ORIGINAL ARTICLE Paulinelli RR et al.

A prospective randomized trial comparing patent blue and

methylene blue for the detection of the sentinel lymph node in
breast cancer patients
Régis Resende Paulinelli1*, Ruffo Freitas-Junior1, Rosemar Macedo de Souza Rahal1, Luis Fernando de Pádua Oliveira2,
Maria Helena Tavares Vilela3, Marise Amaral Rebouças Moreira4, Katyane Larissa Alves5, Marina Berquó Peleja5,
Tatiane Coelho Capel de Resende5
1
MD, PhD, Mastology Program, Department of Gynecology and Obstetrics, Universidade Federal de Goiás (UFG), Goiânia, GO, Brazil
2
MD, MsM, Mastology Program, Department of Gynecology and Obstetrics, UFG, Goiânia, GO, Brazil
3
MD, Department of Pathology and Imaging, UFG, Goiânia, GO, Brazil
4
MD, PhD, Department of Pathology and Imaging, UFG, Goiânia, GO, Brazil
5
MD, Mastology Program, Department of Gynecology and Obstetrics, UFG, Goiânia, GO, Brazil

Summary
Introduction: Methylene blue is more widely available and less expensive than
patent blue, with an apparently lower risk of anaphylaxis.
Objective: The two dyes were compared regarding detection of the sentinel
lymph node (SLN).
Method: A prospective, randomized trial involved 142 patients with invasive
breast carcinoma. Sixty-nine (49.3%) assigned to patent blue (group A) and 71
(50.70%) to methylene blue (group B). Thirty-five patients (25.0%) were clinical
stage III or IV; 55 (38.7%) had axillary lymph nodes affected; and 69 (49.3%)
underwent neoadjuvant chemotherapy. Two patients were excluded because the
Study conducted at Universidade Federal dye type was not recorded.
de Goiás (UFG), Goiânia, GO, Brazil
Results: Patients and tumor characteristics were similar in both groups. SLNs
Article received: 5/16/2016 were identified in 47 women (68.1%) in group A and 43 (60.6%) in group B
Accepted for publication: 5/31/2016
(p=0.35). SLNs were affected in 22 cases (51.2%) in group A and 21 (48.8%) in
*Correspondence: group B (p=0.62). The SLN was the only node affected in 12 cases (54.5%) in
Address: Alameda Americano do Brasil, group A and six (33.3%) in group B (p=0.18). The time and degree of difficulty
282, Ed. City Hall, apto. 801
Goiânia, GO – Brazil involved in identifying the SLN were similar in both groups. There were no
Postal code: 74180-010 complications or allergies.
[email protected]
Conclusion: Methylene blue performed as well as patent blue in identifying the
Funding: Partially funded by the Goiás SLN in breast cancer patients.
State Foundation for the Support of
Research (FAPEG), grant 01/2007
Keywords: breast cancer, sentinel lymph node, patent blue, methylene blue,
http://dx.doi.org/10.1590/1806-9282.63.02.118 randomized controlled trial.

Introduction to have no axillary metastasis, with the intervention there-

Prior to the first studies on sentinel lymph nodes, axillary fore having been unnecessary.1
lymph node dissection was considered the standard treat- The introduction of the sentinel lymph node biopsy was
ment for patients with early stage breast cancer.1,2 Indeed, one of the greatest advances in the surgical treatment of
the extent of axillary involvement is one of the most im- breast cancer and has proved an excellent predictor of axillary
portant independent prognostic factors for tumor recur- involvement in initial tumors.4,5 Since sentinel lymph node
rence and patient survival.2,3 Nevertheless, dissection of biopsy involves fewer risks and less morbidity, it has gained
the entire axillary lymph node chain results in greater followers worldwide and is currently the standard treatment
morbidity, and a considerable percentage of the patients for axillary management in breast cancer patients.6 This
previously submitted to this procedure were later found method enables axillary involvement to be diagnosed with

