Hybrid SPECT CT An Additional Technique (1)
european urology 50 (2006) 83–91
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Bladder Cancer
Hybrid SPECT-CT: An Additional Technique for Sentinel Node
Detection of Patients with Invasive Bladder Cancer
Amir Sherif a,*,1, Ulrike Garske b,1, Manuel de La Torre c, Magnus Tho¨rn d
a
Department of Urology, Uppsala University Hospital, Uppsala, Sweden
Department of Medical Sciences/Nuclear Medicine,Uppsala University Hospital, Uppsala, Sweden
c
Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden
d
Department of Surgery, Karolinska Institute, South Stockholm General Hospital, Stockholm, Sweden
b
Article info
Abstract
Article history:
Accepted March 1, 2006
Published online ahead of
print on March 20, 2006
Objectives: To explore the feasibility of performing lymphoscintigraphy combined with computed tomography (CT) for preoperative detection of sentinel
lymph nodes in patients with invasive bladder cancer.
Materials: Six consecutive patients scheduled for radical cystectomy underwent
lymphoscintigraphy after transurethral injection of Albures-technetium 99m in
the detrusor muscle peritumourally both with planar imaging and with singlephoton emission computed tomography/CT (SPECT/CT). CT for anatomic fusion
was performed directly after the SPECT/CT and both investigations were combined
to a fused image. Radical cystectomy started with extended lymphadenectomy and
intraoperative detection of sentinel nodes with both Geiger probe and dye marker.
The conventional planar lymphoscintigraphies and the fused SPECT/CT were
compared with each other and with the outcome of intraoperative sentinel node
detection and final histopathologic analyses.
Results: The method allowed anatomically detailed preoperative visualisation of
21 sentinel nodes in five of the six patients, whereas planar pictures only
visualised two sentinel nodes in two of six patients. Two patients had lymph
node metastases and in the other four the nodes were negative. The combined
method visualised all metastatic sentinel nodes, whereas planar lymphoscintigraphy detected only one of six node metastases.
Conclusions: The combination of lymphoscintigraphy with CT enhanced preoperative anatomic localisation of sentinel nodes in bladder cancer and aided in
the identification of sentinel nodes during surgery. The yield of detected sentinel
nodes, both metastatic and nonmetastatic, was markedly increased using the
combined method compared to conventional planar lymphoscintigraphy.
Keywords:
Bladder cancer
Computed tomography
Lymphoscintigraphy
Sentinel node
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1
Both authors contributed equally to this work.
* Corresponding author. Department of Urology, Akademiska University Hospital, SE-751 85
Uppsala, Sweden. Fax: +46 18 50 79 07.
E-mail address: amir.sherif@swipnet.se (A. Sherif).
0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2006.03.002
84
1.
european urology 50 (2006) 83–91
Introduction
Detection of sentinel nodes as a tool for node staging
has been explored and implemented with clinical
success in the surgical treatment of breast cancer [1]
and malignant melanoma [2]. Recently, we performed sentinel node detection in patients with
invasive bladder cancer [3]. The dynamic detection
of sentinel nodes reveals not only the pathoanatomic localisation of possible nodal metastases, in
contrast to restricted lymphadenectomy, which is
based on assumptions of lymph drainage in healthy
individuals, but also provides a means to examine
early metastatic progression in aspects of clonality
and biomarker profiles [4]. The majority of patients
undergoing cystectomy and traditional restricted
lymphadenectomy have no lymph node metastases
according to histopathologic examination [5]. A
substantial percentage of these patients still have
recurrences and die from disseminated disease. The
overall 5-yr survival rate of only 50% in patients
undergoing cystectomy is postulated to be caused by
undetected metastatic spread to unidentified nodes.
It is possible that staging could be improved and
result in more accurate assessment of nodal status if
sentinel nodes could be identified and examined in a
majority of patients with invasive urothelial bladder
cancer. The concept of sentinel node detection
includes detection of lymph nodes that are suggested to be primed in receiving metastatic deposits
at one time or another. The individual sentinel node
status is thus considered to reflect the actual
occurrence of primed sentinel nodes at the moment
of excision, with or without metastatic deposits. One
technical problem with the interpretation of planar
lymphoscintigraphy in the conventional manner, as
in our first study, is the difficulty in preoperatively
identifying the precise anatomic localisation of the
detected node. In most cases the nodes can be
identified once intraoperative detection consequently is added to the examination, but still the
certainty of lymphoscintigraphic localisation of
nodes needs to be discussed and reassessed case
by case. The problems of limited detection on planar
lymphoscintigraphy, with an underestimation of
actual number of sentinel nodes, has also been
highlighted by other investigators [6]. In our first
pilot study, planar lymphoscintigraphy yielded a
sentinel node detection rate of 67% and two
metastatic sentinel nodes of four, that is, 50%, were
also recorded.
The purpose of this trial was to use a technique
for better anatomic localisation of sentinel nodes
and also to improve detection rates. Therefore we
explored a newly described method in which single-
photon emission computed tomography (SPECT) was
combined with computed tomography (CT) for
anatomic fusion (SPECT/CT). So far this technique
has been successful in sentinel node detection of
malignant melanoma in two published reports [7,8]
and has been presented as a suitable method for
sentinel node detection in prostatic carcinoma [9,10].
In the study of Even-Sapir et al., in 9 of 21 patients
with a primary tumour located in the head and neck
or trunk region, SPECT/CT fused images detected
sentinel nodes that were missed on planar images.
