6 Lymphatic Mapping and Sentinel Lymph Node Biopsy

2004 WebMD, Inc. All rights reserved.
BREAST, SKIN, AND SOFT TISSUE
ACS Surgery: Principles and Practice

6
Lymphatic Mapping and Sentinel Lymph Node Biopsy 1
6 LYMPHATIC MAPPING AND

SENTINEL LYMPH NODE BIOPSY
Seth P. Harlow, M.D., David N. Krag, M.D., F.A.C.S., Douglas S. Reintgen, M.D., F.A.C.S.,
Frederick L. Moffat, Jr., M.D., F.A.C.S., and Thomas G. Frazier, M.D., F.A.C.S.
Breast cancer and melanoma are among the most common

malignancies treated by U.S. surgeons. In 2003, it was estimated that there were 54,200 new cases of melanoma and 212,600
new cases of breast cancer in the United States.1 The incidence
of melanoma has been rising rapidly in the past few decades, and
the incidence of breast cancer is also likely to keep rising as the
baby-boomer generation ages.
Over the past 20 years, significant strides have been made in
the management of these two diseases from the standpoint of
both surgical and adjuvant treatment. For both patients with
melanoma and those with breast cancer, adjuvant therapies for
high-risk lesions have been shown to have a positive impact on
recurrence rates and overall survival. In melanoma, the administration of adjuvant interferon alfa-2b to patients with T4 (> 4.0
mm deep) primary tumors or nodal metastases has led to lower
recurrence rates and longer overall survival.2 In breast cancer,
there is a much more extensive body of experience with adjuvant
chemotherapy and hormone therapy for optimization of survival
in high-risk patients.3,4 In both diseases, the presence or absence
of lymph node metastases is highly predictive of patient outcome
and is the most important prognostic factor for disease recurrence and cancer-related mortality. Surgical management of the
regional lymph nodes will continue to be an important component of therapy for patients with these malignancies.
Progress in the management of regional lymph nodes in melanoma and in breast cancer has taken different routes to what is
likely to be the same destinationnamely, the use of lymphatic
mapping and sentinel lymph node (SLN) biopsy in clinically
node-negative patients. The development of intraoperative lymphatic mapping and selective lymphadenectomy has made it
possible to map lymphatic flow from a primary tumor to the initial draining node or nodes (i.e., the SLN or SLNs) in the
regional nodal basin.The pathologic status of the SLN is known
to be concordant with the pathologic status of the nodal basin as
a whole. Integration of these techniques, along with increasingly detailed and sophisticated pathologic examination of the
SLN, into the surgical treatment of melanoma and breast cancer offers the potential for more conservative operations, lower
morbidity, and more accurate disease staging.
Lymphatic Mapping and SLN Biopsy for Melanoma
RATIONALE
Assessment of Nodal Status

There are several established factors for predicting the risk of
metastatic disease in melanoma patients. These factors must be
taken into account to ensure that patients are appropriately
stratified into different risk groups and hence can receive appro-
priate treatment. The presence of lymph node metastases is the

single most powerful predictor of recurrence and survival in
melanoma patients: 5-year survival is approximately 40% lower
in patients who have lymph node metastases than in those who
do not. This finding suggests that many melanoma patients are
likely to benefit from accurate nodal staging.
Elective lymph node dissection Until the latter part of
the 1990s, elective lymph node dissection (ELND) was the
mainstay of the surgeons armamentarium for nodal staging of
melanoma patients. ELND removes clinically negative nodes, as
opposed to therapeutic node dissections, which are done for
nodes with gross tumor involvement. Opinions are divided as to
whether ELND actually extends survival or whether it is solely
a staging procedure.Two prospective, randomized trials failed to
demonstrate better survival in melanoma patients treated with
ELND than in patients undergoing wide local excision (WLE)
alone as primary surgical therapy.5,6 Retrospective studies from
large databases, however, suggested that there may be subpopulations of patients who do benefit from ELND. The Intergroup
Melanoma Trial was the first randomized study to show
enhanced survival in patient subgroups after surgical treatment
of clinically occult metastatic melanoma.7 The benefit was found
in patients with melanomas 1.1 to 2.0 mm thick and patients
younger than 60 years.8
Adjuvant therapy for high-risk melanoma Three
national prospective, randomized trials sponsored by the
Eastern Cooperative Oncology Group (ECOG) investigated the
use of adjuvant interferon alfa-2b in patients with high-risk
melanoma.The first trial, ECOG 1684,2 was the impetus for the
Food and Drug Administrations approval of interferon alfa-2b,
in that it was the first study to demonstrate that this agent was
an effective adjuvant therapy for patients with high-risk melanoma. Patients eligible for ECOG 1684 had either thick primary
melanomas (> 4.0 mm thick) or nodal metastases. ECOG 1684
and a subsequent trial, ECOG 1694,9 reported significant overall survival benefits for patients receiving adjuvant interferon
alfa-2b; a third trial, ECOG 1690,10 did not, though it did show
an improvement in disease-free survival for the treated group.
Given the results from the Intergroup Melanoma Trial and
the three ECOG trials, one can make a strong argument that
when the risk of nodal metastases reaches a certain defined level,
a nodal staging procedure should be performed. Because of the
morbidity associated with a negative ELND, lymphatic mapping
and SLN biopsy has become the de facto procedure of choice
for nodal staging in melanoma patients.
Lymphatic mapping and selective lymphadenectomy
SLN biopsy in melanoma was first described in 1992 by Morton

