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ESSENTIALS IN ONCOLOGIC IMAGING (DM PANICEK, SECTION EDITOR)
Radiologic Assessment of Lymph Nodes in Oncologic Patients
Yun Mao • Sandeep Hedgire • Mukesh Harisinghani
Published online: 20 December 2013
� Springer Science+Business Media New York 2013
Abstract Status of lymph node metastasis has important
implications in deciding treatment of oncologic patients.
The appropriate choice of imaging modality is crucial to
obtain accurate evaluation of lymph node status. Current
imaging methods are mainly divided into two categories,
conventional structural imaging and more recently
emerging functional imaging. In depth understanding of
these imaging tools is essential in making the correct
choice for individual patients, and eventually for better
diagnosis and treatment.
Keywords Lymph nodes � Cancer � Metastasis �Sonography � Computed tomography � Magnetic resonance
imaging
Introduction
Lymph node (LN) metastasis is an important prognostic
factor for most malignancies. The site and the number of
metastatic LNs directly influence the staging of the tumors,
and consequently affect selection of a treatment plan and
patient’s survival rate. Over-staging often leads to
unnecessary extended surgical interventions, and added
morbidity; under-staging, on the other hand, may lead to
increase in recurrence rate and may shorten the survival
time. Therefore, it is crucial to choose the right imaging
approach for LN evaluation.
An ideal imaging method should be able to clearly
detect and display the site and structural characteristics of
LNs, accurately distinguish the malignant nodes from
benign ones, and be widely available, affordable, easy to
interpret, non-invasive and non-radiative. Unfortunately,
current-imaging modalities mainly rely on anatomical and
morphological assessment, and provide little information
into the functional aspect of LNs. Our decision-making is
still based on the structural criteria shortcomings that have
been extensively studied and published [1, 2, 3••, 4•]. The
purpose of the following review is to focus on the con-
ventional methods such as ultrasound (US), computed
tomography (CT), magnetic resonance imaging (MRI), and
some novel methods like diffusion weighted imaging of
MRI, positron emission tomography (PET) or PET/CT and
MRI and novel MR contrasts with reference to character-
ization of LNs. Merits and demerits of each modality are
discussed, along with recent advances.
Sonography
Gray Scale US
Gray scale US is the most common method for evaluating
superficial LNs. It is economically affordable, widely
available, easy to use and has a good safety profile [5].
High frequency linear array US transducers are typically
used for evaluating superficial LNs, such as those located
in the neck, inguinal region or the axillary fossa. With high
This article is part of the Topical Collection on Essentials in
Oncologic Imaging.
Y. Mao � S. Hedgire (&) � M. Harisinghani
Division of Abdominal Imaging and Intervention, Massachusetts
General Hospital, Harvard Medical School, 55 Fruit St, Boston,
MA 02114, USA
e-mail: [email protected]
Y. Mao
e-mail: [email protected]
M. Harisinghani
e-mail: [email protected]
123
Curr Radiol Rep (2014) 2:36
DOI 10.1007/s40134-013-0036-6
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spatial resolution, high frequency US can evaluate the
nodes for shape, size, echotexture and anatomical demar-
cation of the cortex and medulla in LNs (Table 1). The
absence of a fatty hilum caused by cortical thickening in a
LN is regarded as the most specific predictive factor for
metastasis [6, 7]. Sonography has much higher sensitivity
than high-resolution CT (29 %) [8] in detecting LN hilum
(Fig. 1). Moghaddam et al. [7] reported an echogenic hilum
of cervical LN in 81 % of benign LNs and 55 % of
malignant ones, thus pointing the absence of hilum as a
marker for LN involvement on US. The sensitivity and
specificity were 45 % and 81 %, respectively. On this
basis, Song et al. promoted the significance of the cortex-
hilum (CH) area ratio on gray-scale US imaging in diag-
nosing axillary LN. They recommend that the CH area
ratio ([ 2) of an axillary LN on US be used as a quanti-
tative indicator for the diagnosis of LN metastasis due to its
superior sensitivity of 94.1 % [9]. But it is important to
note that the invisibility of LN hilum can also occur in
chronically inflamed LNs and small benign LNs [10].