118Rev Assoc Med Bras 2017; 63(2):118-123

A prospective randomized trial comparing patent blue and methylene blue for the detection of the sentinel lymph node in breast cancer patients

good sensitivity. Therefore, complete dissection of the axil- The patients were receiving care within the Breast Program
lary lymph nodes became restricted to those cases in which at the University of Goiás Teaching Hospital. The insti-
metastases are detected in the sentinel lymph node. tutional review board approved the study. All the patients
When only micro-metastases are found in the sentinel signed an informed consent form.
lymph node, complete dissection is considered unneces- The participants were scheduled to undergo sentinel
sary.7 In the case of conservative surgery with convention- lymph node biopsy or complete axillary lymph node dis-
al radiotherapy, standard axillary dissection can be avoid- section. The women were enrolled irrespective of their
ed when only one or two lymph nodes are affected.8 In the clinical staging, comorbidities or previous treatment
case of mastectomy or when up to three lymph nodes are (previous surgeries, chemotherapy or radiotherapy). A
affected, axillary radiotherapy can be performed, with total of 69 patients (49.3%) received a 2-mL injection of
lower morbidity rates compared to axillary dissection.9,10 patent blue (Group A) and 71 (50.7%) a 2-mL injection of
Some investigators have preferred the use of nuclear 1% methylene blue (Group B). Two patients were exclud-
medicine techniques to identify the sentinel lymph node ed from the analysis because the type of dye used had not
due to the greater simplicity of those techniques compared been recorded appropriately.
to the use of dyes.5,11 With dyes, the surgeon may require For the calculation of sample size, the factors taken
slightly more training and the learning curve may be into consideration were the possibility of a sentinel lymph
steeper.12 After the initial training period, however, the node detection rate of 95% with patent blue11,19 and a
sentinel lymph node identification rate with dyes tends hypothetical difference of 20% less in the detection rate
to be similar to that obtained with nuclear medicine tech- with the use of methylene blue. In fact, the few published
niques, reaching 98% in some more recent reports.13 Fur- studies available comparing the two methods failed to
thermore, once the sentinel lymph node is identified, show any difference between them.15,20 Considering a
accuracy is the same irrespective of the method used and confidence level of 5% and a power of the test of 80%, a
the lymph node detection rate. total of 116 patients would be required, divided into the
The principal problems involved in radioactive tracer two groups. To compensate for any possible losses, 142
techniques are their technological complexity and high patients were enrolled to the study.
costs.5 In this respect, the use of dyes is still the most The patients admitted to the study underwent vari-
economically viable alternative, principally in public ous different steps that consisted of a detailed bilateral
healthcare services with few resources, a common sce- breast examination, laboratory tests including full blood
nario in developing countries. The cost of the same pro- count, alkaline phosphatase, aspartate aminotransferase
cedure may be much lower with the use of dyes compared (AST) and alanine transaminase (ALT), chest X-ray (pos-
to the use of radioactive tracers. terior-anterior and lateral), ultrasonography of the upper
Different vital dyes have been used to identify the sen- abdomen, bone scintigraphy, bilateral mammography
tinel lymph node: patent blue, isosulfan blue and, less com- and the preoperative examinations appropriate for each
monly, methylene blue.11,13 Although methylene blue is more individual case.
readily available and considerably less expensive than the Mastectomy or quadrantectomy was performed in
others, some authors claim that it diffuses more rapidly in accordance at the discretion of the attending physician,
peripheral tissues, staining a larger portion of the breast with together with sentinel lymph node biopsy. Level I, II and
the blue dye and, to a certain extent, hampering the proce- sometimes level III axillary lymphadenectomy was per-
dure.14-16 Other authors have reported similar accuracy and formed when axillary involvement was found immedi-
sentinel lymph node detection rates with methylene blue ately prior to surgery, either clinically, by palpation or from
and with patent blue.13,17 There appears to be a lower risk of imaging tests. The patients were previously randomized
anaphylaxis with methylene blue compared to the other using a computer-generated randomization system to the
dyes.18 Therefore, the objective of the present study was to use of patent blue or methylene blue dye. According to the
compare the detection rate and accuracy of two different randomization group, 2 mL of 2.5% sterile patent blue dye
dyes, methylene blue and patent blue, for the identification or 2 mL of sterile methylene blue dye were injected into
of the sentinel lymph node in patients with breast cancer. the peritumoral or periareolar region. Next, the site was
massaged for 5 minutes. Sentinel lymph nodes were defined
Method as all the lymph nodes stained blue or when the afferent
In this prospective randomized study, 142 patients with lymphatic vessels were blue (Figure 1). Clinically suspect
a diagnosis of invasive breast carcinoma were included. lymph nodes were not considered sentinel lymph nodes.