3
and associates,11 who outlined a procedure of intraoperative lymphatic mapping and selective lymphadenectomy in which a vital
blue dye was injected into the skin around the site of the primary
melanoma. These investigators showed that the SLN is the first
node in the lymphatic basin into which the primary melanoma
consistently drains (though not necessarily the closest to the primary lesion).They harvested the SLN separately from the remainder of the regional nodes, and they found that the pathologic status
of the SLN was highly accurate at predicting the pathologic status
of the entire nodal basin, which was surgically removed in all of the
patients studied.These findings suggested that melanoma patients
could be accurately staged with procedures that were far less extensive than complete nodal dissections.
PREOPERATIVE EVALUATION
Selection of Patients
The risk of nodal metastases in melanoma patients depends
on a number of factors, including primary tumor thickness, presence of ulceration, primary tumor location, and patient sex. Any
patient with invasive melanoma (Clark level II or higher) is at
some risk for nodal metastasis; however, before recommending
SLN biopsy, the surgeon should determine what the relative risk

6

of nodal metastasis is with respect to the cost and morbidity of
the procedure.
Patients with intermediate-thickness melanomas (1.0 to 4.0 mm)
are the ones likely to gain most from SLN biopsy: the risk of nodal
metastases in the absence of systemic disease is believed to be highest in this group. In patients with melanomas between 0.76 and 1.0
mm thick, the risk of nodal metastasis is less than 6%, but the procedure can certainly be justified in this population on the basis of
its low morbidity. In patients with thin melanomas (< 0.76 mm),
several prognostic factors have been shown to identify higher risk,
including primary tumor depth of Clark level III or higher, ulceration, the presence of regression, male sex, and axial location.12 Patients with thin melanomas and multiple risk factors may be at
high enough risk to warrant SLN biopsy.
In patients with thick melanomas (> 4.0 mm), the risk of
occult systemic metastases is as high as 70%, and that of occult
nodal metastases ranges from 60% to 70%. The high risk of systemic disease was the main reason why ELND was not recommended for such patients in the past. Now that these patients
have access to effective adjuvant therapy, however, they should
be offered lymphatic mapping and SLN biopsy as a staging procedure. Among patients with thick melanomas, those with negative nodes survive longer than those with microscopic nodal dis-
Choice of Radiocolloid and Vital Blue Dye for Lymphatic Mapping

Choice of Radiocolloid
Little work has been done to determine which radiocolloid is best suited to either preoperative or intraoperative mapping. The ideal radiocolloid for intraoperative SLN mapping would have small particles (< 100
nm) that are uniformly dispersed, would be highly stable, and would
have a short half-life that would not complicate the handling of the
excised specimen. Technetium-99m (99mTc)labeled compounds, being
gamma emitters, satisfy most of these requirements. In a direct comparison between filtered (0.1 m filter) 99mTc-labeled sulfur colloid (TSC)
and 99mTc-labeled antimony trisulfide colloid (T-ATC), which has a particle size of 3 to 30 nm, filtered TSC was transported more quickly to the
nodal basin and emitted less radiation to the liver, the spleen, and the
whole body.98 Unfiltered TSC contains relatively large particles (100 to
1,000 nm), and some investigators have found it to migrate more slowly from the injection site; however, other investigators have found it to be
slow to flow through the first SLN to higher secondary nodes, which is
actually an advantage.
A comparison between Tc-labeled human serum albumin (T-HSA), Tclabeled stannous phytate, and T-ATC with respect to lymphoscintigram
quality showed that T-ATC provided the best images for preoperative lymphoscintigraphy.99 In an animal study comparing T-HSA with TSC, TSC
was actually concentrated in the SLN over a period of 1 to 2 hours, whereas T-HSA passed rapidly through the SLN.100 As a result, TSC yielded
higher activity ratios at intraoperative mapping, improved the success rate
of localization, made the technique easier, and thus was a superior reagent
for this application.
The Sydney Melanoma Unit (SMU) prefers the use of T-ATC because this
agent seems to have smaller, more uniform particles that rapidly migrate
into the lymphatic channels but still are appropriately trapped and retained
by the SLN. At SMU, use of T-ATC allows injection of the radiocolloid and
imaging to be performed on the day before operation. SMU investigators
find that hot spots in the regional basin are maintained even when 24 hours
have elapsed from the time of injection. The radioactivity in the basin over
the hot spot (i.e., the SLN) is decreased because four half-lives of technetium have been expended and because some of the radiocolloid has
passed through, but the ex vivo activity ratio is not substantially affected.
In the United States, T-ATC has been removed from the market and is
unavailable for clinical use. Currently, TSC (filtered or unfiltered) is the agent
favored by most surgeons in the United States.
Choice of Vital Blue Dye