Two of these were metastatic sentinel nodes [8]. In a
report from Wagner et al., comparing planar lymphoscintigraphy with SPECT/CT, 30 patients with
squamous cell carcinoma of the head and neck region
were investigated. Forty-nine sentinel nodes were
detected by SPECT/CT and 38 nodes by planar
lymphoscintigraphy. The investigators even concluded that SPECT/CT is more sensitive to tumoradjacent sentinel nodes than detection by g-probe,
due to the high activity at the injection site causing
obscuring and difficult detection [11].
2.
Patients and methods
2.1.
Patients
The study included six consecutive patients with urothelial
bladder cancer admitted to the University Hospital of Uppsala
from October 2002 to January 2003 for cystectomy. The four
men and two women were aged 59–75 yr. All six tumours
originated from urothelial epithelium and were assessed as
muscle invasive, T2a-T2b in five patients and as T1G3 with
multiple carcinomas in situ (CIS) in one, according to the TNM
classification of 1997 (Union Internationale Contre le Cancer)
and histopathologically graded according to criteria of the
World Health Organization and the International Pathology
Consensus Committee (1988). Preoperative work-up with CT,
intravenous pyelogram, and plain chest radiography did not
show any local or distant metastases.
None of the patients had received neoadjuvant therapy.
The study was approved both by the regional ethical
committee and the regional radiation ethical committee. All
six patients gave their informed consent to participate.
2.2.
Preoperative sentinel node detection
Lymphoscintigraphy was performed after injection of Alburestechnetium 99m (Scanflex, Nycomed Amersham, Milan, Italy)
in the detrusor muscle peritumourally. One surgeon (A.S.) was
the principal investigator in all six patients. A 3.7F, 35-cm long
Williams cystoscopy needle (Cook Urological, Spencer, IN)
directed by an Albarran bridge was used. A total of 50–60 MBq
was injected into each patient; the dose was divided into four
equal parts as described previously [3].The patients were
transferred to the Department of Nuclear Medicine 2–3 h after
injection. First, planar scintigraphy of the pelvis in anterior,
european urology 50 (2006) 83–91
posterior, and lateral views was performed. We defined a
sentinel node detected at planar lymphoscintigraphy as a
delineated spot with increased radioactivity clearly separated
from the sites of injection around the primary tumour. SPECT
and subsequent CT scans were performed in one session and
both acquisition data were fused to produce a combined picture
85
for further interpretation (Fig. 1). The CT scan was low-dose CT
(2.5 mA compared with 150–250 mA as used for a full diagnostic
CT) and no contrast was added. This CT scan did not replace the
ordinary CT scan being performed preoperatively for planning
and work-up. For SPECT, 60 angles at 30 s each were acquired
with a low-energy general (LEG) purpose collimator and a
Fig. 1 – SPECT and subsequent CT scan were performed in one session and both investigations were combined to produce a
fused image for further interpretation. This allowed the investigator to map in anatomic detail the presence and exact
localisations of sentinel nodes.
86
2
6
6
4
3
0
22
20
18
9
6
24
pT2b
pT3b
pT3a
pTa
pT3b
pTcis
0
1
6
2
2
0
1
0
0
1
0
0
2
6
6
4
3
0
1
0
0
0
1
0
T2
T2
T2
T2
T2
T1G3, CIS
(No. of detected nodes)
Dye
marker
SPECT/CT
Lymphoscint: lymphoscintigraphy; SPECT/CT: single-photon emission computer tomography/computed tomography; intraop.: intraoperative.
Sentinel nodes (nonmetastatic and metastatic) were
detected at various pelvic localisations, and in five of
the patients we found bilateral distribution (Fig. 2).
Especially in patients 2 and 3 the combined
lymphoscintigraphy/CT technique yielded a relatively high number of sentinel nodes. The mean
number of detected sentinel nodes, calculated on all
three methods of detection (SPECT/CT, visual
detection of dye marker, and intraoperative gdetection), was 3.5 and the median was 3.5 (range,
M
M
M
F
F
M
Overall sentinel node detection
64
72
74
75
73
59
3.2.
Planar
lymphoscint.
In total, 99 lymph nodes were harvested, with a
range of 6–24 nodes. Twenty-one sentinel nodes
were detected and excised (Tables 1 and 2). All nodes
were subject to routine histopathology, and one of
the sentinel nodes was re-examined with immunohistochemistry (see below).
Clinical
stage
Lymph node yield
Sex
3.1.
Table 1 – Patient characteristics and results of sentinel node detection
Results
Intraop gdetection
One surgeon (A.S.) was the main surgeon in all six laparotomies. All six patients underwent cystectomy with lymphadenectomy and received urinary diversions accordingly.
Lymphadenectomies were mainly carried out after the
cystectomy or cystoprostatectomy, before formation of the
urinary outlet. Lymphadenectomy included all sentinel nodes
by the different described modalities and nonsentinel lymph
nodes in obturator regions and along iliac vessels with the
intent to include nodes up to the aortic bifurcation bilaterally.
3.
pN0
pN0
pN0
pN+
pN+
pN0
pN
stage
pT
stage
Surgery
Age,
y
2.4.
Total no.
harvested nodes
Prior to major surgery the patient was initially in the lithotomy
position and a second cystoscopy was performed. A total of
1 ml Patent blue (Bleu Patente´ V; Guerbet Laboratory, Issy les
Moulineaux, France), divided into four equal portions, was
injected peritumourally, with the intent to spot the same
positions as previously done with radioactive tracer. If >24 h
had elapsed since the latter, renewed injections of Alburestechnetium 99m were performed as described above. Intraoperatively we performed both detections with the help of a
handheld g-probe and visual detection of possibly bluecolored nodes.
1
2
3
4
5
6
Intraoperative sentinel node detection
Patient no.
2.3.