Besides hilum, some other specific signs within LNs can be
displayed by US, such as necrosis and microcalcifications
(Fig. 2). Necrosis is often caused by tumor metastasis,
inflammation and treatments. Microcalcifications are con-
sidered as a better predictor of malignant thyroid carci-
noma, with a high specificity of 96.5 % [11–13]. However,
due to the limited penetration, high frequency US cannot
be used for evaluating deeper LNs, such as deeper LNs in
the neck, abdominal, deep pelvic or retroperitoneal areas,
which could only be evaluated by low frequency US with
less detail of the intranodal architectural changes [14].
Moreover, different etiologies of lymphadenopathy can
show identical appearances on sonogram. For example,
inflammatory LNs and metastatic LNs may present as
enlarged, elliptical LNs with necrosis, which makes the
differential diagnosis difficult.
Color Doppler
Color Doppler is useful in distinguishing non-metastatic
nodes from metastatic nodes based on the vascularity of
LNs (Table 1). Abundant vascularity in LN is often linked
with reactive proliferation, lymphoma and metastasis
(Fig. 2), especially if the vessels are derived from outside
the hilum. Imani et al. [7] reported peripheral and mixed
vascular patterns had 100 % specificity in detecting meta-
static cervical LNs. Dangore-Khasbage et al. [15]
explained these signs may be due to new revascularization
from peripheral vessels inducted by the destruction of hilar
vascularity. Additionally, Color Doppler flow imaging
provides quantitative parameters of vascularity in LN, such
as pulsatility index (PI) and arterial resistive index (RI). In
their assessment of cervical LNs by triplex sonography
(gray scale, color mapping and spectral Doppler), Mazaher
et al. stated the mean RI ([ 0.8) and PI were significantly
higher in malignant LNs ([ 1.5) than in benign LNs,
possibly owing to the compression of intranodal vessels by
the tumor cells.
Advances in Sonography
Contrast enhanced US is emerging as a new technique for
nodal characterization. It is more sensitive than grey scale
imaging in displaying subtle intra-nodular necrosis, which
manifests as rim enhancement [16]. Enhanced US offers
additional advantages in guiding US fine needle aspiration
(USFNA) by avoiding the sampling of nodal necrotic areas.
Endoscopic ultrasonogrphy (EUS) is another method in
predicting deep-seated nodes like mediastinal LNs
Table 1 Differential diagnosis of non-metastatic and metastatic
lymph node on sonography and computed tomography
Characteristics Lymph node status
Non-metastatic Metastatic
Distribution Scattered Clustered
Size (short
diameter)
Neck: \ 1.0 or 1.5 cm;
chest: \ 1.0 cm;
abdominal and pelvic:
\ 1.0 or 0.8 cm
Neck: [ 1.0 or 1.5 cm;
chest: [ 1.0 cm;
abdominal and pelvic:
[ 1.0 or 0.8 cm
L/T or L/S
ratio
C 1.5 \ 1.5
Shape Oblong Round
Texture Homogeneous Hetregeneous
Margin Regular Irregular
Capsule
intactness
Capsule intact Extracapsular spread
Border Well-defined Ill-defined
Internal structures
Absence of
hilum
Seldom with Common with
Necrosis Almost without Commonly but not
always
Calcification Coarse Micro
Doppler
Flow pattern Central Peripheral and mixed
RI values B 0.8 [ 0.8
PI values B 1.6 [ 1.6
Enhanced CT
Uniformity of
enhancement
Homogeneous Ring-enhancement
Enhanced
pattern
Moderate Obvious or moderate
L/T or L/S ratio ratio between the longest (L) and transverse (T) or
short (S) diameters, RI arterial resistive index, PI pulsatility index
36 Page 2 of 13 Curr Radiol Rep (2014) 2:36
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metastasis even smaller than 5 mm with an accuracy of
84 %, while the accuracy of CT is only 49 % [17]. It’s also
provides an opportunity for simultaneous US guided FNA.