Several vital blue dyes have been investigated with an eye to their potential applicability to cutaneous lymphatic mapping. Among these are methylene blue (American Regent, Shirley, NY); isosulfan blue, 1% in aqueous
solution (Lymphazurin; United States Surgical Corp., Norwalk, CT); patent
blue-V (Laboratoire Guerbet, France); Cyalume (American Cyanamid Co.,
Bound Brook, NJ); and fluorescein dye. All substances tested were known
to be nontoxic in vivo and were injected intradermally as provided by the
supplier. In a feline study, patent blue-V and isosulfan blue were the most
accurate in identifying the regional lymphatic drainage pattern.101 These
dyes entered the lymphatics rapidly, with minimal diffusion into the surrounding tissue. Their bright-blue color was readily visible and allowed easy
identification of the exposed lymphatics.
Isosulfan blue has worked extremely well for intraoperative SLN mapping. In some patients with thin skin, the afferent lymphatics can be seen
through the skin after the injection of isosulfan blue. In addition, when the
dye enters the SLN, it stains the node a pale blue, thus clearly distinguishing the SLN from the surrounding non-SLNs. The other dyes have largely
been abandoned as unsatisfactory because they diffuse too rapidly into
surrounding tissue and are not retained by the lymphatic channels in sufficient concentrations to stain the SLN. The fluorescent dyes fluorescein and
Cyalume are readily visualized, but a dark room is necessary for optimal
visualization; moreover, because of the diffusion of these dyes into surrounding tissue, the background fluorescence is unacceptably high.
Methylene blue is relatively poorly retained by the lymphatic vessels and
thus stains the SLN too lightly.
Use of vital blue dyes rarely causes complications but has been associated with severe allergic reactions in the literature.19 Blue dye can be
retained at the primary tumor site for more than 1 year. The color gradually fades with time; however, the patient can be left with a permanent
tattoo if the injected dye is not removed with the wide excision or the
lumpectomy. Fortunately, in the head and neck area, where a permanent tattoo would be unacceptable, the richness of the cutaneous lymphatics allows rapid clearance of the blue dye from the skin and subcutaneous tissues. A small amount of residual blue dye may be left
behind after wide excision, but this typically disappears rapidly and
poses no real problem. All patients report the presence of dye in the
urine and stool during the first 24 hours. In some cases, the dye can
interfere with transcutaneous oxygen monitoring during anesthesia.

3
ease.13 Accordingly, some medical oncologists simply observe T4

patients unless nodal disease is documented.
The extent of any operation done at the primary site before
SLN biopsy may affect the success of the biopsy procedure. In
patients who have had large areas of tissue undermining or have
undergone reconstruction with a rotational flap or Z-plasty, the
normal lymphatic channels may be disrupted, and such disruption
may render SLN biopsy inaccurate. Nevertheless, there have been
reports of SLN biopsy being performed successfully after previous
WLE, which suggests that many of these patients may be salvageable for accurate nodal staging if their primary tumors have been
widely excised.14 These patients may have more SLNs in more
regional nodal basins than patients in whom the primary tumor
has not been resected with curative intent, but at present, there is
no unequivocal evidence that previous WLE of the primary lesion
increases the risk of postoperative nodal relapse.15,16
OPERATIVE PLANNING
Positioning and Anesthesia

Patients should be prepared to undergo wide excision of the
primary melanoma site (where indicated) and SLN biopsy during the same operative session. Depending on the location of the
primary lesion, it may be possible to perform the two procedures
with the patient in a single position; however, it often happens
that the patient must be moved to a different position to afford
the surgeon adequate access to the different locations.The choice
of anesthesia varies, depending on the size and location of the
wide excision and the likely depth of the SLNs. In selected cases,
local anesthesia may be appropriate, but for many lesions, general or regional anesthesia is preferable.
OPERATIVE TECHNIQUE
Although the technical details of lymphatic mapping and SLN

