Sentinel Lymphadenectomy in Breast Cancer
By Armando E. Giuliano, Ralph C. Jones, Meghan Brennan, and Richard Statman
Purpose: We previously demonstrated increased de-
tection of axillary metastases using sentinel lymphade-
nectomy (SLND) and immunohistochemistry. These meth-
ods have evolved and we now report our current use of
these techniques and our most recent results of axillary
staging with SLND.
Patients and Methods: One hundred seven consecu-
tive women (previously unreported) with breast cancer
underwent SLND followed by completion axillary lymph-
adenectomy (ALND). All sentinel nodes were examined
intraoperatively with frozen section and postoperatively
with hematoxylin and eosin staining (H&E) plus immuno-
histochemical staining (IHC) using antibody to cytokera-
tin. The nonsentinel axillary nodes were examined with
H&E, but not IHC.
Results: The median age was 56.6 years (range, 28
to 90). Most patients (58.9%) were postmenopausal,
most primary tumors (62.6%) were palpable, and most
operations (86.9%) were breast-conserving. The mean
D ESPITE THE PROMISE of tumor-associated prog-
nostic factors such as hormone receptors, ploidy, S
phase, and oncogene expression, the presence of axillary
lymph node metastases remains the single best predictor
of overall survival in patients with breast cancer. Axillary
nodal status also has been the primary determinant for
the use of systemic adjuvant therapy, especially in pa-
tients with small tumors. Even so, many oncologists are
questioning the role and value of routine axillary lymph-
adenectomy (ALND) for patients with potentially curable
breast cancer. ALND, especially when followed by radia-
tion therapy, increases the risk of postoperative complica-
tions-notably lymphedema-and greatly increases the
cost, morbidity, hospital stay, and recovery time.`
Approximately 5 years ago, we adapted intraoperative
lymphatic mapping and sentinel lymphadenectomy (SLND)
for use in breast cancer. Our initial report showed that
this technique could predict the tumor status of the axil-
lary lymph nodes draining a primary breast carcinoma.
We demonstrated the feasibility of SLND in breast cancer
by comparing the tumor status of sentinel nodes in the
SLND specimen with that of nonsentinel nodes in the
standard ALND specimen from the same patient. Initial
staging accuracy was 95% in 174 patients.6 As the tech-
nique evolved, we began to examine the SLND specimen
with immunohistochemical staining (IHC) in addition to
standard hematoxylin and eosin staining (H&E); this fur-
ther increased the detection of axillary metastases, partic-
ularly micrometastases. 7 During these studies, technical
aspects of the surgical mapping procedure were refined,
histopathologic techniques were altered, and our clinical
Journalof Clinical Oncology, Vol 15, No 6 (June), 1997: pp 2345-2350
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Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
tumor size was 2.11 + 1.38 cm. Sentinel nodes were
identified in 100 patients: 42 patients had metastases in
sentinel nodes; of these, 28 (66.7%) had no other in-
volved axillary nodes. On average, 1.8 + 1.1 sentinel
nodes were examined and 20.3 ± 7.8 nonsentinel nodes
were removed. Of seven patients with no identified senti-
nel nodes, six had a tumor-negative axilla. SLND was
100% predictive of axillary status in these 100 women.
Conclusion: In this population of breast cancer pa-
tients, SLND with frozen section and IHC was a minimally
invasive, highly accurate intraoperative method of axil-
lary staging. We are evaluating the elimination of rou-
tine ALND for sentinel-node negative women to minimize
the morbidity associated with standard dissections. The
ability to identify node-negative patients without ALND
would be a welcome addition to the management of
women with breast cancer.
J Clin Oncol 15:2345-2350. © 1997 by American So-
ciety of Clinical Oncology.
team's experience increased. We now report the results
of applying the mature technique of SLND for breast
cancer in our most recent consecutive series of 107 pa-
tients.
PATIENTS AND METHODS
Study candidates were all consecutive patients undergoing opera-
tive management of potentially curable breast carcinoma from July
1994 through October 1995. Excluded were patients with large exci-
sions, prior axillary surgery, clinical T3 lesions, or clinically multifo-
cal lesions.
The technique of SLND for patients with breast carcinoma has
been described previously. Briefly, 3 to 5 mL of isosulfan blue
dye (Lymphazurin 1%; Hirsch Industries, Inc, Richmond, VA) was
From the Joyce Eisenberg Keefer Breast Center; John Wayne
Cancer Institute at Saint John's Health Center, Santa Monica, CA.
Dr. Jones is currently affiliated with the Department of Surgery,
National Naval Medical Center, Bethesda, MD.
Submitted December 13, 1996; accepted March 13, 1997.
Supported by the Ben B. and Joyce E. EisenbergFoundation,and
by the FashionFootwear Association of New York.
Presented in part at the American Society of Clinical Oncology
Annual Meeting, Philadelphia, PA, May 18-21, 1996.
The views expressed herein are those of the authors and do not
necessarily reflect the views of the US Army, US Navy, Uniformed
Services University of the Health Sciences, or the Department of
Defense.
Address reprint requests to Armando E. Giuliano, MD, John
Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica,
CA 90404.
C 1997 by American Society of Clinical Oncology.
0732-183X/97/1506-0031$3.00/0
2345
2346 GIULIANO ET AL