Computed Tomography
Since the rapid development both in hardware and software
in the last decade, the temporal and spatial resolution of CT
has seen remarkable improvement. CT has now become the
most important and commonly used method for pretreat-
ment evaluation of cancer patients. As a structural imaging
method, the CT diagnostic criteria for metastatic LNs
mainly depends on location and the structural features,
such as size, shape, margin, density and enhancement
patterns (Table 1). Among them, size is still the most
common criterion, though with a wide variable range from
5 to 15 mm. A short axis diameter beyond 1 cm is gener-
ally accepted as a threshold for malignancy in most studies
[18–20] (Fig. 3). However, the diagnostic sensitivity of this
standard is obviously weakened by a high false negative
ratio, according to 21–74 % metastatic LNs with normal
size [21–23] (Fig. 4). For example, Tiguert et al. found the
proportion of metastatic LNs with an axial size less than
1 cm and 5 mm could reach 74 and 26 %, respectively,
in patients with prostate cancer [23]. Fukuya et al. [22]
also detected 28 % metastatic LNs smaller than 9 mm in
gastric cancer. A submillimeter spatial resolution of CT
has significantly improved the capability of detecting
these normal or small size LNs. The reconstructed
three-dimensional (3D) images help in distinguishing
nodes from small vessels (Fig. 3) and describing the
structural details of LNs. According to Yang et al., an
accuracy for determination of LN metastasis was 90 and
71 % in early and advanced gastric cancer, respectively,
with an overall accuracy of 80 % by using 64-multidetector
CT (MDCT) and multi-plane reformation technique [24].
Even more recently, nodular volumetry based on three-
dimensional (3D) reconstructive technique showed prom-
ising results in malignant lymphoma. Puesken et al. found
that accuracies for volumetry in the cervical/inguinal
region were significantly higher compared with long-axis
diameter (LAD) and 3D diameter in malignant lymphoma.
Therefore, adding LN volumetry to single LAD assessment
was recommended for accurate structural categorization of
LNs in malignant lymphoma [25]. Besides the high spatial
resolution, the prominent temporal resolution of MDCT
provides help to detect perigastric and peribowel LNs for
avoiding motion artifacts from respiratory and bowel
peristalsis to a great extent. Although these advanced
techniques have improved the diagnostic ability of MDCT
in LN evaluation to some degree, it is difficult to have high
sensitivity, especially if we rely only on the nonspecific
structural criteria. The diagnostic accuracy of size is
influenced by reactive hyperplasia of LNs (Fig. 5) and
micrometastasis. The former may increase the number of
benign nodes with abnormal diameter or false-positive
results; conversely, the latter may increase the number of
metastatic nodes with normal diameter or false-negative
Fig. 1 Hilum of lymph node
can be demonstrated by multiple
imaging methods. a Gray-scale
ultrasound shows hyperechoic
hilar structure (arrow) in a
benign enlarged cervical lymph
node. b Gray-scale ultrasound
demonstrated a metastatic
cervical lymph node with
absence of hyperechoic hilar
structure in a woman with
thyroid cancer. c On axial CT
scan, hilar structures are often
visualized as fat density
(arrow), as shown in this right
sided enlarged inguinal lymph
node. d The coronal T1
weighted fat saturated image
showing the hilar structures
(arrow) on MRI
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Fig. 3 A 60-year-old man with
a history of prostate carcinoma.