Total no. detected
sentinel nodes
128 128 matrix. The examination was performed with
anatomic enhancement on a g-camera Millennium VG5 with
Hawkeye (General Electric); attenuation correction using the CT
attenuation map and reconstruction of the raw data were
carried out on an Entegra workstation (General Electric). One
investigator (U.G.) was the sole interpreter of the lymphoscintigraphies and the combined pictures of hybrid SPECT/CT.
–
–
–
–
–
–
False- negative
sentinel nodes
european urology 50 (2006) 83–91
87
european urology 50 (2006) 83–91
Table 2 – Results in detection of metastatic sentinel nodes with planar lymphoscintigraphy versus SPECT/CT
Patient no.
4
5
Total no. metastatic
sentinel nodes
No. of metastatic nodes
detected by planar lymphoscintigraphy
No. of metastatic nodes
detected by SPECT/CT
3
3
0
1
3
3
SPECT/CT: single-photon emission computer tomography/computed tomography.
0–6). Total detection of sentinel nodes for the hybrid
SPECT/CT technique was 21 of 21, 2 of 21 with the
conventional planar lymphoscintigraphy, 2 of 21
with visual detection, and 11 of 21 with g-probe
detection. Thus the detailed background anatomy of
the SPECT/CT allowed us to surgically retrieve the
nodes undetected by intraoperative techniques. We
compared SPECT/CT with planar images and it was
clear that some of the lymph nodes detected using
the new method were not seen when investigating
only planar images. This was particularly the case
for small-sized sentinel nodes (data not shown).
3.3.
Detection of metastatic sentinel nodes
In the two patients with lymph node metastases
(patients 4 and 5), the total numbers of metastatic
sentinel nodes were three of four and three of three
sentinel nodes, respectively. The combined technique visualized all metastatic sentinel lymph nodes
in both patients (Table 2). In patient number 4, the
detected metastatic sentinel node located over the
right iliac bifurcation was primarily considered as
being devoid of metastatic deposits. The pathologist
re-examined the two excised nodes of that area
Fig. 2 – Conclusive drawing depicting the distribution of sentinel nodes in the six patients in this study. Note the bilateral
distribution of tumour-draining sentinel nodes in patients 1–5 and also the bilateral distribution of metastatic sentinel
nodes in patients 4 and 5. The sixth patient illustrates one problem of sentinel node detection, in whom a massive fibrosis
in the pelvis minor might have obstructed any detectable lymphatic drainage. The four different methods of sentinel
detection are marked [a] to [d].
88
european urology 50 (2006) 83–91
Fig. 3 – In patient number 4, hybrid SPECT/CT detected a total of four sentinel nodes. Three (orange circles with a + sign) had
metastatic deposits on histopathologic evaluation. On the left side is a close-up of the original SPECT over the right
common iliac area, and on the right side a conclusive drawing over the distribution of sentinel nodes. [b] indicates detection
by SPECT/CT, [c] by visual detection of blue dye marker, and [d] g-probe detection.
using immunohistochemistry with the anticytokeratin monoclonal antibody AE1/AE3. The result of
that examination indicated that one of the nodes
had a well-defined micrometastatic deposit (2 mm
in size) and thus the patient had three detected
metastatic sentinel nodes (Fig. 3). Both of the
patients with nodal metastases had bilateral nodal
deposits and totally two of metastatic nodes were
detected in non-obturator localisations (Fig. 2).
3.4.
pN staging
Sentinel node detection and ensuing histopathology
adequately staged four patients as pN0, and two
patients as pN+. None of the patients could be
classified as false negative, considering that no
metastases were found in the pathologic examination of the excised nonsentinel nodes.
4.
Discussion
Our feasibility study indicates that a combination of
lymphoscintigraphy and CT improves preoperative
anatomic localisation of sentinel nodes in urinary
bladder cancer. We could now identify a higher
number of sentinel nodes than with the techniques
used in our previous report. The problems with
identification of sentinel nodes with planar lym-
phoscintigraphy in urinary bladder cancer have
recently been highlighted by another group working
with similar concepts. In a series of 75 patients, only
7 of the first 30 patients had detectable sentinel
nodes with planar lymphoscintigraphy, and for the
remaining 45 patients this mode of investigation
was totally abandoned [12].
The identification of bilateral metastatic sentinel
lymph nodes was also a new finding in our own
findings and adheres to the concept of a mandatory
bilateral dissection [13]. The identification of a
sentinel node with micrometastatic deposits
(patient 4), finally being revealed by immunohistochemical examination, encourages us to pursue
further refinement of the different techniques
included. In that patient we found that the hybrid
SPECT/CT technique seemed to be especially valuable. The sixth patient in our series illustrates one
problem of sentinel node detection. This patient
reacted with a massive fibrosis in the pelvis minor
after the primary transurethral resection, due to
perforation of the bladder wall. The fibrosis persisted and ultimately constituted a major intraoperative problem in the course of cystectomy. Our
hypothesis is that the fibrosis might have obstructed
any detectable lymphatic drainage, thus rendering
us no detectable sentinel nodes at all. We find it of
specific value to include this patient in our series, as
an example of technical problems related to sentinel
european urology 50 (2006) 83–91
node detection patients with in urinary bladder
cancer.
