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Annals of Surgical Oncology ( 2007)
DOI: 10.1245/s10434-007-9450-4
Breast Oncology
Blue Dye Injection in the Arm in Order to Conserve the
Lymphatic Drainage of the Arm in Breast Cancer Patients
Requiring an Axillary Dissection
Claude Nos, MD, Benedicte Lesieur, MD, Krishna B. Clough, MD, and Fabrice Lecuru, PhD
Department of Gynecologic and Oncologic Surgery, Hôpital Européen Georges Pompidou, Paris, France
Background: Despite the widespread use of the sentinel lymph node biopsy technique, many
patients with invasive breast cancer still undergo an axillary lymph node dissection and are at
risk of arm lymphedema. With the new awareness of lymphatic spread in the axillary nodes, it
should be possible to define a new surgical approach between sentinel lymph node biopsy and
complete axillary dissection, a procedure preserving specifically lymph nodes in relation to the
arm.
Methods: Twenty-one patients with an operable breast cancer requiring an axillary dissection underwent surgery with an attempt to separate nodes related to the breast from specific
nodes related to the arm. After an injection of blue dye in the arm, the surgeon performed the
axillary dissection trying to identify blue nodes and ducts in order to preserve lymphatic arm
drainage (LAD). If the blue nodes were located in the normal axillary dissection, they were
removed separately.
Results: In 15 of 21 patients (71%), blue nodes in relation with LAD were identified. In 10
(47%) patients, it was possible to dissect the LAD with the preservation lymphatic ducts. In 10
patients, the LAD nodes were removed: none of them contained metastases, despite the fact
that the non-LAD axillary nodes contained metastases in 7 of 10 cases.
Conclusions: Identifying the LAD with blue dye injection in the arm is possible. A subsequent study can now begin to determine if this procedure is safe for patients and able to
prevent lymphedema of the arm.
Key Words: Breast carcinoma—Sentinel lymph node biopsy—Axillary dissection—Blue dye.
The introduction of sentinel lymph node biopsy
(SLN) for breast cancer during the last decade has
been the most important advance in more than a
century in decreasing the morbidity of axillary lymph
node surgery.1–7 However, those patients with metastatic involvement of axillary nodes who undergo a
complete axillary dissection do not benefit from the
SLN biopsy.8 These patients are still subject to
Received February 13, 2007; accepted March 16, 2007
Address correspondence and reprint requests to: Claude Nos,
MD; E-mail: [email protected]
Published by Springer Science+Business Media, LLC 2007 The Society of
Surgical Oncology, Inc.
chronic arm lymphedema, which is the most serious
complication of axillary dissection in breast cancer.9,10
SLN theory is based on the progressive spread of
the metastatic disease from the first involved, i.e.,
sentinel node, to the second and higher echelon
nodes. However, it is, in fact, rare that all nodes of
the axillary dissection are involved, and often only a
few of them are metastatic.11,12 The SLN is the only
lymph node with metastases in 50–60% of occurrences.
The knowledge that chronic lymphedema is related
to the number of lymph nodes retrieved10 has induced
a progressive decrease in the use of complete axillary
C. NOS ET AL.
dissection, leaving in place the lymph nodes located
on the third, or even in the second level of Berg.
The point is to question whether it would be more
judicious to, instead of performing surgery based
only on the anatomic boundaries of the axilla, to
consider physiology instead removing only those
nodes draining the breast, leaving in place lymph
node related to the lymphatic arm drainage (LAD).
This concept has already been tested and validated in
a mice model in which two different drainages were
shown by a two-color spectral fluorescence lymphangiography.13
The aim of this pilot study is therefore to determine
whether the identification and the separation of the
specific lymph nodes related to the arm is possible
during an axillary dissection performed on breast
cancer patients.
PATIENTS AND METHODS
From November 2004 to February 2005, a study
was performed on LAD using blue dye technique at
the Institut Curie and the Hôpital Européen Georges
Pompidou. During this period, 21 patients underwent
an axillary dissection with attempts to individualize
the lymph nodes related to the breast and lymph
nodes related to the arm.
Indications for axillary dissection were patients not
candidates for sentinel lymph node biopsy, i.e., clinical N1, N2, or N3 patients (11 patients), surgery
after neoadjuvant chemotherapy (7 patients), multicentric breast carcinomas (6 patients), prior breast or
axillary surgery (3 patients), and secondary axillary
dissection after a positive sentinel node (1 patient)
(Table1).