a Venous phase CT image
showing multiple enlarged
aortocaval lymph nodes (arrow)
with ill-defined border, and
heterogeneous enhancement
were seen measuring up to
2.2 9 1.3 cm. b Coronal
reconstructed CT image clearly
displayed the adjacent
relationship between nodes
(arrow) and main vessels. c CT-
guided biopsy was performed
and the largest node was
positive for malignant cells on
pathology
Fig. 2 Sonography can identify the changes of the internal structure
and the vascularity in lymph nodes. a Gray-scale ultrasound displays
a cluster of microcalcifications (arrow) in a lymph node that was
pathologically confirmed as metastasis from thyroid cancer. b Gray-
scale ultrasound can clearly show necrosis (arrow) in a cervical
lymph node. c Color Doppler demonstrated a increasing vascularity in
a metastatic lymph node in this patient with thyroid cancer. d An
inflammatory lymph node showed slightly increased vascularity on
color Doppler. e Ultrasound provides a useful tool to guide biopsy of
superficially located LNs
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results, as mentioned above. Consequently, it is difficult to
choose an appropriate cutoff to balance the sensitivity and
specificity at the same time. If taking C 10 mm as a
positive criterion for axillary LN metastasis, the sensitivity
and specificity are 50 and 75 %, respectively [26]. Peters
et al. adopted a smaller criterion of C 5 mm to evaluate the
presence of paratracheal LN metastasis, showing change in
sensitivity and specificity of CT to 70 and 36 %, respec-
tively. For the variable diagnostic accuracy, CT is more
often used as an anatomical location tool to biopsy (Fig. 3)
and PET in LNs evaluation, rather than a differential
diagnostic tool. In addition, relying on subcutaneous
Fig. 4 A 44-year-old woman with a history of breast cancer and
axillary node metastasis. a The axial T1 weighted image showed
multiple enlarged left axillary lymph nodes, with the largest node
measuring 2.0 9 1.5 cm. b On the axial T2 weighted imaging, the
largest node displayed heterogeneous internal texture. c On enhanced
MRI scan, the nodes showed significant enhancement with a small
necrosis in the largest one (arrow head). d Axial CT scan also
demonstrated the necrosis (arrow head). e On axial T1 weighted
image, another small metastatic node with a short diameter of 4 mm
and well-defined border was noted on the anterior chest wall adjacent
axillary. f On axial T2 weighted image, the small node showed similar
high signal intensity with the largest node. g Enhanced T1 weighted
image also demonstrated a significant enhancement of the small node.
h On enhanced CT scan, the small one showed a moderate
enhancement
Fig. 5 A 53-year-old man with
severe peripheral vascular
disease. a On axial non-
enhanced CT scan, a cluster of
enlarged lymph nodes (arrow
heads) with homogeneous
moderate density was identified
in the pelvis along the left
external iliac and inguinal
regions. b PET image showed
an extensive increased
fluorodeoxyglucose (FDG)
uptake in these nodes (arrows
heads). c On color Doppler
image, a diffusely increased
vascularity was observed in the
nodes. d Ultrasound-guided fine
needle biopsy demonstrated
reactive nodal hyperplasia
Curr Radiol Rep (2014) 2:36 Page 5 of 13 36
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injection of some special contrast, iohexol or iopamidol,
CT can provide locating information for sentinel lymph
nodes (SLNs) and display lymphatic pathways of some
tumors [27, 28]. Last but not least, though the lower
interobserver variation and high reproducibility enable
MDCT for follow-up examinations, ionizing radiation risk
should be considered in vulnerable populations such as
children and young adults [29•, 30].
Magnetic Resonance Imaging
Conventional MRI
Conventional MRI has high repeatability and reliability in
evaluating LNs status; however, it is not better than US and
MDCT in diagnostic accuracy based only on structural size
criteria [31]. In a meta-analysis of pelvic LNs in patients
with prostate cancer, Hovels et al. reported the pooled
sensitivity and specificity of CT and MRI were 42 and
82 %, and 39 and 82 %, respectively. The differences in
performance of CT and MRI were not statistically signifi-
cant [32]. Comparing pelvic MRI and endorectal ultraso-
nography (ERUS) in 34 patients with rectal tumor,
Halefoglu et al. concluded that MRI gave an accuracy of
74.50 % with a sensitivity of 61.6 % and a specificity of
80.88 %, similar to those in ERUS, 76.47, 52.94 and
84.31 %, respectively [33•]. In another meta-analysis study
of cervical LNs in patients with head and neck squamous
cell carcinoma, Wu et al. found the sensitivity, specificity
and positive likelihood ratios of MRI were 76, 86 % and
5.47, respectively, and stated that the comparison of MRI
performance with that of other diagnostic tools (PET, CT,
and US) suggested no major differences between any of
these methods [34]. With high spatial and soft tissue res-
olution based on multiple sequences and parameters, MRI
provides additional structural diagnostic information to
demonstrate nodal relationship with adjacent structures and
intranodal textures, which may benefit the characterization
of the small LNs and differential diagnosis. In uterine
cervical cancer patients, Kim et al. demonstrated the
accuracy, sensitivity and specificity of MRI with a short
axis diameter of 1.0 cm had 93.0, 62.2 and 97.9 %,
respectively [35]. In a study about LN detection of pelvic
malignancies, Saokar et al. reported that MRI detected
more LNs compared to CT in all nodal regions, including
the external iliac, obturator, and internal iliac chains. Based
on size, the numbers of nodes detected by CT and MRI
were equal when nodal size above 10 mm; however, when
size is 1–5 mm, MRI is capable to detect more nodes [36].