The original concept of sentinel node detection
was based on the principle of one tumour-one
primary sentinel node. However, the finding of more
than one sentinel node is often reported, as in a large
breast cancer multicentre study from 1998 (n = 443)
where the mean number of sentinel nodes was
2.6 2.2 [14]. The detection of second- and even
third-echelon metastatic sentinel nodes adds more
considerations to the questions of defining the
actual sentinel node [15]. At the time of presentation
and detection, the presence of multiple detectable
nodes, and also the presence of a number of
detected metastatic sentinel nodes, is thus also
being displayed in this present study. The explanation might be found both in the individual biologic
timetable of the actual tumour/patient, the timing of
detection, and the possibility of larger tumours
having different sections being drained into anatomically different lymphatic routes. For example, in a
biologically early setting, a patient might have only
one single detectable sentinel node, with or without
metastatic deposits. Another patient, in a more
advanced biologic setting, might have a number of
detectable sentinel nodes, with a wide variation of
metastatic spread or absence thereof. Simultaneous
sentinel nodes might be considered to originate
from different parts of a tumour with individual and
separate drainage routes being established within
the same time frame. That could also serve as an
explanation for both crossover phenomena and
bilateral distribution of nodal metastatic deposits.
We consider all detected nodes as being so called
‘‘hot nodes,’’ thus being detectable nodes by the
described methods. It should be pointed out that the
term ‘‘hot nodes’’ should be considered as including
both first-echelon sentinel nodes (i.e., ‘‘true’’ sentinel nodes) and second- and third-echelon draining
nodes. Until we have morphologic or biochemical
markers to differentiate between the position of the
nodes in the draining system, we have made the
choice to designate all ‘‘hot nodes’’ as sentinel
nodes. This is especially the case with the abovementioned hypothetical argument of having different sections of the tumour being drained into
different subsets of draining areas. We would
consider it being suboptimal to just search for a
single draining node, especially because we know
that usually more than one affected metastatic node
can be found in many patients with nodal spread
and that distribution of metastatic nodes can be
found in various localisations. In a recently published prospective trial from the Mansourah Center,
bilateral nodal involvement was observed in 39% of
89
the patients with positive nodes [16]. Crossover
phenomena were reported in 7% of the patients in
the Swiss prospective investigation of 83 patients
with positive nodes undergoing cystectomy. This
group also noted that of the 39 patients who had a
lateralized bladder tumour, 16 had nodes involved
on the contralateral side [17]. The insufficiency of
the present TNM classification for describing and
stratifying node-positive patients with urinary
bladder cancer has recently been highlighted in a
review discussing lymph node metastasis in this
cancer [18].
With this biologic background of advanced
urinary bladder carcinomas, defining the first
sentinel node would mainly have an academic
interest, and the concept of one tumour-one node
certainly also has to be challenged. To distinguish
first-, second-, and third-echelon sentinel nodes
from each other is another matter to be dealt with.
In exceptionally clear cases, the suggested prepulsion from one node to the second and so forth, can
be visualised intraoperatively in the initial
moments of traditional dynamic lymphoscintigraphy. We do not propose that any general common
pattern of drainage can be discerned or established
with reference to tumour location and size [19]. The
concept rather entails the possibility of multiple
routes of drainage, to one or more sentinel nodes
or sentinel node regions. It has been suggested
that an early nodal extension starts with the
establishment of specific routes for drainage
through vascular endothelial growth factor (VEGF)
C- and VEGF-D–induced tumor-specific lymphangiogenesis [20,21], followed by independent metastatic progression taking place according to the
specific preconditions in every individual patient.
This model might explain why we can detect a
number of unaffected but still established and
discernable sentinel nodes in some patients. In
other patients one can assume that metastatic
progression occurs at a quicker pace, even though
the patient has only one or a few detectable sentinel
nodes. In this present study we did not encounter
any patients with false-negative sentinel nodes, by
definition, undetected metastatic sentinel nodes.
Still in a numerically larger study in which we are
exploring the immunoresponse in sentinel nodes,
we found a total of four false-negative nodes in
three patients [22]. We have also encountered the
same phenomena later on in a few more subsequent
patients being examined. The false-negative findings could either be explained by technical problems related to the quality of tracer injection or by
the possibility described by other sentinel node
investigators, where a completely tumour-engaged
90
european urology 50 (2006) 83–91
metastatic sentinel node loses its ability to harbour
tracer of any kind [23]. Our feasibility trial includes a
low number of patients, and in future attempts we
would mainly aim to both increase the number of
investigated patients and also to have two separate
investigators doing the preoperative imaging. This
would allow one investigator to interpret planar
lymphoscintigraphy and independently have
another investigator assess the SPECT/CT images.
Ultimately the request for a more accurate
staging of nodal status is linked to our different
attempts to tailor treatment options for individual
patients. Another attempt to combine different
modalities in the investigation of both nodal and
distant metastases in advanced bladder cancer is a
recently published prospective trial on correlating
whole-body fluorine-18 2-fluoro-2-dixoy-D-glucose-positron emission tomography (FDG-PET)
and CT [24]. Attempts to further refine diagnostic
accuracy by combining these methods with sentinel
node detection seems to be the next tempting
option.
By refining the techniques that can be used for
detection of sentinel nodes, one might endeavour to
increase the amount of detected sentinel nodes,
thus extending the options of further basic research
on the intrinsic factors governing routes of metastatic spread, presence or absence of metastatic
nodes, molecular profiling of primary tumours,
nonmetastatic and metastatic sentinel nodes,
examination of immunologic interactions occurring
in primary tumor and sentinel nodes [22], and,
finally, also exploring mechanisms of lymphangiogenesis and metastatic tumor-homing.
5.
Conclusions
The combination of lymphoscintigraphy with CT
enabled preoperative localisation of sentinel nodes
in anatomic detail and facilitated detection during
operation. Identification of more sentinel nodes
than expected might be due to timing of the
scintigraphy; some identified nodes may therefore
be second- and third-echelon nodes. This additional
technique provides us with more information but
should be investigated further before any of the
other methods of detection are excluded.
Acknowledgements
Dr Per Marits, MD, Department of Internal Medicine
Uppsala University Hospital, for providing us with
drawings.
