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18 Radioguided Sentinel Lymph Node Mapping and Biopsy in Colorectal Cancer
https://t.me/med1917
291
(most often 1 ml
99m
Tc solution is applied submucosally around the tumor). If it is possible to
go cephalad, beyond the tumor, the radiocolloid
is administered as four injections; otherwise, it
is administered as three injections (from the two
sides lateral and distal to the tumor). At 1–2 h
before surgery, lymphoscintigraphy is performed. The main issue regarding the use of
radiocolloids is the direct proximity of the main
nodal stations (pararectal lymph nodes) and the
primary rectal tumor, the result of which is an
overlap of radioactivity and more problematic
identifi cation of SLNs than in cases of colon
cancer.
In publications on the ex vivo lymphatic
mapping of rectal cancer, the authors often
underline the advantages of this approach, from
the perspective of both blue dye administration
and lymph node identifi cation. They point out
the relatively short duration of the procedure
(around 10 min) and the lack of allergic reactions. However, they often do not take into
account the limitations ensuing from such a
method of dye application [ 17 , 100 , 102 , 104 ,
109 ]. Accurate ex vivo lymphatic mapping of
the total mesorectum specimen is only possible
if there is truly no disruption of the intrinsic vascular and lymphatic anatomy of the specimen,
including the small lymphatic channels leading
to the lymph nodes harvested within the specimen. Another issue is that the disruption of the
intact total mesorectum specimen during surgery can lead to intravasation of radiocolloid
from the specimen, thus causing a mismatch in
the post-resection imaging as compared with the
preoperative lymphoscintigraphy imaging.
Likewise, ex vivo lymphatic mapping may
entail discrepancies between the pattern of lymphatic fl ow within the total mesorectum specimen and that observed in vivo in the native
mesorectum secondary to aberrant lymphatic
fl ow. The conclusion from ex vivo mapping is
that the analysis of other, non-SLNs is more
important and forces intricate analysis of the
SLN into the background [
17 , 69 , 100 – 102 ,
104 , 109 ]. Details and results of studies of SLN
biopsy in rectal cancer are summarized in
Table 18.2 .
18.5.4 Clinical Use of Radiocolloids
in SLN Biopsy in Anal Cancer
According to current recommendations, the initial therapeutic approach to anal squamous cell
carcinoma is radiochemotherapy, with surgical
management generally being considered only in
selected cases of local recurrent disease.
Synchronous regional lymph node metastases are
found in 10–25 % of patients, but as surgical
treatment is not the standard procedure, the true
state of lymph nodes is not a key issue. The lymphatic drainage from tumors around the anal
canal depends on their location in reference to the
Z-line. For tumors located below this line, the
main route of lymphatic drainage is to the inguinal lymph nodes and further along the femoral
artery. However, around 15–35 % of metastases
to the inguinal lymph nodes are encountered in
patients with tumors located above the Z-line.
This indicates that the Z-line does not represent
an exact borderline for the lymphatic system and
metastatic spread [ 69 , 101 , 109 ]. Drainage is
often bilateral, which signifi cantly increases the
importance of preoperative lymphoscintigraphy.
Furthermore, in most cases the inguinal region is
the predominant lymphatic drainage pathway
[ 98 ]. Hence, if the inguinal lymph nodes seem
clinically or radiologically suspicious, or histopathologic evidence of metastasis is available,
the primary treatment is radiation. In selected
cases, radiation treatment is combined with
inguinal lymphadenectomy. In cases that are not
clinically suspicious, some medical centers
advise strict control and observation. Others,
however, propose elective radiation therapy of
the inguinal region with the exclusion of early
cases, i.e., stages T1 and T2 (which have a
5–10 % frequency of inguinal lymph node invasion). Hence, SLN biopsy has been proposed as a
tool for precise and minimally invasive assessment of the regional inguinal lymph nodes and
also for further therapeutic decision making
(radiotherapy). The method applicable is fi rst and
foremost the radiocolloid procedure, sometimes
in combination with the blue dye method.
Radiotracers such as
colloidal human albumin,
99m
Tc-sulfur colloid,
99m
99m
Tc-
Tc-colloidal
292
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D. Murawa et al.