injected into the breast parenchyma immediately surrounding a pri- Table 1. Characteristics of the Primary Tumor
mary tumor. If the primary tumor had been previously excised, the
Tumors
wall of the biopsy cavity and surrounding tissue were injected. Dye
Characteristic No. %
was injected below the subcutaneous fat to avoid skin tattooing
and to assure parenchymal uptake by breast lymphatics. A separate ER
incision was then made in the axilla; the dye-laden lymphatic tract Positive 85 79.4
was identified and followed to a blue-stained sentinel node(s), which Negative 20 18.7
was excised and processed as a separate specimen. Unknown 2 1.9
In the present study, a thorough search for any additional blue PR
nodes was performed before standard ALND was completed through Positive 69 64.5
the same incision. Standard ALND removed level I, level II, and a Negative 35 32.7
small portion of level III axillary nodes. If the axilla was grossly Unknown 3 2.8
involved with metastatic disease, all level III nodes were removed. Ploidy
The patient then underwent modified radical mastectomy or breast- Diploid 40 37.4
conserving surgery. All operations were performed by the same Aneuploid 51 47.7
senior surgeon (A.E.G.) after informed consent had been obtained. Unknown 16 14.9
The size of the primary tumor as measured on histopathologic S phase
sectioning was recorded according to the guidelines of the American Low 51 53.3
Joint Committee on Cancer.8 Estrogen receptor (ER) status, proges- High 26 24.3
terone receptor (PR) status, HER-2/neu expression, DNA, ploidy, Unknown 24 22.4
and S phase were evaluated as tumor-associated indicators of prog- Her-2/neu
nosis. Each patient's clinical characteristics, tumor histology, and Low 49 45.8
axillary status were recorded prospectively. High 14 13.1
Unknown 44 41.1

