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Part IX
https://t.me/med1917
Clinical Application: Thoracic
Radioguided Sentinel Lymph Node
https://t.me/med1917
Mapping and Biopsy in Non-small
Cell Lung Cancer (NSCLC)
Leili Zarifmahmoudi , David N. Krag ,
Ramin Sadeghi , Reza Bagheri , and Susan Shafi ee
2 0
Contents
20.1 Clinical Value and Relevance in Clinical
Practice 316
20.1.1 Indications for SLN
Mapping and Biopsy 316
20.2 Lymphatic Mapping Using
Radiotracers 316
20.2.1 Route of Administration 316
20.2.2 Intraoperative vs. Preoperative
Injection 323
20.2.3 Dose and Volume of the Injected
Radiotracer 324
20.2.4 Role of Preoperative Lymphoscintigraphy
and SPECT/CT 324
20.3 Alternative Approaches to SLN
Mapping and Biopsy in NSCLC 326
20.3.1 Blue Dyes 326
20.3.2 PET Radiotracers 327
L. Zarifmahmoudi , PhD • R. Sadeghi , MD
S. Shafi ee , MD
Nuclear Medicine Research Center, Mashhad
University of Medical Sciences , Mashhad , Iran
D. N. Krag , MD ()
Division of Surgical Oncology, Department of
Surgery , College of Medicine,
University of Vermont Given Building ,
Rm E309, 89 Beaumont Ave , Burlington ,
VT 05405 , USA
david.krag@uvm.edu
e-mail:
R. Bagheri , MD
Endoscopic & Minimal Invasive Surgery Research
Center, Mashhad University of Medical Sciences ,
Mashhad , Iran
20.3.3 Magnetic Particles 327
20.3.4 Fluorescent Dyes 327
20.3.5 Carbon Nanoparticles Suspension 328
20.4 Intraoperative Detection and Resection
of SLNs 329
20.4.1 Role of Portable Gamma Cameras and
3D Systems (fhSPECT) 330
Conclusion 330
References 330
Abstract
Mediastinal lymph node dissection is an
integral part of non-small cell lung cancer
(NSCLC) surgical treatment. However,
mediastinal lymph nodes are involved in
less than 30 % of clinically stage I patients.
Sentinel lymph node (SLN) mapping and
biopsy has been proposed as an alternative
to mediastinal lymph node dissection in
NSCLC since 1999. Most studies thus far
have used radiotracers for lymphatic mapping in NSCLC. Successful SLN mapping
and biopsy needs careful selection of
patients (only cN0 patients without history
of chemotherapy) and proper administration
route of the radiotracer (peri-tumoral is
preferred over intra-tumoral injections).
Alternative methods such as magnetic particles and fl uorescent dyes seem to be very
promising and need further validation studies in the future.
© Springer International Publishing Switzerland 2016
K. Herrmann et al. (eds.), Radioguided Surgery: Current Applications and Innovative
Directions in Clinical Practice, DOI 10.1007/978-3-319-26051-8_20
315
316
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L. Zarifmahmoudi et al.
20.1 Clinical Value and Relevance
in Clinical Practice
Non-small cell lung cancer (NSCLC) accounts
for almost 85 % of all types of lung cancers and
is one of the major causes of cancer-related death.
Mediastinal lymph node metastasis is one powerful and signifi cant prognostic factor which leads
to the considerable decrease in the 5-year survival rate and increase in disease recurrence possibility. Mediastinal lymph node dissection is an
integral part of NSCLC surgical treatment which
is associated with improved staging and survival.
However, mediastinal lymph nodes may not be
pathologically involved in the majority of patients
with NSCLC (less than 30 % of clinically stage I
patients) [ 1 ]. This is why less invasive methods
for evaluating mediastinal lymph nodes are
actively sought including CT scan, MRI, 18-FFDG PET, mediastinoscopy, and SLN mapping.