In a MRI study of pelvic LNs in cervical carcinoma, Yang
et al. obtained a higher sensitivity and specificity of 70.6
and 89.8 %, respectively, using a size threshold of 1 cm in
long axis diameter or the presence of central necrosis [37].
Moreover, without ionizing radiation, repeated MR scans
can routinely be used for observation of postoperative LN
metastasis and therapeutic effects.
In contrast, a relatively long scanning time makes MRI
more susceptible to motion artifacts from breath or gas-
trointestinal peristalsis [38]. That may limit its use in
evaluating regional LNs of chest and abdominal malig-
nancies. Fortunately, some new emerging techniques have
shown capabilities to improve the quality of MR images in
these regions, through increasing temporal resolution and
reducing the influence of motion artifacts; for instance,
radial gradient echo sequence with K-space weighted
image contrast (KWIC) and periodically rotated overlap-
ping parallel lines with enhanced reconstruction (PRO-
PELLER) sequences [39•, 40, 41].
Diffusion Weighted Imaging
Different from conventional MRI, functional magnetic
resonance imaging (fMRI) may allow a more accurate
evaluation of malignant involvement based on metabolic or
physiological changes in the LNs, aside from the structural
signs mentioned above. As a simple, fast, non-invasive and
non-contrast tool, diffusion weighted imaging (DWI) has
been the most potential representative of fMRI in LNs
mapping in recent years [34, 42, 43]. Some authors
observed that both benign and malignant LNs demonstrated
high signal intensity in pelvic cancers [44, 45], which
formed a strong contrast against the dark background signal
from fat deposited around LNs. Depending on the high
contrast, DWI can provide a greater capacity to detect LNs
and a more simple interpretation for both radiologists and
clinicians [44, 46] (Fig. 6). Moreover, fused with high-
resolution, T2 weighted images can make up for the
weakness of DWI on anatomic details and result in its
increased performance [47]. DWI can reflect the random
(Brownian) motion of water molecules in the microstruc-
ture of LNs, and with the apparent diffusion coefficient
(ADC), it further provides a quantitative evaluation to dif-
ferent physiological status of LNs. In theory, when com-
paring with normal or benign tissue, malignant tissue has a
larger cell size, higher cellularity and nucleus to cytoplasm
ratio, which may limit diffusion movement of water mole-
cules and hence cause a higher signal on DWI with a lower
ADC value [48, 49]. The correlation between cell density
and normalized ADC (r = -0.58; p = 0.023) was studied
by Ginat et al. [50•] for malignant skull lesions. Multiple
studies on nodal DWI demonstrated there is a difference
between benign and malignant nodes on diffusion weighted
images and ADC maps. Lee et al. reported ADC value can
help to differentiate malignant from benign LNs in pre-
dicting of nodal metastasis in head and neck cancer. Using a
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threshold value of 0.851 9 10-3 mm2 s-1, the accuracy,
sensitivity and specificity of ADC value for differential
diagnosis are 91.0, 91.3 and 91.1 %, respectively [51•]. In a
retrospective study of pelvic LNs in patients with prostate
cancer, Eiber et al. found there was a significant difference
between the mean ADC value (910-3 mm2 s-1) of
malignant (1.07 ± 0.23) versus benign (1.54 ± 0.25) LNs,
even in subgroup for LNs smaller versus larger than 10 mm.