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available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Bladder Cancer
Hybrid SPECT-CT: An Additional Technique for Sentinel Node
Detection of Patients with Invasive Bladder Cancer
Amir Sherif a,*,1, Ulrike Garske b,1, Manuel de La Torre c, Magnus Tho¨rn d
a
Department of Urology, Uppsala University Hospital, Uppsala, Sweden
Department of Medical Sciences/Nuclear Medicine,Uppsala University Hospital, Uppsala, Sweden
c
Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden
d
Department of Surgery, Karolinska Institute, South Stockholm General Hospital, Stockholm, Sweden
b
Article info
Abstract
Article history:
Accepted March 1, 2006
Published online ahead of
print on March 20, 2006
Objectives: To explore the feasibility of performing lymphoscintigraphy combined with computed tomography (CT) for preoperative detection of sentinel
lymph nodes in patients with invasive bladder cancer.
Materials: Six consecutive patients scheduled for radical cystectomy underwent
lymphoscintigraphy after transurethral injection of Albures-technetium 99m in
the detrusor muscle peritumourally both with planar imaging and with singlephoton emission computed tomography/CT (SPECT/CT). CT for anatomic fusion
was performed directly after the SPECT/CT and both investigations were combined
to a fused image. Radical cystectomy started with extended lymphadenectomy and
intraoperative detection of sentinel nodes with both Geiger probe and dye marker.
The conventional planar lymphoscintigraphies and the fused SPECT/CT were
compared with each other and with the outcome of intraoperative sentinel node
detection and final histopathologic analyses.
Results: The method allowed anatomically detailed preoperative visualisation of
21 sentinel nodes in five of the six patients, whereas planar pictures only
visualised two sentinel nodes in two of six patients. Two patients had lymph
node metastases and in the other four the nodes were negative. The combined
method visualised all metastatic sentinel nodes, whereas planar lymphoscintigraphy detected only one of six node metastases.
Conclusions: The combination of lymphoscintigraphy with CT enhanced preoperative anatomic localisation of sentinel nodes in bladder cancer and aided in
the identification of sentinel nodes during surgery. The yield of detected sentinel
nodes, both metastatic and nonmetastatic, was markedly increased using the
combined method compared to conventional planar lymphoscintigraphy.
Keywords:
Bladder cancer
Computed tomography
Lymphoscintigraphy
Sentinel node
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1
Both authors contributed equally to this work.
* Corresponding author. Department of Urology, Akademiska University Hospital, SE-751 85
Uppsala, Sweden. Fax: +46 18 50 79 07.
E-mail address: amir.sherif@swipnet.se (A. Sherif).
0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2006.03.002
84
1.
european urology 50 (2006) 83–91
Introduction
Detection of sentinel nodes as a tool for node staging
has been explored and implemented with clinical
success in the surgical treatment of breast cancer [1]
and malignant melanoma [2]. Recently, we performed sentinel node detection in patients with
invasive bladder cancer [3]. The dynamic detection
of sentinel nodes reveals not only the pathoanatomic localisation of possible nodal metastases, in
contrast to restricted lymphadenectomy, which is
based on assumptions of lymph drainage in healthy
individuals, but also provides a means to examine
early metastatic progression in aspects of clonality
and biomarker profiles [4]. The majority of patients
undergoing cystectomy and traditional restricted
lymphadenectomy have no lymph node metastases
according to histopathologic examination [5]. A
substantial percentage of these patients still have
recurrences and die from disseminated disease. The
overall 5-yr survival rate of only 50% in patients
undergoing cystectomy is postulated to be caused by
undetected metastatic spread to unidentified nodes.
It is possible that staging could be improved and
result in more accurate assessment of nodal status if
sentinel nodes could be identified and examined in a
majority of patients with invasive urothelial bladder
cancer. The concept of sentinel node detection
includes detection of lymph nodes that are suggested to be primed in receiving metastatic deposits
at one time or another. The individual sentinel node
status is thus considered to reflect the actual
occurrence of primed sentinel nodes at the moment
of excision, with or without metastatic deposits. One
technical problem with the interpretation of planar
lymphoscintigraphy in the conventional manner, as
in our first study, is the difficulty in preoperatively
identifying the precise anatomic localisation of the
detected node. In most cases the nodes can be
identified once intraoperative detection consequently is added to the examination, but still the
certainty of lymphoscintigraphic localisation of
nodes needs to be discussed and reassessed case
by case. The problems of limited detection on planar
lymphoscintigraphy, with an underestimation of
actual number of sentinel nodes, has also been
highlighted by other investigators [6]. In our first
pilot study, planar lymphoscintigraphy yielded a
sentinel node detection rate of 67% and two
metastatic sentinel nodes of four, that is, 50%, were
also recorded.
The purpose of this trial was to use a technique
for better anatomic localisation of sentinel nodes
and also to improve detection rates. Therefore we
explored a newly described method in which single-
photon emission computed tomography (SPECT) was
combined with computed tomography (CT) for
anatomic fusion (SPECT/CT). So far this technique
has been successful in sentinel node detection of
malignant melanoma in two published reports [7,8]
and has been presented as a suitable method for
sentinel node detection in prostatic carcinoma [9,10].
In the study of Even-Sapir et al., in 9 of 21 patients
with a primary tumour located in the head and neck
or trunk region, SPECT/CT fused images detected
sentinel nodes that were missed on planar images.