N(+) in
H&E (%) Technique Injection Identifi cation DR (%) Sensitivity (%) Upstaging (%) ALD (%)
31 23 BD Post-op Ex vivo 97 57 13 –
92 29 BD Intraop + post-op In vivo + ex vivo 91 93 26 7
71 32 BD Intraop In vivo 92 96 7 4
Dis Colon Rectum
11 ] 2004
Saha [
World J Surg
102 ] 2005
Baton [
34 32 BD Post-op Ex vivo 76 40 6 –
Br J Surg
103 ] 2005
Braat [
Am J Surg
10 ] 2006
Saha [
47 43 BD Post-op Ex vivo 98 80 15 –
Int J Colorectal Dis
104 ] 2007
Yagci [
32 53 BD Post-op Ex vivo 78 57 27 –
Eur J Surg Oncol
17 ] 2009
van der Zaag [
N(+) in H&E (%),the percentage of patients with infi ltrated lymph nodes at H&E staining
DR detection rate, RC radiocolloid, BD blue dye, Pre-op preoperative, Intraop , intraoperative, Post-op postoperative
48 33 RC Pre-op Ex vivo 96 44 0 4
56 29 RC Pre-op In vivo 91 81 – –
No. of
patients
Surgery
Surg Clin North Am
100 ] 2004
99 ] 2000
Bembenek [
Main author Year Journal
Table 18.2 Details and results of studies of SLN biopsy in rectal cancer, performed after the year 2000
Kitagawa [
18 Radioguided Sentinel Lymph Node Mapping and Biopsy in Colorectal Cancer
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Table 18.3 Details and results of studies of SLN biopsy in anal cancer, performed after the year 2000
Pts with
No.
Main author Year Journal
108 ] 2003
Perera [
106 ] 2003
Damin [
105 ] 2003
Bobin [
109 ] 2004
Ulmer [
Gretschel [
Mistrangelo
110 ]
[
DR detection rate, RC radiocolloid, BD blue dye, Pre-op preoperative, Intraop , intraoperative, pts patients, SLN sentinel
lymph node
107 ] 2008
Dis Colon Rectum
Dis Colon Rectum
Cancer Radiother
Ann Surg Oncol
Eur J Surg Oncol
2009
Q J Nucl Med Mol
Imaging
of pts Technique Injection
12 RC + BD Pre-op + intraop 67 67 29
14 RC + BD Pre-op + intraop 100 100 7
33 RC + BD Pre-op + intraop 100 100 21
17 RC Pre-op 76 71 43
40 RC Pre-op 90 56 30
35 RC Pre-op 97 97 20
DR
(%)
SLN in the
inguinal
region (%)
293
Pts with
positive
SLN in the
inguinal
region (%)
rhenium sulfi de, and 99 Tc-antimony trisulfi de are
used. The radiocolloid is administered into the
subcutaneous or submucosal tissue from the four
injection sites around the primary tumor in a total
dose ranging from 5 MBq (0.135 mCi) to 37 MBq
(1.0 mCi). The frequency of localization is
75–100 %, and identifi cation of metastases in the
inguinal lymph nodes is successfully achieved in
10–40 % of patients, with a low rate of complications of between 3 % and 7 % [ 98 , 103 – 110 ]. The
results of selected studies concerning the application of SLN biopsy in anal cancer are shown in
Table 18.3 .
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Radioguided Surgery
https://t.me/med1917
for Gastroenteropancreatic
Neuroendocrine Tumors
Nathan C. Hall , Christina Bluemel ,
Sergi Vidal-Sicart , and Stephen P. Povoski
1 9
Contents
19.1 The Role of Surgery in the Treatment of
Gastroenteropancreatic Tumors 300
19.2 Historical Use of Gamma-Ray-Emitting
Radiotracers for Intraoperative
Localization of GEP-NET During
Radioguided Surgery 301
111
19.2.1
19.2.2
19.2.3
19.2.4
19.2.5
Portions of the contents of this chapter are adapted from 1
prior article:
(1) Hall et al.: Intraoperative utilization of a portable large
fi eld of view gamma camera and handheld gamma detection probe for radioguided localization and prediction of
complete surgical resection of gastrinoma: Proof of concept. J Am Coll Surg. 2015;221(2):300–308 . doi:
dx.doi.org/10.1016/j.jamcollsurg.2015.03.047
N. C. Hall , MD, PhD ()
Department of Radiology , University of
Pennsylvania , Philadelphia , PA 19104 , USA
e-mail:
C. Bluemel , MD
Department of Nuclear Medicine , University Hospital
of Würzburg , Würzburg , Germany
e-mail:
S. Vidal-Sicart , MD, PhD
Department of Nuclear Medicine , Hospital ClinicBarcelona , Barcelona , Spain
e-mail:
In-Pentetreotide (OctreoScan) 301
125
I-Labeled Somatostatin Analogues 302
99m
Tc-Labeled Somatostatin Analogues 302
123
I-MIBG 303
68
Ga-Somatostatin Analogues 304
nathan.hall@uphs.upenn.edu
Bluemel_C@ukw.de
svidalclinic@ub.es
http://
19.3 Intraoperative Imaging for Localization
and Verifi cation of Resection of
GEP-NETs: Illustration of This
Approach Using Real-Time, Large
Field-of-View, Portable Gamma Camera
Imaging during Radioguided Surgery in
Patients with Zollinger-Ellison
Syndrome 304
19.4 Concluding Remarks 307
References 308
Abstract
Gastroenteropancreatic (GEP) neuroendocrine
tumors (NETs) are rare neoplasms, but the
incidence is rising. Surgery plays a central role
in its management, as it is the only potentially