SLN mapping and biopsy was used for
NSCLC in 1999 by Little et al. [ 2 ] for the fi rst
time. However, Little et al. only used blue dye for
this purpose. The fi rst true radioguided SLN
mapping and biopsy for NSCLC was done by
Liptay et al. in 2000 [ 3 ], and since then numerous
groups have published their experience in this
regard [ 4 ]. Table 20.1 shows the characteristics of
available studies on SLN mapping and biopsy in
NSCLC in the medical literature [ 2 , 5 – 50 ]. In
case of duplicate reports, only the most recent
one is summarized in Table 20.1 .
20.1.1 Indications for SLN Mapping
and Biopsy
Patients with cN0 NSCLC tumors are the best candidates for SLN mapping and biopsy. Very large
necrotic tumors (>5 cm in diameter) and history of
previous chemotherapy can also decrease the accuracy of lymphatic mapping in NSCLC. Liptay
reported that reasons of detection failure were hilar
and/or mediastinal adenopathy in eight patients,
nine patients had tumors greater than 5 cm, and two
patients underwent preoperative chemoradiation
[ 13 ]. Melfi et al. in a study on 26 NSCLC patients
reported only one SLN detection failure which was
in a patient with a very large tumor [ 16 ]. In another
study Faries et al. reported only one false-negative
SLN result in 28 NSCLC patients, and this falsenegative case had a history of chemotherapy [ 7 ].
The reason is straightforward: patients with large
tumors and clinical (or radiological) large lymph
nodes are more likely to have their SLNs completely replaced by tumor cells with resulting
detection failure and false negativity.
Histological type and location of NSCLC and
gender of the patients do not seem to be related to
the success or accuracy of SLN mapping and
biopsy in NSCLC [ 4 ].
20.2 Lymphatic Mapping Using
Radiotracers
Most of the studies thus far have used radiotracers for lymphatic mapping in NSCLC.
Tc-99 m-labeled HSA (human serum albumin),
fi ltered or non-fi ltered SC (sulfur colloid), NC
(nanocolloid), phytate, tin colloid, rhenium colloid, and antimony sulfi de colloid have all been
used for SLN mapping in NSCLC with very high
detection rate and sensitivity. Type of the radiotracer does not seem to change the success or
accuracy of SLN mapping and biopsy in NSCLC
[ 4 ].
In a study by Rzyman et al., four radiotracers
(Tc-99 m SC, Tc-99 m NC, Tc-99 m tin colloid,
and Tc-99 m rhenium colloid) were compared for
SLN mapping in 110 NSCLC patients, and no
difference between the tracers was observed [ 36 ].
It should be noted that not all groups agree with
our conclusion on the type of the radiotracer. Most
importantly, Nomori et al. compared Tc-99 m phytate and Tc-99 m tin colloid for SLN mapping and
biopsy of 147 patients. They reported that Tc-99 m
phytate could identify SLNs more readily than
Tc-99 m tin colloid, even in patients with a low
FEV1 [
24 ]. These results need to be validated in
further trials; overall all radiotracers thus far seem
to be reliable enough for SLN mapping and biopsy
in NSCLC.