biopsy for melanoma vary from institution to institution, the reported results of the different approaches have been very similar.
Proper performance of these procedures requires close collaboration between the surgeon, the nuclear radiologist, and the pathologist, with each member playing a critical role in the process.
Step 1: Injection of Radiolabeled Tracer and Lymphoscintigraphy
On the day of the procedure, patients report to the nuclear medicine suite for injection of the radiolabeled tracer and preoperative
lymphoscintigraphy. It is crucial to have a mechanism in place by
which the location of the primary melanoma site and the desired
dose of the tracer can be reliably communicated to the nuclear radiologist. Some melanoma biopsy sites are difficult to locate, particularly if multiple skin biopsies have already been performed.
A radiolabeled agent is then selected; the most common
choices are technetium-99m(99mTc)labeled sulfur colloid (TSC)
and 99mTc-labeled antimony trisulfide colloid (T-ATC) [see Sidebar Choice of Radiocolloid and Vital Blue Dye for Lymphatic
Mapping].The dose of the tracer and the volume of the injectate
are largely determined by the location and size of the primary
tumor site but generally can be kept to 0.5 mCi or less and 1 ml
or less, respectively. Injections are made intradermally around
the circumference of the lesion or biopsy site, and dynamic scans
are taken 5 to 10 minutes after injection. The location of the
SLN can be marked on the skin by the radiologist to assist the
surgeon; however, this location may vary slightly with changes in
patient position and should therefore be confirmed by the surgeon with the gamma probe in the operating room. All regional
basins at risk should be marked, along with any in-transit nodes

6
Nodes in
Series
SLN
Lt
Axilla
Int
node
Nodes in
Parallel
Inj
Lt
Flank
Lt side
Lt Lat Chest W/M
Figure 1 Lymphatic mapping and SLN biopsy for melanoma.

In-transit nodal areas are identified in 5% of melanoma patients;
this is the reason why preoperative lymphoscintigraphy is performed for primary sites on either the upper or the lower
extremity. In a patient with a melanoma on the left hand (a), the
injection site and the left hand are raised above the head, and
cutaneous lymphatic flow into an epitrochlear node can be seen.
This in-transit node then emits a lymphatic vessel flowing to the
left axilla. By definition, the SLN is the first node in the chain
that receives primary lymphatic flow. The epitrochlear node and
any axillary nodes are nodes in series. Hence, the epitrochlear
node is the SLN and thus is the only node that must be harvested.
In a patient with a primary melanoma on the left flank (b), there
are two separate afferent lymphatics, one leading to an SLN in
the left axilla and the other leading to an in-transit node on the
left flank. These are nodes in parallel in that they both receive
primary lymphatic flow from the skin site. Hence, the two nodes
are equally at risk for metastatic disease, and both are considered
SLNs and must be harvested.
that are identified [see Figure 1], to allow accurate nodal staging.
Lymphoscintigraphy is also useful in that it provides a good estimate of the number of SLNs the surgeon can expect to find at
operation.
The timing of tracer injection in relation to the surgical procedure is not critically important. Activity in the SLNs usually
reaches its maximum 2 to 6 hours after injection; waiting longer
to carry out the procedure may increase the labeling of secondary nodes.There have, however, been several reports of SLN
procedures being accurately performed 16 to 24 hours after tracer injection.17 Because of the short half-life of technetium (6
hours), delaying procedures for this amount of time may reduce
the radioactivity at the injection site and lower the background
interference, but because TSC is retained in the SLN dendritic
cells, the SLNs can still be easily identified.
Step 2: Intraoperative Lymphatic Mapping and Identification
of SLN
It is our practice to review the lymphoscintigram when the patient arrives in the OR, then evaluate him or her with the gamma
probe before deciding on positioning; access to nodal basins may
be difficult in certain positions. Probe evaluation begins by defining the diffusion zone around the primary tumor site, where SLN
identification is not possible.The area between this diffusion zone
and the possible nodal drainage sites is then mapped for possible
in-transit nodes by means of a systematic but expeditious evaluation for radioactive hot spots. The gamma probe is moved in a
linear fashion between the diffusion zone and the nodal basin. It is

