Download Blue dye versus combined blue dye—radioactive tracer

EJSO (2004) 30, 913–917
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Blue dye versus combined blue dye—radioactive
tracer technique in detection of sentinel lymph
node in breast cancer
Z. Radovanovica,*, A. Golubovica, A. Plzaka, B. Stojiljkovicb,
D. Radovanovicc
a
Department of Surgical Oncology, Institute of Oncology Sremska Kamenica Novi Sad, Institutski put 4,
21204 Sremska Kamenica, Serbia and Montenegro
b
Department of Pathology, Institute of Oncology Sremska Kamenica, Novi Sad, Institutski put 4, 21204
Sremska Kamenica, Serbia and Montenegro
c
Department of Anaesthesiology and Intensive Care, Institute of Oncology Sremska Kamenica, Novi Sad,
Institutski put 4, 21204 Sremska Kamenica, Serbia and Montenegroe
Accepted for publication 9 August 2004
Available online 15 September 2004
KEYWORDS
Sentinel lymph node
biopsy;
Breast cancer;
Staging;
Blue dye;
Gamma probe
Abstract Background. Sentinel lymph node biopsy in breast cancer can be used
to select patients in which axillary lymph node dissection could be avoided. In
this study we compared the value of two methods for identification of sentinel
node (SN) using either only blue dye or combination of blue dye and radioactive
tracer.
Material and methods. All patients were women with clinically T1K2N0M0 breast
cancer. They were randomized into two groups. In Group A (50 patients) SN marking
was performed only with blue dye and in Group B (100 patients) combined SN marking
with blue dye and radiotracer was done. We used 2 ml of blue dye Patentblau Vw (Byk
Gulden). Radiotracer was Antimony sulfide marked with Tc 99m and of 0.3 mCy
(11.1 MBq) activity. Application method of both contrasts was peritumoral. After SN
biopsy all patients underwent mastectomy or conservative surgery with axillary
lymph node dissection of levels I and II.
Results. In Group A mean of 1.7 SNs were identified (median 1, range 1–4). Falsenegative rate in this group was 3/17 (17.6%) with negative-predictive value 20/23
(86.9%), sensitivity 14/17 (82%), specificity 20/33 (60%) and accuracy 34/50 (68%). In
Group B mean number of SNs excised per case was 1.6 (median 1, range 1–5). Falsenegative rate was 2/44 (4.5%), negative-predictive value 41/43 (95.3%), sensitivity
42/44 (95%), specificity 41/56 (73%) and accuracy 83/100 (83%). The combination
technique was significantly superior to blue-dye alone technique for negativepredictive value (pZ0.033) and overall accuracy (pZ0.048).
* Corresponding author. Tel.: C381-21-615-711x532; fax: C381-21-613-741.
E-mail address: [email protected] (Z. Radovanovic).
0748-7983/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejso.2004.08.003
914
Z. Radovanovic et al.
Conclusions. The prediction of axillary lymph node status in breast cancer patients
using combined technique has significantly higher accuracy than marking of SN with
blue dye alone and therefore should be preferred.
q 2004 Elsevier Ltd. All rights reserved.
Introduction
One of the most important prognostic indicator in
patients with breast cancer is axillary lymph node
involvement.1 It can be determined with three
surgical modalities: axillary lymph node dissection
(ALND), sentinel lymph node biopsy (SLNB) and
axillary node sampling (ANS).
SLNB in breast cancer represents the best
diagnostic modality to accurately stage axilla and
to select patients in which ALND could be avoided.
It is minimally invasive, fast, safe and accurate
procedure with less morbidity than ANS and
ALND.2–4 Introduced in breast surgery by Giuliano
and Krag this procedure is one of the most
important surgical innovations in treatment of
breast cancer patients.5,6 Using this procedure
many patients with early-stage breast cancer can
be spare of unnecessary ALND and its possible short
and long-term morbidity such as seromas, pain,
infection, motor and sensory nerve injury, lymphedema, restricted arm mobility, etc.7–9
Various factors can influence on results of SLNB
and one of them is type of contrast used to mark
sentinel nodes. In this study we compared the value
of two methods for identification of sentinel node
(SN) using either only blue dye or combination of
blue dye and radioactive tracer.
Materials and methods
This prospective study has been performed
between February 1999 and August 2003 at the
Department of Surgical Oncology, Institute of
Oncology Sremska Kamenica, Novi Sad, Serbia. All
patients were women with clinically T1K2N0M0
breast cancer. Preoperative diagnosis was obtained
with the aid of physical examination, mammography, ultrasonography and fine needle aspiration
cytology or core biopsy. The exclusion criteria were
pregnancy, palpabile suspicious axillary lymph
nodes, prior breast or axillary surgery, multicentric
tumours, neoadjuvant chemotherapy or radiotherapy and refusal for procedure by the patient.
Patients were randomized into two groups.