At a cutoff 1.30 9 10-3 mm2 s-1, a good accuracy of
85.6 % with a sensitivity of 86.0 % and specificity of
85.3 % was obtained, which was superior to a size-based
analysis at a cutoff of 8 mm (accuracy, sensitivity and
specificity in their study was 66.1, 82.0 and 54.4 %,
respectively) [52]. The reasons for a more powerful diag-
nostic ability of DWI than other size-dependent imaging
methods may be due to two aspects. One is that more nor-
mal size LNs with micrometastasis are evaluated correctly,
and another is hyperplastic benign nodes are appropriately
excluded. Not all the researchers admitted the advantage of
DWI and ADC value in differential diagnosis of LNs. Roy
et al. reported there were no significant differences in ADC
values in metastatic nodes and control nodes (p [ 0.05),
and the mean ADC (910-3 mm3 s-1 ± SD) of involved
nodes, control iliac nodes, control inguinal nodes and con-
trol iliac plus inguinal were 924 ± 217, 968 ± 182 and
1,036 ± 181, respectively [44]. In addition, a new tech-
nique named as diffusion-weighted whole-body imaging
with background body signal suppression (DWIBS) pro-
vides data which can be post-processed to create a whole
body LN map as similar to PET, so it is also called as ‘‘PET-
like’’ imaging [53]. This technique acquires images during
free breathing, and obtains more outstanding contrast LNs
maps than conventional DWI by means of multiple signal
averaging, fat suppression pre-pulse and heavy diffusion
weighting. But DWIBS needs to be interpreted with T1 or
T2 weighted images for better anatomical correlation.
Although DWI has been widely accepted in the diagnosis of
intracranial diseases, it has not become a clinical standard in
Fig. 6 A 65-year-old woman
with a history of bladder cancer.
a On diffusion weighted image,
multiple left-sided
retroperitoneal lymph nodes
were identified adjacent to the
left renal vein with high signal
intensity. The largest one with a
size of 3.0 9 1.5 cm was
significantly enlarged as per the
size criteria. b On ADC map,
the largest one showed low
signal intensity due to restricted
diffusion. c On T2 weighted
image, the nodes showed high
signal intensity. d Post-contrast
scan demonstrated significant
homogeneous enhancement in
the nodes. e The CT-guilded
biopsy of the node demonstrated
reactive hyperplasia. f On the
follow-up scan after 14 months,
the node remained stable in size
on DWI
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body imaging. In spite of this, the most common sequence
of single-shot echo-planar imaging (EPI) is easily affected
by magnetic susceptibility artifacts and produces image
distortion in the body. These drawbacks may be more
obvious when small LNs in mediastinal and perigastroin-
testinal areas are evaluated. In summary, DWI is a powerful
tool to detect the number and site of LNs, but with a
indefinite accuracy in differential diagnosis and a relative
unstable imaging quality.
Novel MRI Contrast Agents
Compared to DWI and other structural imaging methods,
some novel lymphotropic contrasts such as ferumoxtran-10,
ferumoxytol and gadofluorine M showed a significantly
higher sensitivity and specificity in discriminating meta-
static LNs from non-metastatic ones in recent years [54–57,
58•, 59]. Ferumoxtran-10 and ferumoxytol are reticuloen-
dothelial system–targeted MR imaging contrast agents
consisting of ultrasmall superparamagnetic iron oxide par-
ticles. These nanoparticles can get into the reticuloendo-
thelial system through capillary walls and be carried to LNs
by macrophages [54]. A normal LN contains a large amount
of macrophages which show a low signal intensity with
ferumoxtran-10 because of the T2 shortening effect of the
nanoparticles. In contrast, metastatic LNs retain high signal
intensity for absence of macrophages with nanoparticles
caused by tumor involvement [55, 60] (Fig. 7). An excellent
high diagnostic sensitivity and specificity of ferumoxtran-10
was demonstrated in evaluation of various regional LNs. In a
prostate cancer LNs MRI study with lymphotropic
superparamagnetic nanoparticles, Harisinghani et al. cor-
rectly identified all 33 patients with metastases, and obtained
a perfect sensitivity of 100 % on a patient-by-patient ana-
lysis, as well as a significantly higher sensitivity and speci-
ficity than conventional MRI (90.5 vs. 35.4 %, 90.4 vs.