20.2.1 Route of Administration
Two injection locations have been used thus far
for lymphatic mapping in NSCLC: peri-tumoral
and intra-tumoral. Most studies thus far used
20 Radioguided Sentinel Lymph Node Mapping and Biopsy in Non-small Cell Lung Cancer (NSCLC)
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317
Type of
Time of
Injection
Time from
injection to
Other
Volume
Dose/
volume
surgery
Intraoperative Open
injection
site
surgery
methods
(mL)
(mCi/mL) Blue dye
Intraoperative Open
tumoral
tumoral
Open
Intraoperative
28; through
tumoral
0.5/1 Isosulfan blue 1 N/A N/A Peri-
bronchoscope
3
Intraoperative Open
tumoral
Open
Intraoperative
Peri-
1 N/A N/A N/A 1 h
10 ] and
[
preoperative
tumoral
(50–
70 min)
CT-guided
tumoral
(78–300)
min
(continued)
Open
16 ]
[
Intraoperative Open
15 min Peri-
Intraoperative Open
tumoral
5 mL
3 N/A N/A Peri-
tumoral
green
Intraoperative Open
tumoral
Preoperative
Peri-
1/1.5 N/A N/A N/A 135 ± 55
Table 20.1 Characteristics of the studies on SLN mapping and biopsy in NSCLC
Number
Number
of
Number
of
patients
patients
with
of
patients
with
positive
SLN Radiotracer
positive
lymph
nodes
with
detected
SLN
Number
of
patients
Publication
year
Country of
origin
First author
8 8 N/A N/A Isosulfan blue 5 N/A N/A Peri-
36 17
1999
Little et al. Las Vegas,
5 5 N/A N/A Patent blue V 4 N/A 10 min Peri-
16 13
2001
USA
Klein et al. The Czech
3 3 Filtered
31 25
2002
Republic,
Olomouc
Schmidt et al. Louisiana,
Tc-99 m SC
USA
12 7 N/A N/A Patent blue V 5 N/A N/A Peri-
33 28
2003
Republic,
Brno
Jedlicka et al. The Czech
nanocolloid
7 7 Tc-99 m
26 25
2003
Pisa,
Italy
Melfi et al.
(2003 study)
7 6 N/A N/A N/A N/A Ferumoxide
0 0 N/A N/A Indocyanine
38 31
16 1
2003
Japan,
Sugi et al.
Nakagawa et al. Japan, Akita 2003
5 4 N/A N/A Isosulfan blue 3 N/A N/A Peri-
2003
Japan,
Yamaguchi
Sugi et al.
(indocyanine
green group)
18 9
Yamaguchi
(isosulfan blue
2 2 Tc-99 m tin
14 9
2003
Japan,
group)
Sugi et al.
colloid
Yamaguchi
(radiotracer
group)
318
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L. Zarifmahmoudi et al.
Intraoperative Open
N/A
Preoperative
tumoral
8/1–1.5 N/A N/A N/A 18 h Peri-
CT-guided
Intraoperative Open
tumoral
5 N/A N/A Peri-
Preoperative N/A
tumoral
N/A Peri-
green AND
hyaluronidase
Intraoperative Open
tumoral
tumoral
1.5–2 mL
Intraoperative Open
tumoral
Open
Typ e of
surgery
Preoperative
Time of
injection
Peri-
Injection
site
Time from
injection
to surgery
Other
methods
Vol u m e
(mL)
Dose/
2/1 N/A N/A N/A 1.4 h
volume
(mCi/mL) Blue dye
Intraoperative Open
using
bronchoscope
tumoral
(1–3 h)
0.5–2 N/A 10–15 min Peri-
1 or 0.5 Isosulfan blue
tumoral
(7 patients
only blue dye,
the rest both
methods)
Intraoperative Open
Intraoperative Open
tumoral
0.25–2 N/A N/A N/A 10–15 min Intra-
tumoral
Number
of
Number
of
patients
Number
of
Table 20.1 (continued)
nanocolloid
patients
with
positive
SLN Radiotracer
lymph
detected
of
Publication
Country of
10 9 Tc-99 m
nodes
SLN
20 19
patients
2003
year
origin
Lardinois et al. Switzerland,
First author
Zürich
with
positive
patients
with
Number
HSA or
Tc-99 m SC
11 10 Tc-99 m
28 28
2004
USA
Faries et al. California,
7 6 Tc-99 m SC 2/2 N/A N/A N/A N/A Peri-
12 12
Ni et al. China 2004
Tc-99 m SC
30 21 Filtered
2 2 N/A N/A Patent blue V 2–5 N/A N/A Peri-
148 104
2004
2004
USA
Forte et al. Rome,
Liptay Illinois,
11 6
Italy
colloid
15 13 Tc-99 m tin
2 2 N/A N/A Indocyanine
104 84
38 7
2004
2004
Japan,
Tokyo
Tottori
Nomori et al.