3
then shifted medial or lateral to the previous line, and the process is
repeated until the entire area is evaluated. The location of a radioactive hot spot is confirmed by identifying a discrete location
where the radioactive counts are higher than the counts found in
the tissue 1 to 2 cm more proximal to the injection site (the background skin count). The counts from the hot spot and the background are recorded.The hot-spot site is marked on the skin to allow more direct dissection to the SLN.
Concomitant use of a vital blue dye [see Sidebar Choice of Radiocolloid and Vital Blue Dye for Lymphatic Mapping] is favored
by many surgeons.The blue dye is complementary to the radiolabeled tracer; the combination of the two marking agents improves
the chances of identifying the SLN and facilitates node retrieval.
The blue dye is injected into the dermis immediately adjacent to
the melanoma. For lesions on an extremity, the dye may be injected along the proximal margin of the lesion or biopsy site; for lesions on other areas, it should be injected circumferentially. The
general recommendation is to wait 5 to 10 minutes after injecting
the dye before initiating SLN retrieval.
To minimize the dissection required for node resection, the incision for the SLN biopsy should be made through the hot spot
identified by the gamma probe.The incision should also be situated so that it can be incorporated into a longer incision should the
finding of a positive SLN necessitate performance of a completion
lymph node dissection (CLND).The gamma probe is placed in a
sterile sheath and used again after the incision is made to guide further dissection. If blue dye was used, the surgeon can visually follow the blue lymphatic channels to the blue-stained SLN.
An SLN is defined as either (1) the most radioactive node in
the basin or (2) a node that either is stained blue or clearly has a
blue-stained lymphatic vessel entering it. When an SLN is
removed, the ex vivo radioactivity count in the node is recorded.
This count is then used as a reference for determining which, if
any, of the remaining nodes in that basin (some of which may be
potential SLNs) should be removed. In our view, if the radioactivity count in the hottest remaining node in the basin is less than
10% of the ex vivo count in the hottest SLN, none of the remaining nodes should be considered SLNs, and none should be
removed.18 Any nodes whose radioactivity counts exceed this
10% threshold, however, should be removed.
A final count of the SLN biopsy bed is then taken to document that all significantly radiolabeled SLNs have been accounted for and removed. In addition, the tissues are examined for
blue-stained lymphatic channels or lymph nodes regardless of
radioactivity; as noted, blue staining confers SLN status even if
the node is not radioactive. Finally, when it appears that all relevant SLNs have been removed, as confirmed by the final bed
count, the tissues are palpated for grossly suspicious nodes. Firm
tumor-involved nodes with obstructed afferent lymphatics may
divert lymph flow to non-SLNs, and such diversion is a significant cause of false negative SLN biopsy results.
Once an SLN is identified, it should be dissected out with as little trauma to the surrounding tissues as possible. Lymphatic channels to the node should be identified and either tied or clipped to
reduce the risk of postoperative seroma formation. Because the
gamma probe can localize SLNs with great accuracy, routine dissection of motor nerves is not required; however, knowledge of the
likely location of the motor nerves is critical for preventing inadvertent injury to these structures during dissection.
Step 3: Pathologic Evaluation of SLN
The optimal extent of pathologic evaluation of SLNs in patients
with melanoma has been the subject of some debate. SLN biopsy

6

allows pathologists to focus their efforts on one node or a small
number of nodes, and this focus has led to a process of ultrastaging.
Currently employed methods include serial sectioning, immunohistochemical (IHC) staining for melanoma-associated antigens
(e.g., S-100 and HMB-45), and reverse transcriptase polymerase
chain reaction (RT-PCR) for identification of messenger RNA
(mRNA) transcripts of the enzyme tyrosinase. It is clear that these
techniques can improve identification of node-positive patients,
but it is not yet clear what their prognostic value may be with
respect to determining patient outcome and guiding further therapy. Additional study in this area is required to resolve this issue.
COMPLICATIONS
Complications of SLN biopsy are quite uncommon. Allergic

reactions to the blue dyes occur in fewer than 1% of patients but
can range in severity from mild urticaria to anaphylaxis; thus, the
surgical team and the anesthesia team should always be prepared
for this uncommon but potentially serious problem.19 Motor
nerve injury is rare. In a series of 30 patients who had head and
neck melanomas with SLN drainage to the parotid region, there
were no injuries to the facial nerve when the SLN was removed
without nerve dissection.20 Similar results have been reported for
nodes in the posterior triangle of the neck and the spinal accessory nerve, as well as for axillary nodes and the long thoracic and
thoracodorsal nerves. The incidence of wound complications is
quite low (1.7% wound complication rate; 3.0% seroma rate), as
is the incidence of postbiopsy lymphedema (0.7%). In the Sunbelt
Melanoma Trial, the complication rate in 2,120 patients undergoing SLN biopsy was 4.6%, compared with 23.2% in 444
patients undergoing CLND.21
OUTCOME EVALUATION
Studies of SLN biopsy in melanoma patients have demonstrated consistently good technical success and high pathologic accuracy with a variety of different techniques. There have been three
studies in which SLN biopsy was done with confirmatory CLND
of all lymph node basins in which SLNs were identified.11,22,23
When the results of these studies are considered together, the
pathologic false negative rate for SLN biopsy in clinically nodenegative melanoma patients is about 6%. The pathologic accuracy rate (i.e., the rate at which the pathologic status of the SLN is
the same as that of the entire nodal basin) is 98%.
Several trials have prospectively followed patients treated with
SLN biopsy and subsequent observation if the SLN was negative.24-27
These trials reported similar rates of technical success (94%98%)
and of node positivity (12% to 16%).The rates of first relapse in the
regional nodes in these patients were similar as well (range, 3.8%8%;
mean, 4.4%), a finding that is consistent with the rates of false negative SLNs in the series in which CLND was performed. These
studies also found that the pathologic status of the SLNs was the most
important predictor of disease-free survival and overall survival, a
result that further underscores the accuracy of the procedure and
the importance of nodal staging in predicting melanoma outcomes.
The available data suggest that lymphatic mapping is applicable to all primary body sites, including the head and the neck
(the most technically demanding sites).17,28 The best results are
achieved with a combination mapping approach that employs
both a vital blue dye and a radiocolloid. The procedure is associated with slightly higher false negative rates in patients with head
and neck melanoma than in those with melanoma of the trunk or
extremities (10% versus 1% to 2%). Nevertheless, the false negative rates with head and neck melanoma are still low enough to
justify offering lymphatic mapping to patientsespecially given