Histologic Examination of Axillary Lymph Nodes

All axillary specimens were examined by pathologists at Saint
John's Health Center. The SLND specimen was evaluated indepen-
dently of the ALND specimen.
Sentinel nodes (the SLND specimen) were bivalved and a frozen
section was obtained to confirm the presence of nodal tissue. Tissue
trimming was minimal. Frozen tissue was then processed routinely
for permanent section with H&E. Each node was blocked individu-
ally, which resulted in two permanent section levels per paraffin
block. A cytokeratin IHC was performed on all sentinel nodes that
showed no metastases with H&E. Cytokeratin IHC used an antibody
cocktail (MAK-6; Ciba-Corning, Alameda, CA) directed against low
and intermediate molecular-weight cytokeratin. Approximately six
to eight histologic faces (including the frozen section) were exam-
ined for each sentinel node.
Nonsentinel nodes (the ALND specimen) were processed rou-
tinely by fresh dissection for isolation of lymph nodes. No lymph
node clearing techniques were used. Multiple lymph nodes were
embedded per block, depending on lymph node size. Large nodes
were bivalved. One or two levels of each node were examined with
H&E. IHC was not undertaken unless routine H&E detected suspi-
cious but not diagnostically malignant cells.
StatisticalAnalysis
All data were reviewed and analyzed by the Biostatistical Unit at
the John Wayne Cancer Institute and the University of California at
Los Angeles. Pearson's X2 test was used for comparisons.
RESULTS
During the study period, 110 women were consecu-
tively diagnosed with primary operable breast cancer.
After three patients with large clinical T3 lesions were
excluded, we identified our study population of 107 pa-
tients in whom SLND was attempted. The median age
was 56.6 years (range, 28 to 90). Forty-four patients were
premenopausal and 63 were postmenopausal. Primary
breast carcinomas were palpable in 67 patients and non-
palpable (detected by breast imaging) in 40 patients. Most
patients (93 of 107) underwent SLND in conjunction with
breast-conserving surgery, but mastectomy was per-
formed in 14 patients.
Primary tumor size ranged from microinvasive, arbi-
trarily defined as 1 mm, to 7.5 cm as measured on histo-
pathologic sectioning. The mean tumor size was 2.11 +
1.38 cm. All measurements excluded the noninvasive por-
tion. The majority of tumors were ER-positive (79.4%)
and PR-positive (64.5%). Ploidy, S phase, and Her-2/neu
expression are listed in Table 1. Most tumors (98 of 107)
were invasive ductal carcinoma; only nine were infiltrat-
ing lobular carcinoma.
At least one sentinel node was identified in 100 patients
(93.5%). Of these 100 patients, 42 had a tumor-positive
SLND specimen (Table 2). In 28 of these 42 patients
(67%), the sentinel node was the only node involved.
Tumor cells were detected by routine H&E in 33 SLND
specimens (78.6%) and only by IHC in the nine remaining
SLND specimens (21.4%). Nineteen SLND specimens
(45.2%) had micrometastases (• 2 mm), nine (47.4%)
of which were not detected by H&E. There were no false-
positive sentinel nodes by frozen section. The seven pa-
tients in whom no sentinel node could be found had no
identifiable blue-stained lymphatics.

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SENTINEL NODE IN BREAST CANCER 2347