curative treatment option for limited primary
and recurrent disease and is critical in the
surgical debulking and cytoreduction of
advanced recurrent and metastatic disease. For
preoperative detection of disease, gammaemitting radiopharmaceuticals are available
which can also be intraoperatively used for
radioguided surgery. Most experience exists
S. P. Povoski , MD
Division of Surgical Oncology,
Department of Surgery , Arthur G. James Cancer
Hospital and Richard J. Solove Research Institute
and Comprehensive Cancer Center,
The Ohio State University , Columbus ,
OH 43210 , USA
stephen.povoski@osumc.edu
e-mail:
© 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_19
299
300
https://t.me/med1917
111
for
In-octreotide, a radiopharmaceutical
targeting agent specifi cally binding to somatostatin receptors expressed on the tumor
cell surface. In comparison to traditional
intraoperative inspection and palpation techniques, intraoperative localization using
111
In-octreotide has demonstrated high sensitivity and detection rates. Recently, fi rst
promising results have been reported for utilization of intraoperative scintigraphic imaging
in GEP-NETs in addition to more commonplace gamma probe localization.
19.1 The Role of Surgery
in the Treatment
of Gastroenteropancreatic
Tumors
Gastroenteropancreatic (GEP) neuroendocrine
tumors (NETs) represent a heterogeneous subset
of functioning or nonfunctioning tumors arising
from the neuroendocrine system. GEP-NETs
have the potential of producing, storing, and
secreting a variety of peptide hormones and biogenic amines which can lead to distinct clinical
syndromes which can have signifi cant symptoms.
Based on this, GEP-NETs are broadly subdivided
into “functional” or “nonfunctional” tumors (with
or without a clinical syndrome attributable to biochemical hypersecretion, respectively) [ 1 ]. These
tumors have historically been relatively rare but
are increasing in incidence [
involve a variety of morphologic structures
including the stomach, small intestine, colon, rectum, pancreas, appendix, and liver [ 1 , 6 – 8 ].
In general, GEP-NETs are relatively slowgrowing tumors and have longer survival statistics than their adenocarcinoma counterparts
affecting the same organs [ 8 ]. The symptoms of
these tumors range from asymptomatic nonfunctioning tumors to carcinoid syndrome or carcinoid crisis arising from functioning tumors that
can secrete a variety of hormones and peptides
[ 9 ]. Nonfunctioning GEP-NETs typically
become large and/or widely metastatic before
becoming symptomatic and subsequently diagnosed [ 8 , 10 ].
2 – 5 ]. GEP- NETs can
N.C. Hall et al.
Independent of the functionality and/or anatomic origin, one attribute most of the GEP-NETs
share in common is that the only curative therapeutic option is complete surgical resection in
patients with limited disease [
1 , 6 , 8 , 10 – 13 ].
Radical oncologic surgical resection is generally
indicated unless the tumors are small carcinoids
(<2 cm) of the stomach, small intestine, appendix,
rectum, or insulinomas [ 14 – 20 ]. In these cases,
conservative surgical or endoscopic resections
may be appropriate as these usually have low
malignant potential. Surgical resection has also
proven useful for debulking and cytoreduction of
advanced or metastatic disease and remains integral in the management of recurrent disease [ 6 , 8 ].
Before surgery, the detection and localization of
disease manifestations are crucial. The introduc-
123
tion of
111
I-Metaiodobenzylguanidine (MIBG) and
In-DTPA- D -Phe 1 -octreotide/
123
I-Tyr 3 -octreotide,
binding to somatostatin receptors expressed on
neuroendocrine tumor cells, specifi cally addresses
this issue [ 21 ]. High detection rates for MIBG or
somatostatin- directed imaging were shown,
exceeding magnetic resonance imaging (MRI) or
computed tomography (CT) and also revised staging and management in patients [ 21 – 24 ].
For planning a radioguided surgery approach
to GEP-NETs, a whole-body scintigraphy must
be performed and, if possible, a single photon
emission computed tomography (SPECT) or
SPECT/CT to fully evaluate all sites of disease
that are planned to be surgically removed.
SPECT/CT helps to plan the surgical approach
and contributes to the success of radioguided surgery. In addition, subsequent to preoperative
radiotracer injection and prior to surgical intervention, scintigraphic imaging is recommended
to verify adequate uptake of the radiotracer by all
lesions planned for surgical removal [
25 , 26 ].