3
that the only alternative method of obtaining the nodal staging information is CLND, a procedure that carries a much higher morbidity.
Lymphatic Mapping and SLN Biopsy in Breast Cancer
RATIONALE
Assessment of Nodal Status

In early breast cancer, as in melanoma, the pathologic status of
the regional lymph nodes is the most important predictor of outcome. The presence of regional lymph node metastases in breast
cancer reduces 5-year survival by 28% to 40%.29,30 Prognostic factors related to primary tumor characteristics have consistently
been shown to be inferior to nodal status as predictors of disease
outcome. In addition, regional lymph node dissection in the setting
of breast cancer is superior to observation and at least equivalent to
irradiation for regional disease control in clinically node-negative
patients.31 There is some evidence that adequate regional disease
control may confer a small survival benefit.32
Invasive breast cancer has a relatively high rate of nodal metastasis in clinically node-negative patients. The risk of metastasis is
clearly related to the size of the primary tumor, but it is significant
(15% or higher) even in patients with early (T1a) lesions.33,34 The
primary nodal drainage basin for the breast is the ipsilateral axilla;
however, drainage to extra-axillary sites (e.g., the internal mammary lymph node chain, the supraclavicular nodes, and the intramammary nodes) is also reported. Other potential sites of lymphatic
drainage notwithstanding, the recommended surgical procedure for
evaluating the regional lymph nodes in clinically node-negative
breast cancer patients has been level I and II axillary lymph node
dissection (ALND). Such dissections are, however, associated with
a significant risk of long-term morbidity, primarily related to the risk
of lymphedema in the affected arm. For this reason, SLN biopsy
was developed and investigated as a possible substitute for standard
ALND in the treatment of breast cancer.
PREOPERATIVE EVALUATION

6

phoscintigraphy may help the surgeon identify SLNs located in
extra-axillary sites (e.g., the internal mammary chain). Although
SLN biopsy may be performed with the patient under local
anesthesia, we favor general anesthesia for this procedure, particularly when it is done in conjunction with the breast excision.
OPERATIVE TECHNIQUE
Step 1: Injection of Radiolabeled Tracer and Lymphoscintigraphy

In the United States, the radiocolloid most commonly employed for SLN biopsy in breast cancer patients is TSC, which
may be used either unfiltered or filtered (< 220 nm) [see Sidebar
Choice of Radiocolloid and Vital Blue Dye for Lymphatic
Mapping]. The 99mTc dose generally ranges from 0.45 to 1.0
mCi, and the injectate volume ranges from 4 to 8 ml. TSC is
injected directly into the breast parenchyma in four to eight locations around the primary tumor site or the biopsy cavity.
Because there are fewer lymphatic vessels in the breast parenchyma than in the dermis, it takes longer for the tracer to be transported in sufficient quantity to the SLNs than it does in the setting of melanoma. A minimum of 30 minutes is generally necessary before lymphoscintigraphy is performed or the patient is
brought to the OR [see Figure 2].
When the lesion is palpable, injection is guided by the size,
shape, and location of the mass.When the lesion is not palpable,
injection is guided by ultrasonography or needle-wire localization. If an excisional biopsy was previously performed, the tracer should be injected into the breast parenchyma rather than into
the biopsy cavity; it will not diffuse out of the cavity. This is best
done under ultrasonographic guidance. In addition, injections
should not be made into the retromammary fat or the pectoral
fascia, because doing so would lead to wide diffusion of tracer
throughout the chest area, which would make nodal identification very difficult.
As in melanoma, the timing of SLN biopsy after tracer injection
is not of critical importance. Good results have been obtained with
injection-to-biopsy intervals ranging from 30 minutes to 24 hours.
The usual recommendation is to wait 1 to 2 hours.
Selection of Patients
All clinically node-negative patients with a diagnosis of invasive breast cancer are potential candidates for SLN biopsy. Ideal
candidates are those patients with unifocal lesions who have no
history of previous axillary surgery or prior cancer treatment.
Performing an SLN biopsy after a previous excisional biopsy is
technically feasible; however, SLN biopsy may be easier if the
lesion is still in place. Patients who have undergone extensive
breast procedures (e.g., breast reduction, placement of breast
implants, or multiple open biopsies) may have significant alterations in the lymphatic pathways, which may compromise the
accuracy of SLN biopsy. Patients with multifocal tumors or
inflammatory cancer also are generally poor candidates for SLN
biopsy, though there is some evidence suggesting that using periareolar injection sites may allow the procedure to be performed
accurately in patients with multifocal disease.35 The use of SLN
biopsy in patients who have received preoperative chemotherapy
has been reported in only a very modest number of cases.36-38
OPERATIVE PLANNING
Positioning and Anesthesia