97.8 %, respectively) or nomograms on node-by-node ana-
lysis. This differential diagnostic advantage is more obvious
when detecting small LNs (a short diameter of 5–10 mm), in
which the sensitivity of MRI with ferumoxtran-10 can reach
96.4 %. The improved detecting ability of normal size LNs
with micrometastasis may be a reasonable explanation for
that [55]. Unfortunately, ferumoxtran-10, with its signifi-
cantly high accuracy, is not accepted as a routine tool for LN
evaluation, because of its commercial unavailability, time
consuming scan (at least 24–48 h) [61] and long interpre-
tation time (median reading time: 80 min) [56]. Thoeny
et al. combined ferumoxtran-10 with DWI (USPIO–DW–
MRI) and utilized a larger signal difference between
malignant and benign nodes caused by signal overlay from
diffusion and T2/T2* after ferumoxtran-10 to effectively
reduce the median reading time from 80 to 13 min [56].
Gadofluorine M (Schering, Berlin, Germany) is another
emerging LN-selective MRI contrast agent used in T1
weighted sequence. It is a macrocyclic gadolinium chelate
with a perfluorinated side chain and results in formation of
micelles in aqueous solutions [57, 58•]. This agent has
potential for showing a high signal intensity contrast
between functional and metastatic LNs on T1 weighted
sequence 15–120 min after injection, which is much faster
than ferumoxtran-10 [57]. The superior contrast not only
promises a significantly higher accuracy (sensitivity of
Fig. 7 A 66-year-old man with
a history of prostate cancer.
a Coronal T1 weighted image
showed a 12 mm short axis
right perirectal lymph node
(arrow) with a well-defined
border and low signal intensity.
b On coronal T2 weighted
image, multiple small bilateral
inguinal lymph nodes under size
criterion were noted. c On axial
Ferumoxytol enhanced T2*
weighted image, the small
inguinal lymph nodes (arrow)
showed low signal intensity,
suggesting benign nature of
these nodes. d On axial
Ferumoxytol enhanced T2*
weighted image, the right
perirectal lymph node showed
the high signal intensity
suggesting metastasis, which
was also confirmed by biopsy
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100 % and specificity of 89.5 %) for metastatic node
depiction, but also enables the detective ability on metastatic
LNs with small metastases (long-axis diameter of 3 mm or
less) located at the subcapsular portion of LNs [59]. How-
ever, with the drawbacks of reader dependency and relative
high false-negative rate of 43 % in small LNs without
Fig. 8 A 57-year-old woman
with a history of B cell
lymphoma. a On axial enhanced
neck CT scan, a mass (arrow) of
4.2 9 3.1 cm with a ill-defined
border and heterogeneous
enhancement was noted in the
upper left internal jugular
region. A 1-cm left
parapharyngeal lymph node
(arrow head) was seen medial
to the left internal carotid artery.
b On PET scan, both mass and
node showed increasing FDG
uptake
Fig. 9 A 56-year-old woman
with a history of colon cancer
and retroperitoneal node
metastasis. a The axial T1
weighted image uncovered a
2.2 9 1.8 cm lymph node with
slight low signal intensity
adjacent to the celiac axis. b On
fat-suppression T2 weighted
image, the node showed a
slightly increased signal
intensity. c Enhanced MRI scan
demonstrated a marked contrast
enhancement of the node. d On
the non-enhanced CT image
after 4 months, the node showed
a slightly enlargement and ill-
defined border. e On PET scan,
this metastatic node didn’t show
a high level FDG uptake
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necrosis, it is as of yet far from becoming a routine in clinical
practice [58•].