Rev Assoc Med Bras 2017; 63(2):118-123 119

 Paulinelli RR et al.

FIGURE 1 Sentinel node in the armpit identified by means of the color, after the periareolar injection of the blue dye.

The surgical specimen was sent to pathology and with a radioactive isotope or on their own.22 However, the
histological confirmation was reached by frozen section sentinel lymph node identification rate with dyes is large-
biopsy. The sentinel lymph nodes were submitted to his- ly dependent on the experience of the medical team. Gi-
tological evaluation separate from the rest of the lesion uliano et al. reported an increase in the sentinel lymph
and from the other lymph nodes. node identification rate with patent blue dye from 66 to
The data were collected on a form specifically designed 94% as their experience increased.11,19
for this study and entered into a database. SPSS statisti- Although patent blue and isosulfan blue are the dyes
cal software package, version 15.0, was used for the sta- most commonly used in the sentinel lymph node technique,
tistical analysis. Chi-square test was used to compare some groups have reported success with the use of methy-
accuracy between the two groups using the formulae for lene blue.17,18 The difference in cost between the dyes is
the comparison of two independent samples described considerable and methylene blue is much more readily
by Galen & Gambino.21 P-values < 0.05 were considered available in different hospitals. The cost of methylene blue
statistically significant. may represent as little as 3% of the cost of patent blue or
isosulfan blue.23 For healthcare institutions in developing
Results countries, particularly those that depend on public fund-
There were no statistically significant differences between ing, this cost reduction may make the use of the sentinel
the two groups with respect to the characteristics of the node technique more easily available.
patients or their tumors (Table 1). The type of treatment The risk of allergic reactions ranges from 1 to 2% with
given and the immediate results were similar in both patent blue and isosulfan blue, with these reactions being
groups (Table 2). The time required to identify the sen- severe in some cases.17,18 Up to the present moment, there
tinel lymph node and the degree of difficulty encountered have been no reports of allergies with methylene blue. As the
were similar in the two groups. The sentinel lymph node popularity of the sentinel lymph node technique increases,
identification rate was similar in both groups, as were the preference for the use of methylene blue rather than the
other parameters compared (Table 3). other dyes may avoid many undesirable and potentially fatal
allergic reactions.13 Furthermore, compared to the other dyes,
Discussion methylene blue interferes less with oximetry.24 Nevertheless,
The use of radioactive isotope techniques to identify the a case has been reported in the literature of a pulmonary
sentinel lymph node in patients with breast cancer has edema possibly related to the use of methylene blue for the
been limited, mainly because a considerable proportion detection of the sentinel lymph node.25 Another advantage
of healthcare services cannot afford their costs. Dyes are of methylene blue is the possibility of being able to use it
widely used with acceptable results, both in association during pregnancy, which is not the case with the other dyes.26

120Rev Assoc Med Bras 2017; 63(2):118-123

A prospective randomized trial comparing patent blue and methylene blue for the detection of the sentinel lymph node in breast cancer patients

TABLE 1 Characteristics of the patients and tumors.