The patientÕs mean age was 58 years (range 36–82).
Mean body mass index (BMI) was 26 (range18–44).
Four patients (19%) had clinically stage T1 tumors,
15 (71%) T2, and 2 (10%) T3 tumors. Ten patients
(47%) had clinically stage N0 tumors, 9 (43%) N1, 1
(5%) N2 tumor, and 1 (5%) N3 tumor (Table 1). The
majority of patients underwent a mastectomy (15
patients: 71%) and a small proportion requiring a
lumpectomy (6 patients: 29%). In the 14 patients
undergoing primary surgery, the mean size of the
invasive tumor measured histologically was 27 mm
(range 10–65 mm). The invasive tumors were subclassified as ductal (19 patients: 90%) or lobular (2
patients: 10 %). The tumor grade was I (6 patients:
28%), II (7 patients: 33%), or III (8 patients: 38%).
The majority of tumors were estrogen receptor posi-
Ann. Surg. Oncol. ( 2007)
tive (81 %) and progesterone receptor positive (69%).
Lymphovascular invasion was noted in 33% of cases.
As soon as the general anesthetic took effect, the
surgeon (CN) injected 1–4 mL of Patent blue dye
(Bleu patenté V sodique 2,5 %, Laboratoires Guerbet,
Villepinte, France) in the arm. The therapeutic indication of Patent blue dye referred to the summary of
product characteristics is identification of lymphatic
vessels. Injection was practiced in the deep hypoderm
of the rear part of the triceps, and in one occasion
(Patient 3) 1 mL was injected in the second and third
interdigital web spaces of the hand.
After having performed the breast surgery (lumpectomy or mastectomy), the surgeon began the axillary exploration with the identification of the classic
landmarks of the axillary dissection determined with
axillary vein, the long thoracic nerve, the thoracodorsal neurovascular bundle and the second intercostal brachial nerve. The limits of the axillary
dissection were the axillary vein superiorly, pectoralis
minor medially, and latissimus dorsi laterally but the
surgeon explored this specific zone very carefully,
particularly the lateral aspect of the dissection between the axillary vein and the second intercostal
brachial nerve.
The first step of this study was the identification of
blue ducts or nodes in relation with LAD determining
a LAD identification rate or LAD mapping rate.
The second step involved the ability of the surgeon
to separate the LAD nodes from the others nodes,
determining a LAD dissection rate.
The third step was the removal and analysis of
LAD nodes, comparing them with the histological
results of the other nodes of the axillary dissection.
When lymph nodes in relation to LAD where located
in the lateral pillar of the axillary dissection far outside from the axis of the thoracodorsal neurovascular
bundle (Fig. 1), this chain of nodes was kept in place.
All the patients had a 2-year follow-up to check the
results especially the disappearance of the blue stain
in the arm.
RESULTS
The characteristics of the patients, indications for
axillary dissection, and injection of blue dye are
shown in Table 1.
Mean time between blue dye injection and blue
node research was 34 minutes (range 10–60).
The results of axillary dissection are shown on
Table 2.
BLUE DYE INJECTION TO CONSERVE LYMPHATIC DRAINAGE IN BREAST CANCER
TABLE 1. Characteristics of the 21 patients, indications for axillary dissection, technique of blue dye injection used,
results of lymphatic arm drainage (LAD) identification, persistence of the blue staining (PBS) at the injection site after an
average of 21 months
No.
