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Ajr 10 4865
Ajr 10 4865
Sever et al.
Ultrasound Using Microbubbles in Breast Cancer
FOCUS ON:
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Womens Imaging
Original Research
W O M E N S
IMAGING
Ali R. Sever 1
Philippa Mills1
Susan E. Jones 2
Karina Cox 2
Jennifer Weeks1
David Fish 3
Peter A. Jones 2
Sever AR, Mills P, Jones SE, et al.
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Sever et al.
staging of the lymph nodes [13]. The role of
ultrasound in the axilla has been investigated
in the preoperative assessment of lymph node
status. The sonographic assessment of axillary
nodes in combination with biopsy has been reported to increase the preoperative identification of axillary node metastasis by allowing
a reduction in the number of futile SLN biopsies, with considerable savings of time and
financial resources [14]. On the other hand, a
review study by Alvarez et al. [15] concluded
that axillary ultrasound should not be used in
isolation as a method for deciding whether to
perform ALN dissection.
The use of contrast-enhanced ultrasound
is well established in clinical practice; IV administration of contrast agent has provided enhanced imaging of the tissue microvasculature
in many organ systems. Ultrasound contrast
agents are composed of a dispersion of microbubbles (each of which is smaller than an
RBC) that act as reflectors of the ultrasound
beam [16]. In 2004, Goldberg et al. [17] published their results in a swine melanoma model, where microbubbles injected peritumorally were seen to enter lymphatic channels and
SLNs were identified accurately by sonography in 90% of cases. Recently published preliminary results of our group have shown that
this technique can be used in patients with
breast cancer to identify the SLN [18].
The aim of this article is to discuss from
a radiologic perspective the potential for intradermally injected microbubbles to enter
breast lymphatic channels and consequently permit the preoperative identification of
SLNs in patients with early breast cancer.
Subjects and Methods
This prospective study was approved by the local ethics committee and the Medicines and Healthcare Products Regulatory Agency. All patients gave
written informed consent. Between May 2008 and
November 2009, 80 consecutive consenting patients with breast cancer who were scheduled for
primary surgical treatment were recruited into the
study. Exclusion criteria included histologically or
cytologically proven ALN involvement diagnosed
clinically or using standard sonographic imaging,
receipt of neoadjuvant chemotherapy, and the presence of severe medical comorbidities.
There were 78 women and two men with a median age of 61 years (range, 3282 years). Of these,
51 patients had screen-detected cancers identified
by the Maidstone and Tunbridge Wells National
Health Service Trust Breast Screening Service and
29 were symptomatic referrals to the breast clinic. In the symptomatic group, three patients were
252
into the axilla. Areas of contrast agent accumulation were then imaged with gray-scale or live dual
images to confirm the presence of an architecturally defined lymph node. When no obvious lymphatic
filling was obtained, the areola area was massaged
for 1030 seconds and imaging was repeated. If no
lymph nodes could be identified after three consecutive injections, the study was abandoned and
accepted as a failure. In the patients whose nodes
were successfully identified, the transit time from
injection to arrival in the axillary node was 1545
seconds. Contrast agent remained in the putative
SLN for 13 minutes. Repeating the areola massage often produced a refill of the SLN without the
need for a second injection.
The technique was initially piloted in five
women with breast cancer to check the safety profile of intradermal microbubbles and to ensure
that the contrast agent successfully entered breast
lymphatics and accumulated in architecturally defined axillary nodes. Microbubbles have an excellent safety profile when used with conventional IV administration [1921]. On the basis of this
fact and the safety data from experimental models
when microbubbles were injected intradermally
[17], we received Medicines and Healthcare Products Regulatory Agency approval for this study.
We had concerns about possible local reactions at
injection sites, but these proved to be unfounded.
After this initial five-patient pilot study, in
all subsequent patients, contrast-enhanced ultrasound-identified SLNs were localized with a
19.5-gauge hookwire (X-Reidy, Cook). These are
the same guidewires we use for the localization
of nonpalpable screen-detected breast cancers.