Table 2. Detection of Sentinel Node Metastases
Variable
SLND procedures
Detecting sentinel node(s)
Tumor-involved axillae
Containing tumor-positive sentinel node(s)
With macrometastases
With micrometastases
Detected by H&E staining
Detected by IHC staining
The mean number of axillary lymph nodes examined
in the 107 dissections was 20.3 ± 7.8 (range, seven to
60), excluding sentinel nodes. The mean number of senti-
nel nodes examined in the 100 SLND specimens was 1.8
+ 1.1 (range, one to eight). No SLND specimen was
tumor-negative if the corresponding ALND specimen
from the same patient was tumor-positive; however, 31
SLND specimens (35 sentinel nodes) were tumor-positive
when the remaining axillary lymph nodes were negative.
Thus, SLND produced no false-negative results and in
these 100 patients was 100% predictive of axillary metas-
tases and 100% effective as an axillary staging technique.
Table 3 compares the predictive value of SLND for
the detection of axillary lymph node metastases with that
of other prognostic variables studied in these patients.
Her-2/neu overexpression was the second most effective
predictive factor. Size was also predictive of axillary me-
tastasis, as was ER/PR status. However, only the pre-
dictive values for size and Her-2/neu expression were
significant using a X2 analysis. In this study, most primary
tumors were TI (Table 4). Of four Tla lesions, one metas-
tasized to the axillary lymph nodes; of two T3 lesions,
both metastasized to sentinel nodes.
In patients with clinically suspicious lymph nodes,
SLND was undertaken to determine if the dye targeted a
node suspected of tumor involvement. Of eight patients
whose physical examination was suspicious for axillary
No. metastases, seven (87.5%) had histopathologic confirma-
107 tion of a tumor-involved axillary basin. Of 99 patients
100 (93.5%) with no clinical evidence of axillary metastases, 36
42 (35.4%) had histologically confirmed metastases.
42
There were no complications from the injection of blue
23
19
dye into the breast parenchyma or from the surgical exci-
10 sion of the sentinel node(s). Several patients had a faint
9 blue haze in the area of injection, which persisted for
several months, and most patients noted green urine for
12 to 24 hours. However, all patients had been advised
of these side effects and no patient reported either as
bothersome.
DISCUSSION
Although detection of axillary metastases is essential
to stage patients with breast cancer and is important for
determining systemic adjuvant treatment, routine ALND
is being questioned as the trend for less radical surgery
continues. ALND has already been largely eliminated for
ductal carcinoma in situ' and investigators are questioning
its routine use in patients with small primary tumors.••1
Unfortunately, there are no nonsurgical staging alterna-
tives. No tumor marker or combination of tumor markers
accurately predicts axillary metastasis or the systemic re-
currence of breast cancerl3"14 and no imaging studies have
replaced axillary dissection for staging. Meanwhile, it
is possible that the increasing complexity of adjuvant
systemic treatments has increased the importance of accu-
rate staging, rather than decreased its importance as sug-
gested by some.
Nemoto et al' 5 reported a direct relationship between
breast cancer recurrence and number of tumor-involved
axillary nodes, and National Surgical Adjuvant Breast
and Bowel Project (NSABP) studies have shown that
an increasing number of tumor-involved lymph nodes
increases the likelihood of treatment failure.' 6"17 These

Table 3. Significance of Prognostic Variables

With Respect to Axillary Status Table 4. Size of Primary Tumor and Status of Sentinel Lymph Node

P Sentinel Lymph Node

Variable Univariate Multivariate Size of No. of Positive Negative

Primary Tumor Patients No. % No. %
Tumor size .0183 .0216
ER status .191 NS T1 64 22 34.4 42 65.6
PR status .350 NS Tla 4 1 25 3 75
Ploidy .951 NS Tlb 18 8 44.4 10 55.6
S phase .477 NS T1c 42 13 31 29 69
Her-2/neu .021 .0365 T2 34 18 52.9 16 47.1
Menopausal status .392 NS T3 2 2 100 0 0
All 100 42 42 58 58
Abbreviation: NS, not significant.

