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European Journal of Surgical Oncology 44 (2018) 725e730

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European Journal of Surgical Oncology


journal homepage: www.ejso.com

Radioactive seed localisation of non-palpable lymph nodes e A


feasibility study
C.M.S. Hassing a, *, T.F. Tvedskov a, N. Kroman a, T.L. Klausen b, J.B. Drejøe c, J.F. Tvedskov d,
T.-L. Lambine e, H. Kledal e, G. Lelkaitis f, L. Langhans a
a
Department of Breast Surgery, Rigshospitalet, University of Copenhagen, Denmark
b
Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Denmark
c
Department of Plastic Surgery and Burns, Rigshospitalet, University of Copenhagen, Denmark
d
Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet, University of Copenhagen, Denmark
e
Department of Radiology, Rigshospitalet, University of Copenhagen, Denmark
f
Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Background: Radioactive seed localisation (RSL) is a preoperative localisation method using a small titanium
Accepted 23 February 2018 seed containing iodine-125. The method is increasingly applied for localising non-palpable lesions in the
Available online 6 March 2018 treatment of breast cancer. We believe that RSL has the potential to be used in various surgical specialties. The
aim of this feasibility study was to test RSL as a preoperative localisation of non-palpable lymph nodes.
Keywords: Methods: Between November 24, 2015 and October 26, 2016, 15 patients with suspicious lymph nodes on
Preoperative localisation
imaging were included in the study. The lymph nodes were located in the axillary region (n ¼ 9), the
Lymph node
head and neck region (n ¼ 5) and the inguinal region (n ¼ 1). The seeds were placed in the centre of the
Non-palpable lesion
Iodine seed
lymph node, in the capsule or just outside the capsule guided by ultrasound. During surgery, incision and
Radioactive seed localisation localisation of the lymph nodes were performed based on the auditory signal of the gamma probe. After
excision, lymph nodes including iodine seeds were sent for pathologic examination and the seeds were
returned to the Department of Nuclear Medicine.
Results: The non-palpable lymph nodes were all successfully marked using ultrasound. The lymph nodes
were successfully localised and excised during surgery, and the procedure was performed without
complications in the majority of the cases.
Conclusion: Localisation of suspicious non-palpable lymph nodes using RSL is feasible. RSL may ease the
surgical procedure, minimise trauma to the surrounding tissue and ultimately benefit the patient. Future
prospective studies are necessary to determine the further use of RSL within different surgical specialties.
© 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical
Oncology. All rights reserved.

Introduction Different methods of preoperative localisation exist and include


tracer injection with Technetium-99 (99 mTc)/radio guided occult
The comprehensive use of anatomical and functional imaging lesion localisation (ROLL), wire-guided localisation (WGL) and
modalities has led to an increased number of detected non- intraoperative ultrasound guidance (IOUS) [1]. ROLL and WGL both
palpable lesions including suspicious lymph nodes. Lymph nodes have restricted flexibility in the scheduling of the procedures and
identified on imaging are often small and non-palpable. This makes technical difficulties have been described for both methods [2].
it difficult to localise and differentiate them from normal tissue Intraoperative ultrasound requires a surgeon with experience in
during surgery without preoperative localisation. ultrasound examination.
Radioactive seed localisation (RSL) is a relatively new method of
preoperative localisation involving a small titanium seed contain-
ing radioactive iodine (I-125). The method was introduced in breast
surgery in 2001 and has gained ground due to an increasing
* Corresponding author. Department of Breast Surgery, Rigshospitalet, University
of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. number of non-palpable breast lesions identified through
E-mail address: christina.marie.schioettz.hassing@regionh.dk (C.M.S. Hassing). mammographic screening programs [3,4]. The iodine seed is

https://doi.org/10.1016/j.ejso.2018.02.211
0748-7983/© 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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726 C.M.S. Hassing et al. / European Journal of Surgical Oncology 44 (2018) 725e730