Two of these were metastatic sentinel nodes [8]. In a
report from Wagner et al., comparing planar lymphoscintigraphy with SPECT/CT, 30 patients with
squamous cell carcinoma of the head and neck region
were investigated. Forty-nine sentinel nodes were
detected by SPECT/CT and 38 nodes by planar
lymphoscintigraphy. The investigators even concluded that SPECT/CT is more sensitive to tumoradjacent sentinel nodes than detection by g-probe,
due to the high activity at the injection site causing
obscuring and difficult detection [11].
2.
Patients and methods
2.1.
Patients
The study included six consecutive patients with urothelial
bladder cancer admitted to the University Hospital of Uppsala
from October 2002 to January 2003 for cystectomy. The four
men and two women were aged 59–75 yr. All six tumours
originated from urothelial epithelium and were assessed as
muscle invasive, T2a-T2b in five patients and as T1G3 with
multiple carcinomas in situ (CIS) in one, according to the TNM
classification of 1997 (Union Internationale Contre le Cancer)
and histopathologically graded according to criteria of the
World Health Organization and the International Pathology
Consensus Committee (1988). Preoperative work-up with CT,
intravenous pyelogram, and plain chest radiography did not
show any local or distant metastases.
None of the patients had received neoadjuvant therapy.
The study was approved both by the regional ethical
committee and the regional radiation ethical committee. All
six patients gave their informed consent to participate.
2.2.
Preoperative sentinel node detection
Lymphoscintigraphy was performed after injection of Alburestechnetium 99m (Scanflex, Nycomed Amersham, Milan, Italy)
in the detrusor muscle peritumourally. One surgeon (A.S.) was
the principal investigator in all six patients. A 3.7F, 35-cm long
Williams cystoscopy needle (Cook Urological, Spencer, IN)
directed by an Albarran bridge was used. A total of 50–60 MBq
was injected into each patient; the dose was divided into four
equal parts as described previously [3].The patients were
transferred to the Department of Nuclear Medicine 2–3 h after
injection. First, planar scintigraphy of the pelvis in anterior,
european urology 50 (2006) 83–91
posterior, and lateral views was performed. We defined a
sentinel node detected at planar lymphoscintigraphy as a
delineated spot with increased radioactivity clearly separated
from the sites of injection around the primary tumour. SPECT
and subsequent CT scans were performed in one session and
both acquisition data were fused to produce a combined picture
85
for further interpretation (Fig. 1). The CT scan was low-dose CT
(2.5 mA compared with 150–250 mA as used for a full diagnostic
CT) and no contrast was added. This CT scan did not replace the
ordinary CT scan being performed preoperatively for planning
and work-up. For SPECT, 60 angles at 30 s each were acquired
with a low-energy general (LEG) purpose collimator and a
Fig. 1 – SPECT and subsequent CT scan were performed in one session and both investigations were combined to produce a
fused image for further interpretation. This allowed the investigator to map in anatomic detail the presence and exact
localisations of sentinel nodes.
86
2
6
6
4
3
0
22
20
18
9
6
24
pT2b
pT3b
pT3a
pTa
pT3b
pTcis
0
1
6
2
2
0
1
0
0
1
0
0
2
6
6
4
3
0
1
0
0
0
1
0
T2
T2
T2
T2
T2
T1G3, CIS
(No. of detected nodes)
Dye
marker
SPECT/CT
Lymphoscint: lymphoscintigraphy; SPECT/CT: single-photon emission computer tomography/computed tomography; intraop.: intraoperative.
Sentinel nodes (nonmetastatic and metastatic) were
detected at various pelvic localisations, and in five of
the patients we found bilateral distribution (Fig. 2).
Especially in patients 2 and 3 the combined
lymphoscintigraphy/CT technique yielded a relatively high number of sentinel nodes. The mean
number of detected sentinel nodes, calculated on all
three methods of detection (SPECT/CT, visual
detection of dye marker, and intraoperative gdetection), was 3.5 and the median was 3.5 (range,
M
M
M
F
F
M
Overall sentinel node detection
64
72
74
75
73
59
3.2.
Planar
lymphoscint.
In total, 99 lymph nodes were harvested, with a
range of 6–24 nodes. Twenty-one sentinel nodes
were detected and excised (Tables 1 and 2). All nodes
were subject to routine histopathology, and one of
the sentinel nodes was re-examined with immunohistochemistry (see below).
Clinical
stage
Lymph node yield
Sex
3.1.
Table 1 – Patient characteristics and results of sentinel node detection
Results
Intraop gdetection
One surgeon (A.S.) was the main surgeon in all six laparotomies. All six patients underwent cystectomy with lymphadenectomy and received urinary diversions accordingly.
Lymphadenectomies were mainly carried out after the
cystectomy or cystoprostatectomy, before formation of the
urinary outlet. Lymphadenectomy included all sentinel nodes
by the different described modalities and nonsentinel lymph
nodes in obturator regions and along iliac vessels with the
intent to include nodes up to the aortic bifurcation bilaterally.
3.
pN0
pN0
pN0
pN+
pN+
pN0
pN
stage
pT
stage
Surgery
Age,
y
2.4.
Total no.
harvested nodes
Prior to major surgery the patient was initially in the lithotomy
position and a second cystoscopy was performed. A total of
1 ml Patent blue (Bleu Patente´ V; Guerbet Laboratory, Issy les
Moulineaux, France), divided into four equal portions, was
injected peritumourally, with the intent to spot the same
positions as previously done with radioactive tracer. If >24 h
had elapsed since the latter, renewed injections of Alburestechnetium 99m were performed as described above. Intraoperatively we performed both detections with the help of a
handheld g-probe and visual detection of possibly bluecolored nodes.
1
2
3
4
5
6
Intraoperative sentinel node detection
Patient no.
2.3.