Group A: In 50 patients SN marking was performed
only with blue dye with visual intraoperative
identification of SNs. Group B: In 100 patients
combined SN marking was performed (blue dye and
radiotracer) with intraoperative visual and gamma
probe identification of SNs.
The day before surgery, Antimony sulfide
(Sb2S3), marked with Technetium (Tc 99m) was
injected peritumorally. Mean injected radioactivity
was 0.3 mCi (11.1 MBq). Lymphoscintigraphy was
performed only in first 15 patients. 10–15 min
before incision 2 ml of blue dye Patentblau Vw
(Byk Gulden) was injected peritumorally. The
breast was massaged for a few minutes to facilitate
identification of blue lymphatic vessels and nodes
more easily. After general anaesthetic induction,
the axilla was searched for radioactive areas using
the gamma probe (Gammed IVw-Capintec) and for
blue-stained lymph nodes and afferent lymphatics.
SN was defined as any node that was blue, hot and
blue, hot alone or node whose afferent blue
lymphatic vessel was coming directly from tumour.
After SN biopsy all patients underwent mastectomy or conservative surgery with ALND of levels I
and II. All procedures were performed by two
surgeons.
Immediately after harvesting, sentinel lymph
nodes were sent to pathology department for
intraoperative frozen section evaluation. SNs larger
than 5 mm were bisected along the longitudinal
axis, while smaller nodes remained uncut. Ten
sections were obtained from each block of tissue
and stained with hematoxylin and eosin (H&E) or
immunostained for epithelial membrane antigen
(EMA; DAKO, Denmark). Remaining SNs tissue was
fixed in formalin and embedded in paraffin for
routine pathologic examination. Sections of paraffin embedded tissue blocks were stained with H&E
or EMA immunohistochemistry and these results
were compared with frozen section analysis.
Formalin fixed paraffin embedded tissue sections
of non-sentinel lymph nodes were stained with
H&E. In the first 50 cases frozen sections were not
performed.
All data were analyzed with SPSS statistical
package for Windows version 12.0 (SPSS, Chicago,
IL, USA). Fisher’s exact test, chi-square test and t
test were used to compare data between the two
groups. Values of P%0.05 were considered to be
statistically significant.
Radioactive tracer technique in detection of sentinel lymph node in breast cancer
Results
Patients characteristics in groups A and B such as
age, histological tumour size, type of cancer and
type of surgery are presented in Table 1.
In groups A and B number of harvested SNs was
1.7 (median 1, range 1–4) and 1.6 (median 1, range
1–5), respectively.
In the first set of patients (blue-dye group) SNs
were positive in 27 cases and in 13/27 (48%) SNs
were the only positive nodes (false-positive cases).
Three cases out of 23 (13%) were false-negative.
False-negative rate in this group was 3/17 (17.6%)
with negative-predictive value 20/23 (86.9%),
sensitivity 14/17 (82%), specificity 20/33 (60%)
and accuracy 34/50 (68%). Seventeen patients
(34%) in this group had positive axillary nodes.
Mean number of removed axillary nodes was 12.5
(range 4–18) and mean number of positive axillary
lymph nodes (pNC) was 3.2 (55/17, range 1–14).
Micrometastases in SNs were detected in two cases
and axilla was negative in these patients.
In group B (blue-dyeCradiotracer) the SN was
the only positive node in 15/57 (26%) of the cases
while number of false-negative cases was 2/43
(4.6%). Positive axillary lymph nodes with negative
SNs were found in 2/44 patients with metastatic
axillary involvement (false-negative rate 4.5%).
Negative-predictive value was 41/43 (95.3%), sensitivity 42/44 (95%), specificity 41/56 (73%) and
accuracy 83/100 (83%). Mean number of removed
axillary nodes was 13.4 (range 7–23). Forty-four
(44%) patients in this group had positive axillary
nodes and mean number of pNC nodes was 4.6
(201/44, range 1–22). In three cases SNs contained
only micrometastases while most of removed
axillary nodes were metastatic in these patients.
On the other hand, two patients with micrometastases in axillary nodes had negative SNs at final
histology.
No statistically significant differences were seen
between two groups regarding to number of falsenegative (pZ0.333) and false-positive (pZ0.081)
cases, false-negative rate (pZ0.127), sensitivity
(pZ0.129) and specificity (pZ0.244). However,
differences in negative-predictive value and overall
accuracy reached statistical significance (pZ0.033
and pZ0.048, respectively) (Table 2).
Discussion
A sentinel lymph node is defined as the first lymph
node in a regional basin that receives lymphatic
drainage from the site of a primary tumour. For
915
more than a decade, SLNB in breast cancer patients
is used to predict axillary lymph node status and
avoid ALND if possible. Sentinel nodes are marked
with either blue-dye, radioactive tracer or their
combination. Because it is cheap and safe many
institutions use blue dye as contrast of first choice.