preoperatively placed in the centre of the suspicious lesion guided Surgery: The handheld gamma probe was used to localise the
by ultrasound or mammography. The non-palpable lesion is then iodine seed during surgery. The transdermal auditory signal of the
localised during surgery with a handheld gamma probe [5]. probe guided the localisation of the incision, and the lymph node
In our institution, RSL has been tested in a large randomised trial including the iodine seed was excised. The surgeon confirmed that
where the aim was to compare the rate of positive resection mar- both lymph node and iodine seed were removed correctly as ac-
gins between RSL and WGL in breast conserving surgery [6]. The tivity was detected only in the surgical specimen and not in the
experience from this trial has prompted us to investigate further resection bed. The iodine seeds were sent to the Department of
use of the method. We believe that RSL has the potential to be used Pathology in either separate bags or located in the lymph nodes.
in various surgical specialties as preoperative localisation of sus- Pathologic examination: The pathologic examination was per-
picious, non-palpable lesions. RSL may overcome some of the formed according to standard procedures. The iodine seeds, located
limitations of the existing methods and ease the surgical identifi- in the lymph nodes, were identified with a gamma probe if not
cation of the lesion. However, only a limited number of studies have visualised immediately. The iodine seeds were removed and
been published on the use of RSL outside breast surgery and the returned to the Department of Nuclear Medicine.
evidence is sparse.
Accordingly, the aim of this study was to test the feasibility of RSL
Outcomes
of suspicious non-palpable lymph nodes within Otorhinolaryn-
gology/Head and Neck Surgery, Plastic Surgery and Breast Surgery.
The primary outcome was identification rate of lymph nodes
suspicious on imaging.
Methods
Secondary outcomes were duration of the surgical procedure,
defined as time from skin incision to the end of surgery, and
Patients
complication rate. Assessment of complications was done from the
time of surgery until the postoperative visit at the outpatient clinic
15 patients with suspicious non-palpable lymph nodes and no
and included infection, hematoma, seroma and wound rupture.
primary tumour site present, referred to the Department of
Otorhinolaryngology/Head and Neck Surgery, Plastic Surgery or
Breast Surgery, were identified in the outpatient clinic and asked to Results
participate (five patients in each department, Table 1). The inclu-
sion criteria were: a suspicious lymph node in the axillary, inguinal Patients were included between November 24, 2015 and
or head and neck region, visible on ultrasound, accessible for October 26, 2016. Characteristics of the included patients are out-
marking and in accordance with the lymph node seen on PET/CT, CT lined in Table 1. The median age was 57 years, (range: 38e81).
or mammography. Exclusion criteria were: patients not capable of Preoperatively, 73% (n ¼ 11) of the patients had a Positron
understanding the information, pregnant or breast-feeding pa- Emission Tomography/Computed Tomography (PET/CT) scan per-
tients, patients under the age of 18 years. formed. The suspicious lymph nodes in all of the 11 patients were
Patients were given comprehensive oral and written informa- PET positive. The remaining 4 patients had their suspicious lymph
tion about the study, and if they decided to participate, an informed nodes detected on either CT (n ¼ 3) or diagnostic mammography
consent was signed. Permission was obtained from the National (n ¼ 1). Four of the patients had inconclusive biopsies performed
Committee on Health Research Ethics. Record No. H-I-2013-066 prior to surgery, further details regarding the indication for the
and approved by the Danish Medicine and Health Authorities and open diagnostic lymph node biopsy are described in Table 1.
the Danish Data Protection Agency. The operative findings and definitive pathology of the lymph
nodes are outlined in Table 2. The iodine seeds were placed in the
Procedures centre of the lymph node, in the capsule or just outside the capsule
in 12 patients. In three patients the iodine seed had been placed in
I-125 seed placement: The seeds consisted of I-125 encapsu- the tissue surrounding the lymph node, which complicated the
lated by titanium and measure 4.5  0.8 mm. Seeds used in the identification during surgery, but all suspicious lymph nodes were
study had an activity between 0.8 and 4.7 MBq. Two different kinds successfully identified and excised. The mean duration of the sur-
of seeds were used in the study: separate seeds (BARD Brachy- gical procedures was 75 min. However, five of the procedures had
therapy, INC. Carol Stream, IL, USA) and prepacked seeds (Intra- prolonged duration due to more widespread pathologic tissue than
Medical Imaging, Hawthorne, CA, USA). expected preoperatively (n ¼ 3), frozen section microscopy (n ¼ 1)
The marking of the lymph nodes was performed either on the or ultrasound examination to verify that the excised lymph node
day of surgery or the day before at the Department of Radiology. was the correct one, as the iodine seed had been placed in the
Separate seeds (BARD) were placed in an 18-gauge needle (CP surrounding tissue (n ¼ 1). In the majority of patients only the
Medical, Inc., Portland, OR) with bone wax occluding the tip to keep marked node was removed at surgery. An additional lymph node
the iodine seed fixed until placement. A stilette was then carefully was removed in five of the patients due to suspicious characteris-
inserted without advancing it completely. The needle was intro- tics. In four patients more tissue than the lymph nodes was
duced under ultrasound guidance, and the stilette was advanced removed due to extensive disease. After pathologic examination
completely to place the iodine seed in the centre of the lymph node, seven lymph nodes were diagnosed as reactive, two as benign and
in the capsule or just outside the capsule. In patients in Head and the remaining six lymph nodes contained metastasis from either
Neck Surgery, the iodine seed was placed just outside the capsule to ductal or lobular carcinoma, squamous cell carcinoma or malignant
avoid capsule rupture. Deployment of the seed in the tissue was melanoma. All iodine seeds were identified during gross exami-
confirmed with a handheld gamma probe (Neo-2000; Johnson and nation and returned to the Department of Nuclear Medicine.
Johnson, Ethicon Endo-surgery, Cincinnati, OH). This probe is also Postoperative complications were only observed in one of the 15
used in the sentinel node procedure. Radiologists, experienced patients, where the patient developed a moderate hematoma seven
with the procedure, performed the ultrasound-guided placement. days after surgery. Surgical evacuation was not performed due to
The administration of iodine seeds in our institution has been the size of the hematoma and a planned inguinal lymph node
described previously [7]. dissection.