(2004 study)
Ito et al. Japan,
0 0 N/A N/A N/A N/A Iopamidol
17 14 N/A N/A Patent blue V 2–4 N/A 5–10 min Peri-
9 8
48 40
2004
2004
Yamaguchi
Ueda et al. Japan,
Bohanes et al. The Czech
15 11 N/A N/A Isosulfan blue 4 N/A N/A Peri-
Republic,
Olomouc
Zhu et al. China 2005
50 33
20 Radioguided Sentinel Lymph Node Mapping and Biopsy in Non-small Cell Lung Cancer (NSCLC)
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Intraoperative Open
Peri-
tumoral
(5–30 min)
2 N/A 18.5 min
(fi rst two
1.6 Patent blue V
patients only
had blue dye)
Open
Preoperative
(percutaneous)
Intraoperative Open
tumoral
Intraoperative Open
Peri-
tumoral
0.25 N/A N/A N/A 45 min
tumoral
(30–
60 min)
Intraoperative Open
4 N/A N/A Peri-
Intraoperative Open
tumoral
28.4 Peri-
blue
Intraoperative Open
Peri-
tumoral
5 mL
4 N/A 15–
0.5/2 Patent blue V
tumoral
100 min
(median
42;
methylene
50 min)
blue 68
Intraoperative Open
Intraoperative Open
tumoral
N/A N/A N/A N/A Peri-
1
Intraoperative Open
tumoral
15 min Peri-
(30 MBq)
(continued)
tumoral
1.6 mL
NC or
Tc-99 m SC
6 5 Tc-99 m
24 13
2005
UK
Tiffet et al. France, the
(one patient
had only
tracer
injection)
3 3 N/A N/A N/A N/A Iohexol 1 mL N/A Peri-
15 14
2005
Japan,
Yamaguchi
Sugi et al. (2005
study)
11 10 N/A N/A Isosulfan blue 0.5–2 N/A 5–21 min Peri-
15 13
2005
Pulte et al. New York,
USA
Tc-99 m SC
7 7 Filtered
28 26
Atinkaya et al. Turkey 2005
N/A N/A N/A N/A Methylene
4 4 N/A N/A N/A N/A Ferumoxide
60 55
20 16
Minamiya et al. Japan, Akita 2006
Ma et al. China 2006
35 30 Tc-99 m
110 110
2006
Rzyman et al. Norway,
nanocolloid
OR Tc-99 m
Poland
rhenium
colloid OR
Tc-99 m tin
colloid OR
Tc-99 m
fi ltered SC
4 4 N/A N/A Isosulfan blue 2.5 N/A N/A Peri-
Napoli 2007
Di Lieto et al.
24 12
(dye group)
HSA
12 12 Tc-99 m
29 29
Napoli 2007
Di Lieto et al.
10 7 N/A N/A N/A N/A Ferucarbotran
49 41
Japan, Akita 2007
Minamiya et al.
(radiotracer
group)
(peri-tumoral
group)
320
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L. Zarifmahmoudi et al.
bronchoscopy
or CT-guided)
70 min)
Open
Preoperative
2–8 N/A N/A N/A 1 day Peri-
CT-guided
Intraoperative Open
tumoral
4 N/A N/A Peri-
Intraoperative Open
tumoral
blue
0.25 N/A N/A N/A N/A Intra-
Intraoperative Open 25;
tumoral
15 min Peri-
VATS 26
tumoral
1.6 mL
Typ e of
surgery
Intraoperative Open
Time of
injection
site
to surgery
methods
(mL)
(mCi/mL) Blue dye
tumoral +
15 min Peri-
1.6 mL
Injection
Time from
injection
Other
Vol u m e
Dose/
volume
Intraoperative Open
subpleural
Peri-
Every
0.4 Patent blue V 2 Fluorescein
Intraoperative Open
Peri-
60 min
tumoral
(in 12.5 %
tumoral
10 min till
10 % (1 mL)
Open; 2 VATS
Preoperative
Peri-
more than
30 min)
1 N/A N/A N/A 1 h
(by
tumoral
(50–
Number
of
Number
of
patients
Number
of
Table 20.1 (continued)
nanocolloid
patients
with
positive
SLN Radiotracer
lymph
nodes
detected
SLN
of
patients
Publication
year
Country of
origin
First author
3 3 N/A N/A N/A N/A Ferucarbotran
27 22
Japan, Akita 2007
Minamiya et al.