Patent blue Methylene blue p-value
Age (years)a 51.00 (+11.48) 52.82 (13.44) 0.39
Size of the tumor (mm)b 35.00 (25.00–50.00) 33.00 (25.00–50.00) 0.78
Clinical stagingc 0.34
I 8 (11.6%) 11 (15.5%)
IIa 28 (40.6%) 30 (42.3%)
IIb 14 (20.3%) 14 (19.7%)
III 17 (24.6%) 15 (21.1%)
IV 2 (2.9%) 1 (1.4%)
Clinical involvement of axillae 32 (46.4%) 22 (31.0%) 0.06
Histological gradec 0.90
I 13 (23.6%) 16 (28.6%)
II 32 (58.2%) 28 (50.0%)
III 10 (18.2%) 11 (19.6%)
Skin colord 0.73
White 27 (39.1%) 32 (45.7%)
Black 7 (10.1%) 6 (8.6%)
Brown 35 (50.7%) 32 (45.7%)
Histological typed 0.56
Invasive ductal carcinoma 61 (88.4%) 60 (84.5%)
Invasive lobular carcinoma 3 (4.3%) 3 (4.2%)
Others 5 (7.3%) 8 (11.3%)
Multicentric tumor d
13 (18.8%) 15 (21.4%) 0.70
a
Mean (± standard deviation), Student’s t-test.
b
Median (interquartile range), Mann-Whitney U test.
c
n (%), Mann-Whitney U test.
d
n (%), Chi-square test, with or without Yates’ correction, or Fisher’s exact test.

TABLE 2 Characteristics of the techniques and of the treatment.

Patent blue Methylene blue p-value
Lymph node dissection a
15.2 (±6.8) 15.9 (±8.5) 0.67
Lymph nodes affectedb 1.0 (0.0-2.5) 0.0 (0.0-5.0) 0.93
Previous open biopsyc 15 (21.7%) 21 (29.6%) 0.29
Neoadjuvant chemotherapy c
39 (56.5%) 47 (66.2%) 0.24
Conservative surgeryc 37 (53.6%) 35 (49.3%) 0.87
a
Mean (± standard deviation), Student’s t-test.
b
Median (interquartile range), Mann-Whitney U test.
c
n (%); Chi-square test.

TABLE 3 Results of sentinel lymph node investigation.

Patent blue Methylene blue p-value
Detection of sentinel lymph node 47 (68.1%) 43 (60.6%) 0.35a
Involvement of sentinel lymph node 22 (51.2%) 21 (48.8%) 0.62
Sentinel lymph node was the only node affected 12 (54.5%) 6 (33.3%) 0.19a
Number of sentinel lymph nodes 1.0 (0.0-2.0) 1.0 (0.0-2.0) 0.43b
Time until detection of sentinel lymph node (minutes) 14.0 (4.0-45.0) 11.0 (1.0-31.3) 0.34b
a
n (%); Chi-square test for trend (Mann-Whitney U test).
b
Median (interquartile range); Mann-Whitney U test.

Rev Assoc Med Bras 2017; 63(2):118-123 121

 Paulinelli RR et al.