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Table 1
Indications and ultrasound characteristics for RSL of non-palpable lymph nodes in 15 patients.

Patient Specialty Age Indication Previous medical history Localisation Ultrasound characteristics
no.

1 Plastic 50 PET/CT with positive lymph node, extirpation Diffuse large b-cell Right axilla US compared to most recent PET/CT. Spherical
surgery planned to exclude recurrence of lymphoma. lymphoma lymph node with echo-poor islets. Size of 16 mm.
2 Plastic 40 PET/CT with positive lymph node. Inconclusive US Malignant melanoma, Right axillaa US compared to most recent PET/CT. Echo-poor,
surgery guided biopsy. Extirpation planned to exclude left ala nasi spherical lymph node. Signs of biopsy. Size of
malignancy. 14 mm.
3 Plastic 70 PET/CT with positive lymph node. Extirpation Low grade lymphoma, Right axilla US compared to most recent PET/CT. Two
surgery planned to exclude recurrence of lymphoma. €grens disease
Sjo enlarged lymph nodes. Not suspicious on US.
Largest node with a size of 15 mm.
4 Plastic 48 Trauma-CT detected enlarged lymph node. No previous relevant Left axilla Two enlarged lymph nodes just by one another.
surgery Extirpation planned to exclude malignancy. medical history Echo-poor. Size of 22 mm.
5 Plastic 57 PET/CT with positive and enlarged lymph node. Malignant melanoma, Right inguen US compared to most recent PET/CT. Echo-poor,
surgery Extirpation planned to exclude metastasis. vulva low grade of vascularization. Size of 30 mm.
6 Breast 80 Mammography detected enlarged lymph node. Right C. Mammae Right axillaa Two suspicious lymph nodes, size of 18 mm and
surgery Inconclusive US guided biopsy. Extirpation 10 mm.
planned.
7 Breast 54 CT performed because of weight loss. Enlarged Rheumatoid arthritis Right axilla Multiple enlarged lymph nodes. The most
Surgery lymph node was detected. Extirpation planned. superficial with no sign of hilum and size of
13 mm.
8 Breast 51 PET/CT with positive lymph node. Extirpation Polymyositis Left axilla US compared to most recent PET/CT. Not
surgery planned. suspicious of malignancy. Size of 30 mm.
9 Breast 52 CT with enlarged lymph node. Inconclusive US Systemic lupus Right axillaa Enlarged, pathologic lymph node. Size of 22 mm.
surgery guided biopsy. Extirpation planned. erythematosus
10 Breast 38 PET/CT with positive lymph node. Inconclusive US Right C. Mammae Left axilla US compared to most recent PET/CT. Pathological
surgery guided biopsy. Extirpation planned to exclude lymph node, size of 22 mm.
malignancy.
11 Head 71 PET/CT with positive lymph node suspicious of C. pulmonis, c. hypo- Left angulus US compared to most recent PET/CT. Spherical,
and malignancy. Extirpation planned to exclude pharynx mandibulae echo-poor, few vessels. Size of 5 mm.
Neck malignancy.
12 Head 81 PET/CT with positive lymph node. Extirpation C. mammae, c. palatina Right US compared to most recent PET/CT. Echo-poor,
and planned to exclude malignancy. supraclavicular solid process.
Neck region
13 Head 58 PET/CT with positive lymph node. Extirpation Squamous cell carcinoma, Right US compared to most recent PET/CT. Irregular
and planned to exclude malignancy. right neck region, unknown supraclavicular lymph node, no hilum, vascularized. Size of
Neck primary tumour region 10 mm.