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Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
2348
findings underscore the importance of determining the
presence and extent of axillary lymph node involvement,
not only for therapy, but also for prognosis and coun-
seling.
However, the accuracy of axillary staging depends on
the surgical sampling technique. Removing more lymph
nodes increases the chance of identifying metastases, but
also increases operative morbidity.',2,4' 5 Some complica-
tions, such as brachial plexus injury, although serious,
are so unusual as to be clinically irrelevant. Others, such
as wound seroma after the removal of a drain, are dis-
tressing to the patient, but can usually be resolved with
minimal intervention. Vascular injury is serious but rare.
The most distressing problem to the patient is lymph-
edema of the arm, which is not uncommon after ALND.
The incidence of lymphedema varies directly with the
amount of nodal tissue removed2 ; level I dissection or
blind biopsy of a few lymph nodes is associated with
the lowest incidence of lymphedema, but carries a high
incidence of false-negative axillary staging.' 8 2 The con-
sensus statement from the National Institutes of Health
recommended dissection of levels I and II in patients who
undergo breast-conserving surgery and radiation.2 3 This
dissection will identify approximately 95% to 97% of
patients with recognized axillary metastases because only
approximately 3% to 5% of patients will have tumor
involvement of level III lymph nodes without metastasis
to levels I and II.1,2427 Removal of level III nodes appears
to greatly increase the incidence of lymphedema and is
not routinely performed.2 Regardless of the extent of dis-
section, occult metastases may not be recognized unless
special histologic studies are performed.
SLND was developed to stage patients accurately with-
out removing most of the axillary contents. When we
first developed the technique in 1991, we encountered
problems with timing and site of injection, volume of
injectate, identification of lymphatics, and other technical
issues. We were also at the beginning of a learning
curve,6' 28 which in retrospect explains why most of our
errors occurred early in our experience with this tech-
nique. This learning curve was greatly exaggerated be-
cause we were developing the technique at the same time
we were evaluating it. Surgical fellows now introduced
to the technique gain proficiency after approximately 10
cases.
Data from the present study demonstrate that SLND
has evolved to reach 100% specificity, 100% sensitivity,
and 100% predictability when compared with standard
ALND. We expect that this exceptional degree of accu-
racy will of course decrease, but probably by no more
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Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
GIULIANO ET AL
than one or two percentage points, which would approxi-
mate the success rates reported by various investigators
for SLND in melanoma.2 8 None of the standard tumor
markers that we examined is likely to reach this degree of
accuracy for predicting axillary metastasis or prognosis.
There were no adverse effects of dye injection, except the
infrequent subtle blue staining of the breast parenchyma,
which appeared in a few patients after axillary dissection.
This usually occurred in patients with nodal involvement
who underwent radiation and experienced breast edema;
altered lymphatic flow probably impaired processing of
the vital blue dye through the lymphatic system. No pa-
tient complained that this was a problem, and it was
unnoticed by most. We have seen none of the allergic
reactions previously reported with isosulfan blue."29
IHC with antibodies for specific breast epithelial anti-
gens such as cytokeratin, mucin, and milk fat globulin
can identify micrometastatic deposits not detected by rou-
tine H&E. 30 -32 Special techniques can easily be applied
for focused analysis of one or two sentinel nodes, but are
impractical for the entire axillary contents. We have found
that routine IHC of SLND specimens significantly in-
7
creases the detection of axillary lymph node metastasis.
Indeed, most of the patients with small tumors in this
study had their metastases detected by IHC alone, and
our incidence of axillary metastasis in Tla/b tumors is
higher than usually reported. 33 IHC was not used to exam-
ine all excised nodes because it is time-consuming and
expensive.
Although the prognostic significance of axillary micro-
metastases requires further examination in a prospective
trial, various retrospective studies show that patients with
axillary occult metastases detected using special stains
have a higher disease recurrence and a 10% to 20% lower
rate of overall survival than patients with tumor-free
lymph nodes.34-38 A meta-analysis by Cote has shown a
statistically significant increase in overall and disease-
free survival for patients with occult metastases detected
by special histologic techniques (personal communica-
tion, November 1996). These reports are not surprising
since axillary occult metastases are likely to be associated
with more distant occult metastases. At our institution, the
identification of micrometastases in an SLND specimen is
considered an indication for adjuvant systemic therapy.
IHC-detected metastases have altered the therapy for pa-
tients with T1 breast cancers.
In conclusion, we have shown that the mature tech-
nique of SLND is an accurate predictor of axillary status.
The technique continues to evolve. Other techniques to
identify the sentinel node, such as intraoperative radio-
 SENTINEL NODE IN BREAST CANCER
lymphoscintigraphy,39 may increase the detection rate by
surgeons not experienced with intraoperative lymphatic
mapping, but there are few reports of their use in breast
cancer. Radiolymphoscintigraphy is unlikely to increase
the rate of sentinel node detection significantly beyond
that associated with blue dye alone. Because we are con-
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