There have been reports of a few cases of skin necro- identifying the sentinel lymph node that exceeded the
sis and fat necrosis following injection of different dyes; limit considered acceptable following chemotherapy.32,33
however, no complication of this type was found in the It is not yet known whether slightly more false-negative
present study.27,28 findings could translate into unfavorable oncological results
In our study, the sentinel lymph node detection rate such as a greater incidence of recurrence of the disease and
was 68.1% in the patent blue group and 60.6% in the higher mortality. In those studies, the best and most ac-
methylene blue group, with no statistically significant ceptable results were obtained when two types of markers
difference between the two groups. This detection rate were used, a dye in association with radioactive technetium,
may appear low, but this can be explained by the large and when more than two lymph nodes were removed.
number of locally advanced tumors, of cases in which Despite the financial limitations imposed by the
axillary involvement was present and of cases in which healthcare system and by the teaching hospital, we believe
neoadjuvant chemotherapy had been performed. Further- that this study represents an important contribution
more, physicians undergoing training are given the op- towards being able to offer an alternative to the use of
portunity to start learning a new specialty in this univer- nuclear medicine even when circumstances are unfavor-
sity teaching hospital. Studies with patent blue alone able such as in this study population.
have shown a detection rate of 60 to 75% at the beginning
of the learning curve.19,29 Conclusion
For various reasons, we decided that all patients with Methylene blue can be used as a substitute for patent blue
invasive carcinomas should be included in the study, even in sentinel lymph node biopsies, with no increase in the
cases lacking conventional indication for sentinel lymph complication rate or in the degree of technical difficulty,
node. This would allow a greater number of cases to be and with the added advantage of lower cost.
included, providing the team with a better training op-
portunity and conferring greater statistical power to the Resumo
analysis. Since the patients were allocated randomly into
the groups, there does not appear to be any type of selec- Estudo randomizado prospectivo comparando o azul
tion bias in comparing the efficacy of each method. Once patente ao azul de metileno para a detecção do linfonodo
the sentinel lymph node was identified, the accuracy of sentinela em pacientes com câncer de mama
the different dyes appears to be similar to rates published
in the literature.5,30 The degree of technical difficulty ap- Introdução: O azul de metileno é mais facilmente encon-
pears to be the same in the two groups. trado para comercialização e a um preço menor que o azul
Since the physical examination and imaging tests patente. Parece ainda haver menor risco de anafilaxia.
performed may raise false suspicions, a biopsy of the Objetivo: Comparar a taxa de detecção do linfonodo sen-
sentinel lymph node was performed rather than percuta- tinela com o azul patente e com o azul de metileno.
neous lymph node biopsy, and the suspect lymph node Método: Foram incluídas, de forma randomizada e pros-
was removed separately if not simultaneously, followed pectiva, 142 pacientes com diagnóstico de carcinoma
by intra-operative evaluation by cytology or histology. mamário invasor, que consentiram em participar livre-
Due to the strict study methodology, a lymph node that mente do estudo. Foram injetados 2 mL de azul patente
was considered suspect from a clinical point of view but (grupo A) em 69 (49,3%) mulheres e de azul de metileno
that had not been stained was not considered a sentinel (grupo B) em 71 (50,70%), em localização periareolar ou
lymph node. peritumoral, seguido de 5 minutos de massagem. Trinta
Use of sentinel lymph node biopsy in clinical practice, e cinco (25,0%) apresentavam estadiamento clínico 3 ou
despite still involving considerable morbidity, provides 4, e 55 (38,7%) apresentavam a axila clinicamente com-
better results for the patients than complete axillary dis- prometida. Sessenta e nove (49,3%) fizeram quimioterapia
section.31 In certain cases, such as those with larger tumors, neoadjuvante. Duas pacientes não tinham anotação do
following neoadjuvant chemotherapy, or when there is corante utilizado e foram excluídas.
prior axillary involvement, identification of the sentinel Resultados: Os dois grupos apresentaram características
lymph node is more difficult and there is a greater risk of das pacientes e dos tumores semelhantes. Foram detec-
false-negative findings. The American College of Surgeons tados linfonodos sentinela em 47 (68,1%) mulheres no
Oncology Group (ACOSOG)’s Z1071 trial and the Sentinel grupo A e em 43 (60,6%) no grupo B (p=0,35). Havia lin-
Neoadjuvant (SENTINA) study both reported errors in fonodos sentinela comprometidos em 22 (51,2%) casos

122Rev Assoc Med Bras 2017; 63(2):118-123

A prospective randomized trial comparing patent blue and methylene blue for the detection of the sentinel lymph node in breast cancer patients

no grupo A e em 21 (48,8%) casos no grupo B (p=0,62). O among experienced surgeons: a prospective tabular cumulative sum (CUSUM)
analysis. BMC Surg. 2009; 9:2.
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Palavras-chave: câncer de mama, linfonodo sentinela, reactions associated with isosulfan blue versus methylene blue dye in sentinel
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