14 Head 60 PET/CT with positive lymph node. Extirpation C. vestibulum nasi Right cervical US compared to most recent PET/CT. Echo-poor,
and planned to exclude malignancy. region minor vascularization. Size of 7 mm.
Neck
15 Head 67 PET/CT performed because of a large weight loss C. testis Right cervical US compared to most recent PET/CT. Two
and and detected positive lymph node. Extirpation region enlarged lymph nodes, just next to one another.
Neck planned to exclude malignancy. Irregular, size of 12 mm and 8 mm.

PET: Positron emission tomography.


US: Ultrasound.
a
Localisation was complicated due to placement of iodine seed in the surrounding tissue.

The activities of the seeds used in the study are displayed in pathologists at our institution did not report any difficulties with
Table 2. The median activity was 1.69 MBq (range: 0,8e4,7). the pathologic examination of the lymph nodes or removal of the
iodine seeds.
Discussion Placement of an iodine seed inside a lymph node causes a
rupture of the capsule, which potentially creates a risk of tumour
This study is the first to our knowledge to test the feasibility of cell dissemination from lymph node metastases through the needle
RSL of non-palpable lymph nodes in various anatomical regions. tract. The existing literature regarding this risk is, to our knowledge,
This study shows that RSL of non-palpable lymph nodes in the head very limited. A systematic review regarding tumour seeding after
and neck, axillary and inguinal region is feasible. Excision of the fine and core needle biopsy of lumps in the head and neck region
suspicious nodes was successful in all of the 15 patients. has been published [8]. This study concluded that the risk of
In our study the radiologists were all experienced with the tumour seeding along the needle track is very low, and the risk is
procedure, and the surgeons had experience in either RSL itself or regarded even lower, if only the clinically important development
similar procedures such as the sentinel node procedure or ROLL. of a tumour is taken into account. In general, the risk increases with
Both radiologists and surgeons reported that the technique was size of the needle, depth of the tumour site (e.g. greater risk in
feasible and easy to perform. RSL is a safe procedure with logistic abdominal organs) and number of passes [9]. Contrary to a biopsy,
advantages, and the probe used for identification is present in most no tissue is withdrawn when placing the seed in the lymph node
of the surgical departments due to the widespread use of the during RSL, and the risk of tumour cell dissemination is presumed
sentinel node procedure. to be even lower in this procedure. Placement of iodine seeds in
An important step in the procedure of RSL is correct and fixed relation to the lymph node will have to be adjusted according to the
placement of the iodine seed. In three patients the iodine seed was group of patients in order to minimise the risk of tumour cell
displaced, not because of actual seed migration but because of less dissemination. If the lymph node is suspicious of metastasis from
optimal placement of the iodine seed. The iodine seeds were still squamous cell carcinoma, the seed must be placed outside the
located close to the lymph node making identification possible. The capsule to avoid rupture.