Total no. detected
sentinel nodes
128 128 matrix. The examination was performed with
anatomic enhancement on a g-camera Millennium VG5 with
Hawkeye (General Electric); attenuation correction using the CT
attenuation map and reconstruction of the raw data were
carried out on an Entegra workstation (General Electric). One
investigator (U.G.) was the sole interpreter of the lymphoscintigraphies and the combined pictures of hybrid SPECT/CT.
–
–
–
–
–
–
False- negative
sentinel nodes
european urology 50 (2006) 83–91
87
european urology 50 (2006) 83–91
Table 2 – Results in detection of metastatic sentinel nodes with planar lymphoscintigraphy versus SPECT/CT
Patient no.
4
5
Total no. metastatic
sentinel nodes
No. of metastatic nodes
detected by planar lymphoscintigraphy
No. of metastatic nodes
detected by SPECT/CT
3
3
0
1
3
3
SPECT/CT: single-photon emission computer tomography/computed tomography.
0–6). Total detection of sentinel nodes for the hybrid
SPECT/CT technique was 21 of 21, 2 of 21 with the
conventional planar lymphoscintigraphy, 2 of 21
with visual detection, and 11 of 21 with g-probe
detection. Thus the detailed background anatomy of
the SPECT/CT allowed us to surgically retrieve the
nodes undetected by intraoperative techniques. We
compared SPECT/CT with planar images and it was
clear that some of the lymph nodes detected using
the new method were not seen when investigating
only planar images. This was particularly the case
for small-sized sentinel nodes (data not shown).
3.3.
Detection of metastatic sentinel nodes
In the two patients with lymph node metastases
(patients 4 and 5), the total numbers of metastatic
sentinel nodes were three of four and three of three
sentinel nodes, respectively. The combined technique visualized all metastatic sentinel lymph nodes
in both patients (Table 2). In patient number 4, the
detected metastatic sentinel node located over the
right iliac bifurcation was primarily considered as
being devoid of metastatic deposits. The pathologist
re-examined the two excised nodes of that area
Fig. 2 – Conclusive drawing depicting the distribution of sentinel nodes in the six patients in this study. Note the bilateral
distribution of tumour-draining sentinel nodes in patients 1–5 and also the bilateral distribution of metastatic sentinel
nodes in patients 4 and 5. The sixth patient illustrates one problem of sentinel node detection, in whom a massive fibrosis
in the pelvis minor might have obstructed any detectable lymphatic drainage. The four different methods of sentinel
detection are marked [a] to [d].
88
european urology 50 (2006) 83–91
Fig. 3 – In patient number 4, hybrid SPECT/CT detected a total of four sentinel nodes. Three (orange circles with a + sign) had
metastatic deposits on histopathologic evaluation. On the left side is a close-up of the original SPECT over the right
common iliac area, and on the right side a conclusive drawing over the distribution of sentinel nodes. [b] indicates detection
by SPECT/CT, [c] by visual detection of blue dye marker, and [d] g-probe detection.
using immunohistochemistry with the anticytokeratin monoclonal antibody AE1/AE3. The result of
that examination indicated that one of the nodes
had a well-defined micrometastatic deposit (2 mm
in size) and thus the patient had three detected
metastatic sentinel nodes (Fig. 3). Both of the
patients with nodal metastases had bilateral nodal
deposits and totally two of metastatic nodes were
detected in non-obturator localisations (Fig. 2).
3.4.
pN staging
Sentinel node detection and ensuing histopathology
adequately staged four patients as pN0, and two
patients as pN+. None of the patients could be
classified as false negative, considering that no
metastases were found in the pathologic examination of the excised nonsentinel nodes.
4.
Discussion
Our feasibility study indicates that a combination of
lymphoscintigraphy and CT improves preoperative
anatomic localisation of sentinel nodes in urinary
bladder cancer. We could now identify a higher
number of sentinel nodes than with the techniques
used in our previous report. The problems with
identification of sentinel nodes with planar lym-
phoscintigraphy in urinary bladder cancer have
recently been highlighted by another group working
with similar concepts. In a series of 75 patients, only
7 of the first 30 patients had detectable sentinel
nodes with planar lymphoscintigraphy, and for the
remaining 45 patients this mode of investigation
was totally abandoned [12].
The identification of bilateral metastatic sentinel
lymph nodes was also a new finding in our own
findings and adheres to the concept of a mandatory
bilateral dissection [13]. The identification of a
sentinel node with micrometastatic deposits
(patient 4), finally being revealed by immunohistochemical examination, encourages us to pursue
further refinement of the different techniques
included. In that patient we found that the hybrid
SPECT/CT technique seemed to be especially valuable. The sixth patient in our series illustrates one
problem of sentinel node detection. This patient
reacted with a massive fibrosis in the pelvis minor
after the primary transurethral resection, due to
perforation of the bladder wall. The fibrosis persisted and ultimately constituted a major intraoperative problem in the course of cystectomy. Our
hypothesis is that the fibrosis might have obstructed
any detectable lymphatic drainage, thus rendering
us no detectable sentinel nodes at all. We find it of
specific value to include this patient in our series, as
an example of technical problems related to sentinel
european urology 50 (2006) 83–91
node detection patients with in urinary bladder
cancer.