(peri-tumoral
with
positive
patients
with
Number
N/A N/A Tc-99 m
10 0
2007
Lausanne
and subpleural
group)
Meyer et al. Switzerland,
5 4 N/A N/A Patent blue V 2 N/A 15–30 min
32 15
Bustos et al. Brazil 2008
NC
8 8 Tc-99 m
19 16
2008
Pisa,
Italy
Melfi et al.
(2008 study)
colloid
32 32 Tc-99 m tin
9 8 N/A N/A Methylene
170 133
30 27
2008
Japan,
Yamaguchi
Liu et al. China 2009
Sugi et al.
(2008 study)
Tc-99 m SC
6 2 Filtered
39 24
2009
USA
Liptay et al. Illinois,
4 3 N/A N/A N/A N/A Ferucarbotran
51 41
Ono et al. Japan, Akita 2009
20 Radioguided Sentinel Lymph Node Mapping and Biopsy in Non-small Cell Lung Cancer (NSCLC)
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Open 58;
Preoperative
6–8/1–1.5 N/A N/A N/A 18 h Peri-
VATS 15
CT-guided
tumoral
Open 58;
Preoperative
6–8/1–1.5 N/A N/A N/A 18 h Peri-
VATS 15
CT-guided
Intraoperative Open
tumoral
N/A Peri-
tumoral
green
fl uorescence
Intraoperative Open
5 Peri-
2–5 mL
tumoral
green
fl uorescence
Intraoperative Open
0.25 mL
0.25 N/A N/A N/A 5 min Peri-
Intraoperative Open
tumoral
N/A Peri-
Intraoperative VATS
tumoral
nanoparticles
tumoral
10 min Peri-
suspension
green
VATS
Preoperative
(by
tumoral
N/A Peri-
fl uorescence
3 mL
bronchoscopy)
VATS in 40
Preoperative
CT-guided
tumoral
1/0.2 N/A N/A N/A 1–2 h Peri-
Intraoperative VATS in 26
1/0.2 N/A N/A N/A 5 min Peri-
tumoral
(continued)
Intraoperative Open
tumoral
0.25 N/A N/A N/A 1 h Peri-
colloid
5 5 Tc-99 m tin
2009
Japan,
Nomori et al.
73 54
Tokyo
(tin colloid
6 6 Tc-99 m
74 66
2009
Japan,
group)
Nomori et al.
phytate
8 7 N/A N/A N/A N/A Indocyanine
20 20
2009
Tokyo
Tokyo
(phytate group)
Ichinose et al. Japan,
2 2 N/A N/A N/A N/A Indocyanine
12 8
2009
Tokushima
Matsuoka et al. Japan,
albumin
7 5 Tc-99 m
7 6 N/A N/A N/A N/A carbon
37 35
15 11
Spain 2009
Jiang-Peng et al. China 2010
Barcelo-
Galindez et al.
2 1 N/A N/A N/A N/A Indocyanine
61 49
Yamashita et al. Japan, Oita 2011
2 2 N/A N/A N/A N/A Iopamidol
13 12
2012
Tokushima
Takizawa et al. Japan,
MSA
11 11 Tc-99 m
48 46
South Korea 2012
Kim et al.
(preoperative
group)
MSA
6 6 Tc-99 m
34 33
South Korea 2012
Kim et al.
(intraoperative
group)
nanocolloid
11 6 Tc-99 m
25 23
Turkey 2013
Karamustafaoglu
et al.