Furthermore, there is no need for nuclear medicine
department and gamma probes, so procedure can
be performed even in small hospitals or hospitals
with limited financial support. Sometimes fear of
radiation exposure is reason for avoiding use of
radioactive tracer although it has been proven that
radiation dose levels are very low.10–13
With only blue dye marking (injected peritumorally) in 50 patients we achieved false-negative rate
of 17.6%, sensitivity of 82%, specificity of 60% and
accuracy of 68%. In literature, false-negative rates
for SLNB using only blue dye are usually higher than
the 5% guidelines, even as high as 55%.14–17
However, results in number of studies represents
the first experience with SLNB and therefore do not
represent the real capability of procedure. The
addition of radioactive tracer to the blue-dye
(Group B, 100 patients) increased sensitivity,
specificity and accuracy to 95, 73 and 83%,
respectively. False-negative rate in this group was
4.5%. Motomura et al. also compared these two
techniques with results that combined SLNB was
significantly superior to the blue-dye alone method
for sensitivity and accuracy.18 Similar study by
Canavese et al. showed that addition of radiotracer
to blue-dye increased sensitivity and overall accuracy from 77 to 87% and from 91.5 to 95.5%,
respectively.19 Looking at our own results, with
combined technique we achieved recommended
false-negative rate of less than 5% and sensitivity
higher than 95%. Statistically significant differences
in negative-predictive value and overall accuracy
confirmed that combined method of SLNB is highly
recommended.
Number of removed SNs and axillary nodes was
similar in both groups with no statistical significance. In three cases in group B SNs contained only
micrometastases although large number of axillary
nodes removed in these patients had macrometastases. This emphasizes the role of thorough
pathohistological examination of SNs and search
for micrometastases. There is an on going debate in
literature should every SN positive patient underwent routine ALND especially in case of micrometastases.20–22 Our data suggests necessity of
ALND in all SN positive patients.
High percentage of mastectomies, 60% in group A
and 45% in group B, is mainly due to limited
radiotherapy facilities and often malfunction of
LINAC (unfortunately this situation can be seen in
916
Table 1
Z. Radovanovic et al.
Patients characteristics
Mean patient age
Mean histological tumor size
Type of cancer
Ductal
Lobular
Medular
Other types
Type of surgery
Mastectomy
Conservative surgery
Table 2
Group A (50)
Group B (100)
59.1 years (range 27-83 years)
14.3 mm (range 3–20 mm)
55.3 years (range 30–78 years)
(range 3–40 mm)
36 (72%)
9 (18%)
2 (4%)
3 (6%)
57 (57%)
24 (24%)
5 (5%)
4 (4%)
30 (60%)
20 (40%)
45 (45%)
55 (55%)
Results of SLNB in groups A and B
Number of harvested SNs
Number of removed axillary nodes
Number of positive axillary nodes
False-negative cases
False-positive cases
Negative-predictive value
False-negative rate
Sensitivity
Specificity
Accuracy
Group A (50)
Group B (100)
1.7 (median 1, range 1–4)
12.5 (range 4–18)
3.2 (55/17, range 1–14)
3/23 (13%)
13/27 (48%)
20/23 (86.9%)
3/17 (17.6%)
14/17 (82%)
20/33 (60%)
34/50 (68%)
1.6 (median 1, range 1–5)
13.4 (range 7–23)
4.6 (201/44, range 1–22)
2/43 (4.6%)
15/57 (26%)
41/43 (95.3%)
2/44 (4.5%)
42/44 (95%)
41/56 (73%)
83/100 (83%)
many developing countries in Eastern Europe).
Preoperative lymphoscintigraphy was performed
only in first 15 patients in group B; it was not
performed in other patients due to organizational
reasons. Results of lymphoscintigraphy from our
study as well as others show that, irrespective of
the tumour site, most cancers drain to the axilla,
obviating the need of a preoperative lymphoscintigram.23,24 We find lymphoscintigraphy very helpful
in detection of SNs especially those outside of the
axilla but this procedure is not necessary for axillary
SLNB. Concerning injection site, peritumoral injection was simply our matter of choice without any
ideas that this injection site is better than others.
Many studies compared subareolar, intradermal,
subcutaneous, peritumoral and intratumoral injection. Some of these studies showed that there is no
statistical difference in results of SLNB due to place
of injection.25,26 On the other side, some authors
claim that subareolar, intradermal and subcutaneous injections are better than other sites.27
Team from NKI/AvL Amsterdam prefers intratumoral injection for years with results comparable to
other institutions experienced in this procedure.28
From our point of view every site has its potential
advantages and disadvantages and experienced
surgeon will achieve good results with axillary
SLNB no matter of injection site.
Conclusion
This study confirms that prediction of axillary lymph
node status in breast cancer patients using combined technique has significantly higher accuracy
than marking of SN with blue dye alone and
therefore should be preferred.
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