrast, and, consequently, the potentially highest diagnostic yield can be achieved when performing PET imaging at approximately 3 or 4 hours after 18FDG administration rather than at 60 minutes as is the case with most studies.6 Several studies (e.g., in lung, esophageal, and cervical cancer7480) have shown that delayed or dual-time-point 18FDG-PET imaging may be beneficial for lymph node staging compared to early, single-time-point 18FDG-PET imaging alone (i.e., 50 to 60 minutes after 18FDG administration). However, other studies (e.g., in lung and nasopharyngeal cancer8183) did not show any advantage of this method.6 These discrepant findings may be explained by heterogeneity in the expression of glucose transporters, hexokinase, and glucose-6-phosphatase in different cancers. More research is warranted to elucidate in which cancers delayed or dual-time-point 18FDG-PET imaging is beneficial for nodal staging.6

The limitations of 18FDG-PET are apparent in slow-growing tumors such as prostate carcinomas because of their lack of an increased glucose metabolism. Many primary prostate cancers show either relatively low 18FDG uptake84or no visible uptake. Furthermore, 18FDG is less useful in the pelvic area as 18FDG accumulates in the bladder and thus obscures parailiac and pelvic structures. An alternative PET radiotracer is 11C-choline. Tumor cells are characterized by their ability to actively incorporate choline to produce phosphatidylcholine (a membrane constituent) to facilitate tumor cell duplication. 11C-choline is incorporated into tumor cells by conversion into 11C-phosphorylcholine, which is trapped inside the cell. Upregulation of the enzyme choline kinase and the rapid biosynthesis of cell membranes in tumor cells lead to increased uptake of choline and upregulation of the enzyme choline kinase. Several authors compared 11C-choline to 18FDG for diagnosis and staging of prostate carcinoma lymph node metastases. Whereas FDG accumulates in the bladder, 11C-choline has minimal urinary excretion and activity in the bladder. These advantages underlie reports on 11C-choline PET/CT (choline PET/CT) as accurate and sensitive in preoperative staging of pelvic lymph nodes.8587 As 11C-choline has a rapid clearance from the blood pool and rapid uptake in prostate cancer tissue (primary tumor and metastases), optimal tumor-to-background contrast is reached within 5 to 7 minutes. Just like FDG-PET, 11C-choline PET is also limited in spatial resolution. A recent study underlined this limitation in comparison to better spatial resolution (and therefore better detection of small lymph node metastases) in USPIO MRI.17

FIGURE 27.11. Summarized time activity curves of SUVmax in malignant lesions (A) and normal organs (B) of three patients with nonsmall cell lung cancer who had undergone FDG-PET at several time points, beginning at 5 minutes and extending up to 8 hours after FDG administration. These figures well demonstrate that the highest ratio of SUVmax of malignant lesions to that of normal organs can potentially be achieved when performing PET imaging at approximately 3 or 4 hours after FDG administration rather than at 60 minutes as is the case with most studies. (Reprinted with permission from Basu S, Kung J, Houseni M, et al. Temporal profile of fluorodeoxyglucose uptake in malignant lesions and normal organs over extended time periods in patients with lung carcinoma: Implications for its utilization in assessing malignant lesions. Q J Nucl Med Mol Imaging, Edizioni Minerva Medica.2009;53(1):9–19.)

An important limitation of 11C-choline is that it is limited to PET centers that have onsite cyclotrons because of its short half-life (approximately 20 minutes). This drawback prompted the development of 18F-flurocholine, a radiotracer with a half-life of 110 minutes, to image prostate cancer and associated lymph node involvement.88 18F-flurocholine can be produced commercially and is potentially readily available in clinical PET centers. It provides higher resolution images as a result of its shorter positron length path. 18F-flurocholine, like FDG, has greater urinary excretion than 11C-choline, but routinely performed dynamic pelvic acquisition overcomes this drawback as pathologic uptake begins 1-minute post injection, before urinary excretion and bladder filling. It is likely that 18F-flurocholine PET/CT will even be more useful as an accurate and noninvasive staging tool, at least in selected groups of patients with high suspicion of metastatic lymph node disease.

Other PET radiotracers have been tested for evaluating lymph node metastases. The PET radiotracer 3′-deoxy-3′-(18F) fluorothymidine (18F-FLT) can image tumor cell proliferation and it may provide biologic tumor information in enlarged lymph nodes. However, in recent literature, the value of 18F-FLT PET is limited to determining the lymph node status, for example, in head and neck squamous cell carcinoma or rectal carcinoma.89,90

CONCLUSION

Lymph node status in patients with cancer has important implications with regard to treatment planning and prognosis. Knowledge about the dissemination of lymph node metastasis is increasing and may improve both diagnostic and therapeutic strategies. Excision followed by histopathologic examination is still the gold standard for the assessment of lymph nodes, but this is invasive, costly, and only provides information about lymph node status in the surgical area. There is, therefore, an important role for noninvasive imaging techniques in lymph node staging.

Conventional imaging techniques that are frequently used in routine clinical practice for lymph node assessment include CT, MRI, and US. However, these conventional imaging techniques rely on size criteria, which is insensitive and nonspecific. To overcome this disadvantage, functional imaging techniques, which go beyond structural assessment and allow in vivo visualization and quantification of physiologic and biochemical processes, have been developed. There are a multitude of functional imaging techniques that can be used for lymph node metastasis assessment. Sentinel lymph node mapping and biopsy, DW-MRI, USPIO-enhanced MRI, and PET (most frequently with FDG) are functional imaging techniques that are currently in or approaching clinical use.

Sentinel lymph node mapping with biopsy has shown its value in determining the status of the lymphatic basin drainage in malignant melanoma, early-stage breast cancer, and penile carcinoma. However, it is an invasive and costly procedure and its false-negative rate is nonnegligible.

DW-MRI can be regarded as a useful technique for lymph node detection and, to some extent, lymph node characterization. On the other hand diffusivity of metastatic and nonmetastatic lymph nodes may overlap and diffusion measurement of normal-sized lymph nodes may be prone to error.

USPIO-enhanced MRI is a negative contrast agent targeting nonmetastatic lymph nodes. It has shown to be valuable to discriminate metastatic from nonmetastatic lymph nodes, but still has to be proved by the FDA and EMA for clinical use.

PET, with radiotracers such as FDG, directly targets metabolic processes in (tumor) cells, but its drawbacks include lack of specificity (particularly FDG), and limited signal-to-noise ratio and spatial resolution.

In conclusion, the advantage of functional imaging techniques is that they do not use size criteria in the evaluation of lymph nodes. Although each of these functional imaging techniques has its limitations, their clinical role in lymph node imaging is increasing.

FUTURE CONSIDERATIONS

Conventional structural imaging is not expected to enhance its role in lymph node imaging because it uses insensitive and nonspecific size criteria. MRI and PET, however, have tremendous potential to assess multiple different physiologic and biochemical processes in lymph nodes in the entire body. The future for lymph node assessment in patients with malignant tumors lies in the further development of functional imaging techniques.

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