Age
BMI
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
53
69
84
76
61
45
62
58
40
60
54
47
58
60
82
42
79
40
70
36
42
21.5
29.4
17.8
35.3
25.8
20.7
44
21.7
23
27.5
27.5
22.4
26.2
27
30
25.5
22.3
25.6
25.3
23.3
24.3
a
Indication
b
T1N0 (II)
T1N0 (pl)
T2N2
T2N0 (pl)
T2 N0 (pl)
T2 N1 (+)
T1 N0 (mc)
T2 N1
T1 N0 (mc)
T2 N1 (mc)
T2 N1 (mc)
T2 N1
T2 N0 (mc)
T2 N0 (mc)
T2 N0
T2 N1
T3 N1 (+)
T3 N1 (+)
T2 N0
T2 N3 (+)
T2 N1
Neo adjuvant chemo
Injection technique
No
No
Yes
No
No
Yes
No
Yes
No
No
Yes
Yes
No
No
No
No
No
No
No
Yes
Yes
T 2 mL
T 2 ml
H 2 · 1 mL
T 2 mL
T 2 mL
T 1 mL
T 4 mL
T 2 mL
T 2 mL
T 1.5 mL
T 2 mL
T 2mL
T 2 mL
T 2 mL
T 2 mL
T 2· 1 mL
T 4 · 0.5 mL
T 4 · 0.5 mL
T 4 · 0.5 mL
T 4 · 0.5 mL (ac)
T 2 · 0.5 mL (ac)
c
Timing
LAD identification
PBS
15
15
40
15
10
15
25
20
30
30
30
30
30
60
60
60
45
60
60
30
40
Yes
No
Yes
No
No
No
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
++
0
0
+
++
0
+
0
+
0
++
++
++
0
0
+
0
+
0
+
0
mm
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
mn
d
Body Mass Index (BMI) was calculated using the Quetelet index: weight (kg)/height2 (M).
(II): secondary axillary dissection for positive sentinel node. mc, multicentric tumor; pl, prior lumpectomy; +, fine needle aspiration
positive.
c
T, triceps; H, hand; ac, arm cuff used.
d
Absence, 0; slightly blue, +; pale blue, ++; blue, +++.
a
b
FIG. 1. Identification of a blue node in relation with the lymphatic
arm drainage in the external part of the axilla. (Patient 18).
Identification blue dye LAD rate was 71 % (15 of
21), with only 50% identification for the first 10 cases
(5 of 10) and 91% in the last 11 cases (9 of 11). In 10
of 21 cases, it was possible to dissect the non-LAD
nodes from the LAD node. The LAD dissection rate
was 47 % (10 of 21) because in five cases, afferent or
efferent ducts were accidentally cut during the surgery. Those nodes were always located in the same
position, i.e., at the lateral part of the dissection,
under the axillary vein and just above the second
intercostal brachial nerve.
Mean number of axillary nodes removed in the
axillary dissection was 10.8 (range 3–37).
LAD lymph nodes were separately removed and
analyzed in 10 of 15 patients. Mean number of LAD
lymph nodes removed was 1.7 (range 1–3).
All these nodes were negative after standard HE
pathological analysis, despite the fact that the non
LAD axillary nodes contained metastases in 7 of 10
patients. One case was particularly interesting with 11
metastatic lymph node of 15 lymph node removed
with one negative LAD lymph node (Case 17).
In September 2005, 20 of 21 patients were
questioned as to whether the blue stain in the arm
had faded or disappeared. The time between the
Ann. Surg. Oncol. ( 2007)
C. NOS ET AL.
TABLE 2. Results of the research of the lymphatic arm drainage (LAD); pathological results of the nodes in relation with the
axillary dissection and the nodes in relation with the LAD
Lymphatic arm drainage
No,
Identification
Dissection
Preservation
Results of axillary dissection
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Yes
No
Yes
No
No
No
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
No
—
No
—
—
—
Yes
Yes
Yes
—
Yes
Yes
No
Yes
No
Yes
Yes
Yes
No
—
Yes
No
—
No
—
—
—
No
No
Yes
—
No
No
Yes
Yes
No
No
No
Yes
No
—
Yes
5 N3 N2 N+/7
20 N13N5 N+/7
1 N+/21
17 N3 N1 N+/11
1 N+/10
2 N+/6
1 N+/11
1 N+/7
5 N1 N+/14
11 N+/14
1 N+/37
1 N+/5
5 N2 N+/7
operation and the injection of blue dye and the
interview was 7–11 months. In 2 of 20 patients
interrogated (10%), the stain had indeed disappeared
completely. In 6 (30%), the stain was still slightly
visible; in an other 9 (45%) the stain was pale, while in
the remaining 3 (15%), the stain had not changed
color at all. In September 2006 (19–23 months after
surgery), all 21 patients underwent another control:
in 10 (47%) patients, the blue color had disappeared
completely; for the other patients, the blue color was
slightly visible. However, none of them had a persistent disaesthetic blue stain (Table 1).
DISCUSSION
It is agreed that chronic lymphedema is the most
serious complication resulting from axillary dissection, and progress is still necessary to reduce this risk
for breast cancer patients being treated by axillary
dissection. However, axillary dissection is not the
only reason for chronic lymphedema. Other important factors such as radiotherapy of the axilla
performed after or before an axillary dissection10,14,15
or obesity9 are associated with lymphedema.