Positron Emission Tomography
Positron Emission Tomography (PET) is a powerful functional
imaging technique for tumor evaluation based on metabolic
markers labeled with the positron-emitting radionuclides such
as fluorine-18, carbon-11, and oxygen-15. With these agents,
PET discriminates the differences in metabolism between
benign and malignant cells [62] (Fig. 8). The radiopharma-
ceutical most commonly used with PET for oncologic imaging
is fluorine 18 fluorodeoxyglucose (18F-FDG), which allows the
detection of abnormal high glucose uptake of tumors [3••]. Most
studies demonstrated that 18F-FDG PET improved the accu-
racy for identifying LN involvement compared to other struc-
tural imaging examinations. Gould et al. compared the
diagnostic accuracy of CT and 18F-FDG PET for mediastinal
staging in patients with non–small-cell lung cancer by meta-
analysis, and found that both median sensitivity and specificity
of CT were lower than FDG-PET (61 and 79 %, 85 and 90 %,
respectively). Meanwhile, 18F-FDG PET was more sensitive
but less specific when CT showed enlarged LNs (median sen-
sitivity and specificity: 100 vs. 82 % and 78 vs. 93 %, respec-
tively) [63]. Part of the reason for the lower sensitivity of PET in
detecting normal size LNs may lie in its inaccurate anatomical
localization, which can be complemented by fusing PET ima-
ges with other high spatial resolution anatomical images from
CT and MRI. In detection of cervical metastatic LNs in head
and neck tumors by 18F-FDG PET/CT, the sensitivity, speci-
ficity, accuracy reached 100, 98.2, and 95 %, respectively [14,
64]. In an intention-to-treat analysis of non-small cell lung
cancer, Fischer et al. obtained a significantly improved sensi-
tivity (from 59 to 75 %) and similar high specificity (from 98 to
100 %) of mediastinal staging after adding prior PET/CT to
invasive diagnostic procedures [65••]. PET/CT or/and PET/
MRI studies in pelvic malignancies, for example penile cancer
and cervical cancer, also showed a considerably high sensitivity
of 80–80.6 % and a specificity of 92.4–100 % for diagnosing
inguinal LN involvement [66•, 67]. However, not all
researchers obtained such optimistic results in LN assessment
by fusing PET technique [68, 69•]. Heusch et al. reported rel-
atively low sensitivity for the detection of cervical LN metas-
tases of head and neck squamous cell carcinoma (HNSCC) in a
series of fusing PET images including 18F-FDG-PET/CT
(30 %), 18F-FDG-PET-MRI (52 %) and 18F-FDG-PET-MRI
plus DWI (53 %). This might be due to the fact that a stringent
histological reference standard with detection of a higher fre-
quency of micrometastases was used in this study [69•]. The
FDG uptake in nodes tends to vary. Low uptake of FDG in some
tumors and metastatic nodes may result in false negative cases
(Fig. 9). In patients with prostate cancer, slow-growing tumor
results in a low, undifferentiating, uptake of FDG [70], and a
large amount of excretion from 18F-FDG PET via the urinary
tract and bowel may limit its accurate evaluation of pelvic
nodes [3••]. Replacing 18F-FDG with 11C-Choline validly
covers this drawback. In a meta-analysis of prostate cancer,
Evangelista et al. [71] reported a pooled sensitivity of 100 %
and a pooled specificity of 81.8 % for LN metastases. The false
positive cases due to uptake of benign inflammatory LNs,
necrosis and small node volume decrease the diagnostic accu-
racy of PET. Onal et al. [72] obtained a false-positive rate of
75 % in evaluating isolated mediastinal LNs for patients with
cervical cancer by FDG-PET/CT alone caused by intranodal
granulomatous changes. Besides, partial volume effects may
induce PET/CT or PET/MRI with an unreliable explanation in
nodes \0.8 cm [73]. Lastly, the expensive cost and limited
coverage of fusing PET examination also decreases its utili-
zation rate in LN assessment.
Conclusion
An accurate imaging assessment of LN status has high direc-
tive value in making therapy plans for patients with tumors.
Structural imaging methods, including US, CT and conven-
tional MRI, show the strong abilities to depict the location,
size, shape, and texture of LNs, but do not reliably distinguish
benign LNs from malignant ones. Conversely, functional
imaging methods, including DWI, lymphotropic contrasts and
PET, demonstrate relatively high sensitivities and specificities
in differential diagnosis of LNs, while all evaluation abilities
are limited by relatively low spatial resolution or time-con-
suming processes. The emerging fusing imaging techniques,
such as DWI-T2WI, USPIO-DW-MRI, and PET/CT or MRI,
bypass these shortcomings. As the clinical paradigm shifts
from structural to functional imaging, these techniques will be
of prime importance in detecting and characterizing the LNs in
cancer patients.
Acknowledgments The authors would like to acknowledge Aiza
Zia and Rachel Borczuk for their contribution to the manuscript.
Compliance with Ethics Guidelines
Conflict of Interest Yun Mao, Sandeep Hedgire and Mukesh Ha-
risinghani declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent This article
does not contain any studies with human or animal subjects per-
formed by the authors.
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