The wires are 9 cm long and, after insertion, are
coiled and taped to the skin and covered by a sterile gauze and waterproof sterile dressing. There
were no dislodged wires or infections. Most procedures were completed in 15 minutes.
The next morning, patients underwent surgical
resection of the breast cancer. Immediately after
induction of anesthesia, patients received a 2-mL
subdermal injection of blue dye (Bleu Patente V
2.5%, Guerbet) in the periareolar upper outer
quadrant region. A standard axillary incision was
made, and a gamma probe (Navigator GPS, RMD
Instruments) was used to facilitate the identification of SLNs. All radioactive lymph nodes, all
blue dyecontaining lymph nodes, and all guidewire-containing lymph nodes within the axilla
were excised and sent for standard histologic analysis together with the breast cancer specimen.
Results
Clinical Data
There were 78 women and two men with a
median age of 61 years (range, 3282 years).
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site of injection and traced to the level of axilla, where contrast agent pooling was identified (Fig. 1). Guidewire insertion was performed in all 71 cases. The visibility of the
axillary nodes was quite variable both before
and after the administration of contrast agent.
In 43 patients, the gray-scale images revealed
a clearly visible lymph node corresponding to
the area of contrast agent pooling. This node
was also seen on gray-scale imaging before
injection of contrast agent. In 25 patients, a
guidewire was deployed into an SLN that was
recognized only after microbubble enhancement as an area of contrast agent accumulation and only then seen as a typical lymph
node on gray-scale imaging. In three cases,
the guidewire was inserted into the areas of
pooled contrast agent without any recognizable lymph node architecture even on the subsequent gray-scale imaging.
The procedure was not successful in nine
patients. In one, a technical error occurred
with the ultrasound machine and the procedure was abandoned. In three patients, the
breast lymphatics were not visualized by contrast-enhanced ultrasound. In three patients,
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Sever et al.
the breast lymphatics were visualized but a
draining lymph node was not identified. In
two patients, despite the fact that SLNs were
not identified by contrast agent accumulation, guidewires were deployed into prominent ALNs visualized only with gray-scale
imaging. At the time of surgery, these wired
lymph nodes were not SLNs. This emphasizes the importance of contrast enhancement
in assisting successful SLN identification.
Although only one SLN was visualized
on contrast-enhanced ultrasound in most patients, two patients had concordant lymphatic drainage to two SLNs. A single guidewire
was deployed into both enhancing lymph
nodes (Fig. 2).
The ability of preoperative contrast-enhanced ultrasound to identify axillary SLNs
correctly was validated at surgery by comparison with the standard SLN localization
techniques. At surgery, wired SLNs were radioactive and blue in 63 patients. In eight cases, the nodes were radioactive only and none
contained blue dye only. At histologic examination, 48% (38/80) of the excised sentinel
nodes were 10 mm or smaller, as measured on
their long axis (range, 530 mm). Insertion of
an axillary guidewire was deemed successful
if the tip was found in or on the surface of a
lymph node. The overall sensitivity of SLN
detection by microbubble contrast-enhanced
ultrasound was 89% (71/80 patients).
Histopathologic Results
Fourteen patients had metastatic deposits
in the excised SLNs. These results are summarized in Table 1. SLNs had been identified correctly and guidewires were inserted
into the node before surgery in all patients
with lymph node metastases. In three patients, only one SLN was retrieved that also
contained the guidewire. In one patient, two
axillary SLNs were identified and excised,
but the wired node contained isolated tumor
cells only. The second retrieved lymph node
contained a micrometastasis. In nine cases,
there were no further involved nodes found
in the axillary specimen on the completion
of ALN dissection, and, in six of these cases,
the wired node was the only abnormal node.
Of the nine patients in whom contrast-enhanced ultrasound did not identify the draining SLNs, two had small (< 20 mm) grade
II invasive lobular carcinomas on final histologic examination. One patient had a 34-mm
grade II invasive lobular carcinoma. The remaining six patients had small invasive ductal carcinomas (< 20 mm); three were grade
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Sever et al.
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