Patients should be placed in the supine position, with all
potential nodal sites within the operative field. Preoperative lym-
SLN
Rt Axilla
Inj
Rt breast
Upright 40 min
Pt Ant
Arm Up
Marker View
Arm Outline
Figure 2 Lymphatic mapping and SLN biopsy for breast cancer.

Whereas flow of the radiocolloid to the SLN takes 5 to 10 minutes
for melanoma mapping, it takes 30 to 40 minutes for breast cancer mapping. In addition, the primary site is usually closer to the
regional basin in breast cancer than it is in melanoma, and shinethrough from the primary site may be a problem. Invariably, the
lumpectomy or mastectomy is performed first, followed by axillary SLN harvesting.

3
Comment Several alternative routes of tracer injection have

been investigated for SLN biopsy in breast cancer patients, primarily in response to the difficulties sometimes associated with
peritumoral injection (e.g., delayed tracer uptake and wide diffusion zones that can overlap the nodal basins). These routes
include intradermal or subdermal injection in the area overlying
the tumor, subareolar injection, and periareolar injection. The
rationale for the development of these alternatives is that there is
significant overlap between the lymphatic vessels of the breast
skin and those of the breast parenchyma. Multiple studies have
confirmed that the use of these injection routes yields high localization rates and results in accurate removal of SLNs that reflect
the pathologic nodal status of individual patients. A notable deficiency of these techniques, however, has been the low reported
rate of tracer migration to nodes outside the axilla, particularly
to the internal mammary lymph node chain. This result is
thought to be attributable to a unique set of lymphatic channels
deep in the breast parenchyma, separate from the overlying skin,
that drain to the internal mammary chain.
Another injection route that has been described is intratumoral
injection.This technique employs a very small volume of injectate,
thereby avoiding much of the injection-site diffusion issues associated with peritumoral injection. Intratumoral injection gives the radiolabeled tracer access to the deeper lymphatic vessels and identifies SLN drainage to the extra-axillary nodal sites significantly
more frequently than even peritumoral injection does.
The various tracer-injection methods have not been directly
compared; thus, at present, the optimal route of injection can
only be inferred by comparing studies from different institutions.
The potential importance of the extra-axillary sites is not entirely clear, but it appears that these sites may be the sole locations
of metastatic disease in as many as 20% of the node-positive
patients from whom they are removed.39,40 Most patients in
whom SLNs are found outside the axilla have additional SLNs
in the axillary basin.
Step 2: Intraoperative Lymphatic Mapping and Removal of SLN
Intraoperative mapping of SLNs is done in essentially the
same fashion for breast cancer as for melanoma. Our approach
begins by performing a primary survey of the potential nodal
sites with the handheld gamma detector. First, the radiotracer
injection-site diffusion zone is defined [see Figure 3]. The points
at which the probes audio output peaks are marked circumferentially on the skin surrounding the injection site. Within this
zone, the probe is unable to identify an SLN.
Next, as in a melanoma survey, the probe is placed close to the
skin and moved away from the diffusion zone in a linear manner.
As the probe moves further from the injection site, the radioactivity counts decrease. If there is an SLN beneath the area being evaluated, a discrete radioactive hot spot will be identified. The location of the hot spot is marked on the skin, and the remainder of the
primary survey is completed, focusing on detecting any additional
SLNs. All potential nodal sites (including the supraclavicular and
infraclavicular nodes, the internal mammary chain, intramammary
sites, and the upper abdomen) are carefully assessed, and finally,
the axilla is evaluated. By routinely assessing the other potential
sites before the axilla, the surgeon can ensure that they are not
overlooked and can confirm that each patient has been optimally
evaluated.
Once the hot spots have been identified and marked, the radioactivity counts over each hot spot are recorded, as well as a
background count from an area between the hot spot and the injection site, about 2 to 3 cm from the hot spot. If there is indeed a