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Table 2
Operative findings and definitive pathology for RSL of non-palpable lymph nodes in 15 patients.

Patient Operative findings Number of lymph Seed Duration Seed in Diagnosis Complications
no. nodes removed activity of situ
(MBq) surgery (hours)
(min)

1 The marked lymph node was The marked lymph node was 1.69 55a 3.5 Benign lesion. No
suspicious. removed.
2 The marked lymph node was The marked lymph node was 1.25 64 7.1 Reactive changes. No
suspicious. US performed to verify removed. PET/CT 2 months after surgery: no
that the excised lymph node was the suspicious lesion in the region.
correct one.
3 The marked lymph node was not The marked lymph node was 1.2 41 3.6 Reactive changes. No
suspicious, but enlarged. removed. PET/CT 3 months after surgery, no
suspicious lesion in the region.
4 The marked node was suspicious. The marked lymph node and an 1.2 53 1.5 Progressive germinal cell No
additional suspicious lymph node transformation in both of the lymph
were removed. nodes. No malignancy.
5 The marked lymph node was The marked lymph node was 1.03 32 4.4 Metastasis, malignant melanoma. Hematoma
enlarged and suspicious. removed. Axillary lymph node dissection
performed after 3 weeks.
6 Two suspicious lymph nodes. The marked lymph node and an 3.01 129b 4.1 Frozen microscopy with macroscopic No
additional suspicious lymph node metastases in both of the lymph
were removed. nodes.
Metastasis, invasive lobular
carcinoma.
7 The marked lymph node was The marked lymph node was 1.55 25 19.7 Reactive changes. No
enlarged, but not suspicious. removed.
8 The marked lymph node was difficult The marked lymph node was 0.83 37 25.7 Reactive changes. No
to palpate during surgery. removed. No PET/CT control scan was
performed.
9 The marked lymph node was The marked lymph node was 4.68 29 2.2 Castleman's disease. No
enlarged. removed.
10 The marked lymph node was The marked lymph node and an 2.63 42 6.2 Reactive changes in the marked No
enlarged. additional lymph node were lymph node. The additional lymph
removed. node was normal.
CT control scan after 2 months, no
suspicious lesion in the region.
11 Extensive fibrosis and scar tissue. The marked lymph node was 1.72 36 4.4 Metastasis, squamous cell carcinoma. No
Marked lymph node located in scar removed.
tissue.
12 Extensive pathologic tissue. Lymph The marked lymph node and 1.59 99c 24.6 Metastasis, invasive ductal No
node adherent to carotid artery, vagus pathologic tissue were removed. carcinoma.
nerve and jugular vein.
13 Extensive pathologic tissue. Marked The marked lymph node, an 4.21 175c 5.3 Metastasis, squamous cell carcinoma. No
lymph node adherent to jugular vein, additional lymph node and
cervical plexus and surrounding pathologic tissue were removed.
tissue.
14 Radiation-related tissue changes. The marked lymph node and 2.66 270c 26.7 Metastasis, squamous cell carcinoma. No
Extensive disease, marked lymph pathologic tissue were removed.
node adherent to surrounding
structures.
15 The marked lymph node was The marked lymph node, two 1.70 52 4.4 Normal lymph nodes. No
enlarged. additional lymph nodes and No PET/CT control scan was
additional tissue were removed. performed.
a
Intraoperative ultrasound prolonged surgery.
b
Prolonged duration due to frozen section microscopy.
c
Prolonged duration due to widespread pathologic tissue.