As shown in this study, the identification and
conservation of specific lymphatic ducts and nodes
related to the arm is technically possible. As in the
sentinel lymph node biopsy technique using blue dye
alone, this technique will depend on the surgeonÕs
Ann. Surg. Oncol. ( 2007)
Results of the nodes
in relation with LAD
2 N3 N-
1 N1 N2 N1 N1 N2 N1 N3 N-
qualifications, and a period of learning curve will
probably be necessary before finding a blue chain for
each patient.2,3 After a few such procedures, and with
the understanding that blue dye migrates more slowly
in the arm than in the breast, it was found that almost
each patient shows a blue node practically at the
same place. This blue node is located at the lateral
pillar of the axillary dissection after blue dye injection
performed in the deep subcutaneous fat in regard to
the triceps, and this place seems to be different
from the usual location of the sentinel node in relation with the breast. So, the postulate that ‘‘sentinel
node’’ of the arm is different from the sentinel node
of the breast was the object of this study.
Such a procedure, which is time consuming and
demanding for the surgeon should now be evaluated
at the light of three questions: Does this technique
imply risks for the patients? Is it a safe procedure
without toxic side effects? And can this technique
bring a functional benefit for the patient, reducing the
risk of lymphedema?
In reply to the first question, one could say that by
not retrieving all nodes, as usually practiced, the main
risk is to leave in the axilla a metastatic node
exposing the patient to an axillary recurrence. To
calculate this risk, it is necessary to assess the invasion rate of these nodes to know precisely in which
circumstances these specific nodes are metastatic or
not. However, the oncological attitude that consists
of leaving lymphatic nodes in the axilla in breast
BLUE DYE INJECTION TO CONSERVE LYMPHATIC DRAINAGE IN BREAST CANCER
cancer patients is becoming more and more acceptable. The complete axillary dissection removing the
three levels of Berg is the gold standard for staging
the axilla, but since the 1970s, many surgical teams
are only removing the nodes in relation with BergÕs
level I or II, with the objective of removing a minimum of 10 nodes in the axilla in order to have a
significant sampling.16,17 Since 1993, sentinel lymph
node biopsy technique has shown that the sampling
of 1–3 nodes is sufficient to know the axillary status,
and studies about axillary follow-up after a negative
sentinel node biopsy show almost no axillary recurrences.18–20 Further studies are being developed in
order to not systematically perform an axillary dissection, even after positive sentinel node. A randomized trial (ACOSOG Z0011) was specially
developed to answer this point. Patients with clinical
T1-2 N0M0 breast cancer and a positive sentinel
node were randomized in two groups: immediate
axillary lymph node dissection versus observation.
The aim of the study was to assess whether the overall
survival rate for patients randomized in the group
without immediate axillary lymph node dissections
was equivalent to that for patients with immediate
axillary lymph node dissection. Interestingly, the
event rates such as disease recurrence and/or death, in
both study arms, were lower than expected and because of the difficulty of increasing the number of
patients, this trial had to be closed in December 2005
with only 889 patients registered.21 Another related
study called AMAROS (After Mapping of the Axilla:
Radiotherapy or Surgery)22 is ongoing in Europe
(EORTC trial 10981-22023). This randomized trial
including more than 2500 patients compares after a
positive sentinel node, axillary lymph node dissection
versus axillary radiotherapy. Its main objective is to
prove an equivalent locoregional control of the axilla
and not the long-term survival of patients in the two
groups. This latter issue is particularly difficult to
answer, and we can actually conclude that the suggestion to leave the nodes in the axilla after a positive
sentinel node biopsy is one of the main questions
presently debated. Our study is proposing a new approach to progress in this field.
The second problem resulting from this technique
is the possible side effects of blue dye injection. Patent
blue dye is a vital color commercialized since 1977
and authorized to be used to color lymphatic and
vessels by intravascular or subcutaneous injection.