322
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L. Zarifmahmoudi et al.
18 ],
20 ]
Thoracoscopic
Typ e of
surgery
[
Open
Intraoperative Open
Time of
injection
Intraoperative Open [
Injection
site
tumoral
Time from
injection
to surgery
5 min Peri-
Other
methods
green
fl uorescence
Vol u m e
(mL)
Dose/
volume
(mCi/mL) Blue dye
Number
of
patients
with
positive
SLN Radiotracer
Intraoperative Open
N/A N/A 30 min Peri-
tumoral
blue
tumoral
Intraoperative Open
tumoral
2/0.3 N/A N/A N/A 59 min Peri-
nanocolloid
Pre operative
CT-guided
tumoral
1–3 h Peri-
for PET/CT
imaging
Number
of
patients
with
Number
of
patients
Table 20.1 (continued)
positive
with
Number
6 6 N/A N/A N/A N/A Indocyanine
lymph
nodes
15
(success
rate
increased
with
increasing
dose of
the
mapping
detected
SLN
38
of
patients
2013
Publication
year
origin
First author
USA
Gilmore et al. Boston,
Country of
material)
Hong et al. China 2014 61 59 14 13 Tc-99 m SC N/A Methylene
Zeybek et al. Turkey 2014 12 10 1 1 Tc-99 m SC 5/5 N/A N/A N/A 96 min Peri-
Spain 2014 29 29 N/A N/A Tc-99 m
Galbis Caravajal
et al.
Eo et al. South Korea 2015 34 34 8 8 N/A N/A N/A N/A Ga-68- MSA
20 Radioguided Sentinel Lymph Node Mapping and Biopsy in Non-small Cell Lung Cancer (NSCLC)
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peri-tumoral injection of the tracer for SLN mapping and biopsy with excellent results [ 4 , 51 ]. On
the other hand, intra-tumoral injection was used
in two studies by Liptay et al. with lower detection rate and sensitivity [ 13 , 14 ]. The latter study
(CALGB 140203 multicenter phase II trial) was
terminated due to disappointing accuracy of the
technique [ 14 ]. In another study by Melfi et al.,
the reason of three SLN detection failures was
reported to be intratumoral injection of the radiotracer [ 17 ]. It seems that intra-tumoral injection
of the tracer should be avoided and only peritumoral injection should be used.
20.2.2 Intraoperative vs.
Preoperative Injection
The time of radiotracer injection in relation to the
surgery is a matter of debate. Rationale of preoperative CT-guided or bronchoscopy-guided injection is to let the time pass enough for the
radiotracer to reach the SLNs in the lymphatic
system. Several studies used preoperative injection of the tracer with excellent detection rate and
sensitivity. Taghizadeh et al. in a systematic
review showed pooled detection rate and
sensitivity of 82.1 % [75.4–87.3 %] and 97 %
[90–99 %], respectively [ 4 ].
However, experience of SLN mapping and
biopsy in breast cancer showed that radiotracer
movement in the lymphatic system is very rapid,
and there is no need for a long time interval between
injection and surgery [ 52 – 55 ]. Experience on
NSCLC also showed the same fi ndings (Fig. 20.1 ),
and intraoperative injection of the radiotracer
showed comparable detection rate and sensitivity
as the preoperative injection technique. Mean time
of injection to SLN detection by a gamma detection probe was 10 min. Taghizadeh et al. showed
pooled detection rate and sensitivity of 88.5 %
[75.4–95.17 %] and 92 % [72–98 %], respectively,
for intraoperative injection technique.
Overall, it seems that intraoperative radiotracer
injection is as accurate and as successful as preoperative injection without any need for CT for
Fig. 20.1 Time course of sentinel lymph node visualization after preoperative injection of the radiotracer. The
sentinel node could be easily identifi ed as early as 30 min
to 21 h postinjection (Reproduced with permission
10.1016/j.ejcts.2010.01.012 ) )
(
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