A few studies on the use of RSL for a different purpose than cell carcinoma in a patient suffering from a cystic kidney disease.
localising non-palpable breast lesions have been published. Several RSL made tumour resection possible despite the numerous cysts
studies have tested RSL of axillary lymph nodes in breast cancer surrounding the tumour [15]. A recently published study investi-
patients after neoadjuvant treatment. In these studies RSL was gated the patient and surgeon satisfaction through surveys after RSL
performed either prior to neoadjuvant treatment or in combination of soft tissue masses in 10 patients [16]. All masses were success-
with clips, where RSL was performed after neoadjuvant therapy. fully removed, no seed migration was reported, and both patient
These studies concluded that RSL of axillary lymph nodes has a high and surgeon satisfaction was high. Two case-reports have also
identification rate and that it is possible to perform the sentinel described the use of RSL to guide removal of non-breast tissue
node procedure simultaneously [10e13]. RSL has also been tested in [17,18].
non-visible or non-palpable lung lesions prior to video assisted Other methods of preoperative localisation of lymph nodes
thoracic surgery with wedge resection in 28 patients. This study include WGL and ROLL. In addition to the widespread use in breast
concluded that RSL of parenchymal lung lesions is a feasible method surgery, WGL has been used for non-palpable cervical lymph nodes
with complication rates comparable to the standard method WGL [19e21]. WGL has been shown to have several technical difficulties
[14]. In our institution RSL has been tested for localisation of a renal such as displacement, migration or fracture of the wire, and higher

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levels of patient discomfort have been reported [2]. The ROLL Due to the above-mentioned advantages of RSL, it may become
technique has been used for localisation of lymph nodes suspicious an alternative localisation method in a wide range of surgical
of metastasis from malignant melanoma [22]. The ROLL signal is specialties, and it has the potential to improve treatment by easing
however more diffuse compared to RSL, due to spreading of Tc- the surgical approach. This may lead to reduced surgical time,
99 m into the surrounding tissue [23]. Only minor migration of the minimise trauma to the surrounding tissue and ultimately benefit
iodine seeds was found in RSL when examined in breast tissue [24]. the patient.
RSL has greater flexibility than ROLL and WGL, where the local-
isation has to be performed on the day of surgery [2,25]. The iodine Research or publication funding
seed can be placed several days before surgery due to the 59-day
half-life of I-125. A different method of preoperative localisation This study was supported by The Danish Cancer Society (J.
is preoperative placement of sonographically detectable clips, no.R100-A6761). The funding sources did not participate in the
which has been tested mainly in breast tumours, but also in lymph generation of the study design, data acquisition, data analysis and
nodes [26]. Intraoperative ultrasound requires that the surgeon is data interpretation or statistical analysis. Furthermore, the funding
experienced with the use of ultrasound or that a radiologist is sources have not participated in manuscript preparation, editing of
present during surgery. The advantage of the iodine seed is that it the manuscript and have no role in the decision to submit the
can be detected during surgery with a gamma probe often present manuscript for publication.
in the surgical department, due to the widespread use of the
sentinel node procedure, and the surgeons are familiar with the use Conflict of interest statement
of the gamma probe. The radioactivity is emitted from a small pin
source permitting an accurate localisation and it can guide the None.
surgeon to the optimal place of the incision.
A disadvantage of the RSL procedure is the use of a radioactive Acknowledgements
source. However, the iodine seeds used in this pilot study had a
median activity of 1.69 MBq, which leads to an effective dose less The authors thank F. Jensen for performing the placement of the
than 10 mSv and an equivalent dose around 2 mGy to the sur- iodine seeds.
rounding tissue (sphere of 100 ml). This dose is considered
acceptable for the patient. These calculations have been approved
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