This product has been successfully used for SLN
biopsy for the last 10 years, using breast injection
with few problems except allergic reactions, which
occur rarely. The other problem was the risk of blue
skin coloration, which can persist for many months
whether the injection is intradermal or superficial. It
is known that the identification of lymph nodes related to the arm must be superficial because superficial collecting lymphatic of the arm are present in
much greater number than deep collecting vessels
with practically no connection between both networks.23 The easiest site of injection remains the
hand. Upper arm lymphoscintigraphy is performed
after injection of radioisotope in the hand, in the first
and second metacarpal web space, sometimes using
intradermal injections.24 However, due to high risk of
immediate tattooing, injections of blue dye were not
performed in the hand. Only one patient had blue dye
injection in the hand with the latter being very blue
right after the surgery but fully gone after a period of
9 months. All other patients had injections in the
back part of the upper arm. Although the injections
were made quite deep, a blue coloration always appeared at the injection site at the end of the procedure. To decrease the surface of the coloration, the
volume of injection was then divided into two
amounts of 1 cc or four amounts of 0.5 cc. Because
the migration of the blue dye is slow and the total
amount of the product must be limited, the lymphatic
drainage was accentuated for some patients with an
arm cuff put at the elbow below the injection site
measuring the blood pressure every 2 minutes.
The persistence of the blue dye after some 9
months cannot be neglected. All patients have been
re-interviewed after 2 years to definitively evaluate
the consequences of this pilot study in this regard.
For all patients, it appears that the blue stain has
either disappeared or is in the process of disappearing. One proposed solution to reduce this potential
problem, that still needs to be tested, could be to
inject a smaller dose (i.e., 1 · 0.5 cc) of blue dye the
day before the surgery, leaving thus enough time for
the product to migrate, and reducing considerably the
risks of long-term tattooing. Another site of injection
could also be tested, with a small dose of blue dye (1 ·
0.5 cc) injected subcutaneously the day before surgery
near the arm vessels at the anterior face of the elbow.
Finally, optimizing the method could be achieved
through the integration of radioactive tracers into the
technique. Radioactive tracers could be injected in
the hand the day before surgery, thus allowing the
lymphoscintigraphy of the axilla to show the specific
nodes related to the arm. During the surgery, blue
dye would be injected in the breast, peritumorally,
localizing the blue sentinel nodes in relation with the
breast tumor. We thus should be able to compare
them with hot radioactive nodes in relation with the
Ann. Surg. Oncol. ( 2007)
C. NOS ET AL.
arm. This is one possible development of the technique.
The last and most important issue concerning this
research is to assess the efficiency of such a procedure
on the prevention of lymphedema. Even if a blue
chain can be isolated, dissected, and kept in place in
the axilla, there is not yet straightforward evidence
that preservation of the lymphatic channels, which
are seen at the time of surgery, will decrease the rate
of arm lymphedema. Indeed, the mechanisms of the
creation of arm lymphedema can be caused by scar
formation from the surgery and/or to radiation
therapy. Concerning radiotherapy, the axilla can receive it as tangents with whole breast radiation or it
can be directly irradiated. In Europe and in France in
particular, patients with a massive invasion of axillary lymph nodes (pN + >4) have a treatment
protocol comprising of an axillary clearance followed
by a complete radiotherapy of all the axilla, the infraclavicular and supraclavicular region and the
internal mammary chain. These patients are at high
risk of rapidly developing an arm lymphedema.10,25,26
However, it is ‘‘evidence-based medicine’’ that leaving in place lymphatic channels can only have a positive impact on the lymphedema occurrence rate. In
a study with patients at high risk of lymphedema (as
described above) in which we would keep the nodes in
relation to the arm, we should be able to demonstrate
a lower incidence of lymphedema, regardless of the
fact that patients will be or not irradiated directly on
the axilla according to the applied protocols.
CONCLUSION
The identification of specific lymph nodes related
to lymphatic arm drainage is technically possible in
patients requiring an axillary dissection for breast
carcinomas. In this pilot study, this technique was
performed with blue dye only. The research can
probably be improved to identify specific lymphatic
arm drainage for each patient.
Many questions can be asked about the reproducibility of the procedure, but the main issue remains, however, to make sure that the nodes
identified are not metastatic and can be preserved
during axillary dissection. However, as shown
through this procedure, the knowledge that arm
nodes can be distinguished from breast nodes is
interesting. Further studies need to be performed in
relation to this new concept derived from sentinel
lymph node biopsy for breast cancers.
Ann. Surg. Oncol. ( 2007)
ACKNOWLEGMENT
I thank particularly Prof Charles E Cox and
Dr Charles Elboim for their contribution to this
article.
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