Despite improvements in preoperative imaging technologies, intraoperative localization of
small tumor lesions remains challenging.
Therefore, various intraoperative localization
techniques have been investigated [ 6 , 27 ].
Many groups have reported improved success
of intraoperative GEP-NET detection using a
handheld gamma detection probe (HGDP) during
surgery in conjunction with preoperatively administration of various radiotracers [ 28 – 38 ]. When an
19 Radioguided Surgery for Gastroenteropancreatic Neuroendocrine Tumors
https://t.me/med1917
301
HGDP is used to assist the surgeon in identifi cation of small tumors within the abdominal surgical fi eld, a high degree of technical profi ciency is
required by the surgeon [ 39 – 41 ]. Successful use
of the HGDP to identify all sites of disease
requires: (1) appropriate preoperative diagnostic
imaging to map the general locations of the sites
of disease, (2) obtaining adequate surgical exposure, and (3) the performance of a methodical and
systematic HGDP survey of the abdominal surgical fi eld. Despite improvements demonstrated by
utilization of the HGDP in combination with preoperative diagnostic imaging for verifi cation of
the general locations of the sites of disease, incorporation of the preoperative imaging data into
useful real-time information for localization of
tumor with the HGDP is limited. Real-time intraoperative images during the radioguided resection
procedure could be very benefi cial for verifying
resection of all sites of disease, a technique which
is described in detail later in this chapter.
19.2 Historical Use of GammaRay- Emitting Radiotracers
for Intraoperative
Localization of GEP-NET
during Radioguided Surgery
There are a variety of specifi c and nonspecifi c
radiotracers and radionuclides that target multiple cellular components used in the diagnosis and
intraoperative localization of GEP-NETs during
radioguided surgery. It has been demonstrated by
a number of research groups that an improvement
in intraoperative detectability of GEP-NETs can
result from combining preoperative GEP-NETtargeted radiotracer scintigraphy with real-time
intraoperative localization assistance using an
HGDP.
19.2.1
111
In-Pentetreotide
(OctreoScan)
111
In-pentetreotide is widely used in scintigraphic
imaging of NETs and also used in radioguided
surgery. Fortunately, most GEP- NETs express
somatostatin (SS) receptors, specifi cally sub-
types 2 and 5. As a result, long-acting somatostatin analogues, such as octreotide, have been
developed to target these receptors [
42 , 43 ]. By
labeling octreotide with radionuclides, those
GEP-NETs expressing somatostatin receptors,
specifi cally subtypes 2 and 5, can be successfully
identifi ed [ 32 , 44 , 45 ].
The most frequently used radiotracer is
111
In-pentetreotide.
111
In-pentetreotide is a radiolabeled eight-peptide protein segment of somatostatin binding well to the SS2 and SS5 receptors
[ 46 ]. Somatostatin has a relatively short half-life
with respect to its usefulness in imaging (≈2 min),
whereas
111
In-pentetreotide has a longer biological half-life (1 h) and is, therefore, more useful for
diagnostic imaging as the radiotracer requires
time to reach and bind to the tumor receptors after
injection and prior to imaging.
111
In-pentetreotide
is commonly used in diagnosis and staging of a
variety of NETs, including the GEP-NETs. The
detection rate of somatostatin receptor scintigraphy with
111
In-pentetreotide was reported between
80 and 100 % in different studies. Somatostatin
receptor scintigraphy also provides information
about somatostatin receptor expression that might
indicate effi cacy of treatment with octreotide or
other somatostatin analogues.
The injected activity reported in literature
ranges from 120 to 220 MBq (3.2–5.9 mCi). The
recommended activity to obtain good image quality is about 200 MBq (5.4 mCi). However, activities lower than 200 MBq can be administered
without loss of imaging quality by adjusting the
acquisition parameters accordingly. The amount
of injected
111
In-pentreotide for radioguided surgery ranged between 111 and 275 MBq [ 35 , 47 –
49 ]. Injection was mainly performed 24–48 h
prior to surgery [ 35 , 47 , 48 ], but radiotracer injec-
tion up to 7 days prior to surgery is suitable [ 49 ].
Planar images (anterior and posterior of the
head, neck, chest, abdomen, pelvis, and lower
extremities; 15 min per view in a gamma camera
fi tted with a medium-energy, parallel-hole collimator) should be acquired at 4 and 24 h or 24 and
48 h post-injection. Four-hour images benefi t from
a minimal bowel activity. At least one SPECT or
SPECT/CT should be acquired in order to more
precisely localize disease and assist in preoperative planning for resection. Spot views may be
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