The original concept of sentinel node detection
was based on the principle of one tumour-one
primary sentinel node. However, the finding of more
than one sentinel node is often reported, as in a large
breast cancer multicentre study from 1998 (n = 443)
where the mean number of sentinel nodes was
2.6 2.2 [14]. The detection of second- and even
third-echelon metastatic sentinel nodes adds more
considerations to the questions of defining the
actual sentinel node [15]. At the time of presentation
and detection, the presence of multiple detectable
nodes, and also the presence of a number of
detected metastatic sentinel nodes, is thus also
being displayed in this present study. The explanation might be found both in the individual biologic
timetable of the actual tumour/patient, the timing of
detection, and the possibility of larger tumours
having different sections being drained into anatomically different lymphatic routes. For example, in a
biologically early setting, a patient might have only
one single detectable sentinel node, with or without
metastatic deposits. Another patient, in a more
advanced biologic setting, might have a number of
detectable sentinel nodes, with a wide variation of
metastatic spread or absence thereof. Simultaneous
sentinel nodes might be considered to originate
from different parts of a tumour with individual and
separate drainage routes being established within
the same time frame. That could also serve as an
explanation for both crossover phenomena and
bilateral distribution of nodal metastatic deposits.
We consider all detected nodes as being so called
‘‘hot nodes,’’ thus being detectable nodes by the
described methods. It should be pointed out that the
term ‘‘hot nodes’’ should be considered as including
both first-echelon sentinel nodes (i.e., ‘‘true’’ sentinel nodes) and second- and third-echelon draining
nodes. Until we have morphologic or biochemical
markers to differentiate between the position of the
nodes in the draining system, we have made the
choice to designate all ‘‘hot nodes’’ as sentinel
nodes. This is especially the case with the abovementioned hypothetical argument of having different sections of the tumour being drained into
different subsets of draining areas. We would
consider it being suboptimal to just search for a
single draining node, especially because we know
that usually more than one affected metastatic node
can be found in many patients with nodal spread
and that distribution of metastatic nodes can be
found in various localisations. In a recently published prospective trial from the Mansourah Center,
bilateral nodal involvement was observed in 39% of
89
the patients with positive nodes [16]. Crossover
phenomena were reported in 7% of the patients in
the Swiss prospective investigation of 83 patients
with positive nodes undergoing cystectomy. This
group also noted that of the 39 patients who had a
lateralized bladder tumour, 16 had nodes involved
on the contralateral side [17]. The insufficiency of
the present TNM classification for describing and
stratifying node-positive patients with urinary
bladder cancer has recently been highlighted in a
review discussing lymph node metastasis in this
cancer [18].
With this biologic background of advanced
urinary bladder carcinomas, defining the first
sentinel node would mainly have an academic
interest, and the concept of one tumour-one node
certainly also has to be challenged. To distinguish
first-, second-, and third-echelon sentinel nodes
from each other is another matter to be dealt with.
In exceptionally clear cases, the suggested prepulsion from one node to the second and so forth, can
be visualised intraoperatively in the initial
moments of traditional dynamic lymphoscintigraphy. We do not propose that any general common
pattern of drainage can be discerned or established
with reference to tumour location and size [19]. The
concept rather entails the possibility of multiple
routes of drainage, to one or more sentinel nodes
or sentinel node regions. It has been suggested
that an early nodal extension starts with the
establishment of specific routes for drainage
through vascular endothelial growth factor (VEGF)
C- and VEGF-D–induced tumor-specific lymphangiogenesis [20,21], followed by independent metastatic progression taking place according to the
specific preconditions in every individual patient.
This model might explain why we can detect a
number of unaffected but still established and
discernable sentinel nodes in some patients. In
other patients one can assume that metastatic
progression occurs at a quicker pace, even though
the patient has only one or a few detectable sentinel
nodes. In this present study we did not encounter
any patients with false-negative sentinel nodes, by
definition, undetected metastatic sentinel nodes.
Still in a numerically larger study in which we are
exploring the immunoresponse in sentinel nodes,
we found a total of four false-negative nodes in
three patients [22]. We have also encountered the
same phenomena later on in a few more subsequent
patients being examined. The false-negative findings could either be explained by technical problems related to the quality of tracer injection or by
the possibility described by other sentinel node
investigators, where a completely tumour-engaged
90
european urology 50 (2006) 83–91
metastatic sentinel node loses its ability to harbour
tracer of any kind [23]. Our feasibility trial includes a
low number of patients, and in future attempts we
would mainly aim to both increase the number of
investigated patients and also to have two separate
investigators doing the preoperative imaging. This
would allow one investigator to interpret planar
lymphoscintigraphy and independently have
another investigator assess the SPECT/CT images.
Ultimately the request for a more accurate
staging of nodal status is linked to our different
attempts to tailor treatment options for individual
patients. Another attempt to combine different
modalities in the investigation of both nodal and
distant metastases in advanced bladder cancer is a
recently published prospective trial on correlating
whole-body fluorine-18 2-fluoro-2-dixoy-D-glucose-positron emission tomography (FDG-PET)
and CT [24]. Attempts to further refine diagnostic
accuracy by combining these methods with sentinel
node detection seems to be the next tempting
option.
By refining the techniques that can be used for
detection of sentinel nodes, one might endeavour to
increase the amount of detected sentinel nodes,
thus extending the options of further basic research
on the intrinsic factors governing routes of metastatic spread, presence or absence of metastatic
nodes, molecular profiling of primary tumours,
nonmetastatic and metastatic sentinel nodes,
examination of immunologic interactions occurring
in primary tumor and sentinel nodes [22], and,
finally, also exploring mechanisms of lymphangiogenesis and metastatic tumor-homing.
5.
Conclusions
The combination of lymphoscintigraphy with CT
enabled preoperative localisation of sentinel nodes
in anatomic detail and facilitated detection during
operation. Identification of more sentinel nodes
than expected might be due to timing of the
scintigraphy; some identified nodes may therefore
be second- and third-echelon nodes. This additional
technique provides us with more information but
should be investigated further before any of the
other methods of detection are excluded.
Acknowledgements
Dr Per Marits, MD, Department of Internal Medicine
Uppsala University Hospital, for providing us with
drawings.
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