6

The diffusion zone of radioactivity around the injection site is
circled on the breast. The hot spot in the axilla is marked (HS)
as well.
radioactive SLN below the marked hot spot, the background

count should be significantly lower than the hot-spot count.
Next, after the primary survey and counts have been recorded, 5 ml of vital blue dye is injected into the breast parenchyma
around the tumor or the biopsy cavity. The breast is gently massaged for 5 to 10 minutes to enhance transport of the dye to the
SLNs. A small incision is made at the hot-spot location marked
on the skin. The gamma probe is placed in a sterile sheath and
inserted into the wound, and the line of sight to the point of
maximal radioactivity, along which dissection proceeds to the
hot node or nodes, is identified. During the dissection, the surgeon looks for blue-stained lymphatic channels and nodes [see
Figure 4]. Most of the time, the radiocolloid and the vital blue
dye identify the same SLNs. The SLNs are then carefully
removed, and the lymphatic vessels entering them are tied off
whenever possible.
Once the SLNs have been excised, the ex vivo radioactivity
count for each one is recorded, as is the presence or absence of
blue dye in either the node itself or the lymphatic vessels entering
it.The ex vivo count of the excised node is then used as a guide for

A small incision is made in the axilla on the basis of the hot-spot
location. The SLNs identified are both radioactive and stained
blue.

3

In touch-imprint cytology, slides are touched to tissue from a
hot specimen, and cells on the section or the margin are exfoliated onto the slide for cytologic preparation. Shown are (a) permanent histology of an infiltrating ductal carcinoma extending
down to an inked margin and (b) a touch preparation demonstrating bizarre malignant cells from the sampling of the margin. The
advantages of this technique are that the entire margin can be
sampled and that tissue is not lost in the cryostat.
determining the completeness of radioactive SLN removal. As in

melanoma, if the remaining radioactivity in the nodal basin is more
than 10% of that in the hottest node removed, there may be SLNs
still in place that should be sought out and, if found, removed. If
the residual radioactivity in the nodal basin is less than 10% of that
in the hottest node, the remaining nodes should not be removed.
These guidelines apply equally to SLN biopsy in extra-axillary locations. The remaining nodes in the nodal basin should also be
evaluated for blue staining of the nodes themselves or of the lymphatic channels entering them; any nodes meeting these criteria
should be removed and labeled as SLNs.
Finally, before the SLN procedure is completed, the remaining nodes in the basin should be palpated. If a firm, hard tumorreplaced node is identified, it should be removed and categorized
as an SLN. As in melanoma, the presence of a tumor-replaced
node can increase the risk of a false negative SLN biopsy.

6

false negative rate can be reduced to about 5%,41,43 but at the cost
of 45 to 60 minutes of operating time and loss of tissues for permanent histopathologic evaluation. In comparison, touch-imprint cytology consumes much less time and tissue, is far more accurate
(false negative rate, 0.8%),44 and does not contaminate the cryostat. It has also been applied to the evaluation of lumpectomy margins [see Figure 5]. The chief limitation of the touch-imprint
method is that for optimal results, it requires a pathologist who is
highly skilled in the cytologic evaluation of lymph nodes. Some
centers use rapid immunohistochemical (IHC) analysis for cytokeratin staining to detect tumor cells in touch-imprint or frozensection specimens, anticipating that detection of such cells can
thereby be improved, particularly in patients with invasive lobular
or well-differentiated ductal carcinomas.
Techniques used to date for permanent pathologic evaluation
of SLNs in the setting of breast cancer include (1) serial sectioning of the nodes with routine hematoxylin-eosin (H&E)
staining, (2) cytokeratin IHC staining [see Figure 6], and (3)RTPCR detection of mRNA transcripts specific for epithelial cells.
Each of these techniques is more sensitive in detecting tumor
cells in the SLNs than routine H&E analysis of bivalved nodes.
There is, however, some controversy surrounding their use, centering on the clinical relevance of a positive result. Some of these
techniques (i.e., IHC and RT-PCR) are sensitive enough to identify
single tumor cells in SLNs, but it is not clear whether such individual cells are actually capable of forming metastases. In the
current staging system for breast cancer, metastases large
enough to be seen on H&E sections are the benchmark for nodal
staging. Metastases 2 mm in size or larger are known to have a
negative impact on survival45; however, it is not certain that the
same can be said of smaller metastatic lesions. In 1999, the
College of American Pathologists issued a consensus statement
recommending that the staging of SLNs be based on routine histologic evaluation of the nodes cut at approximately 2 mm intervals.46 Routine use of cytokeratin IHC staining should not be
adopted as standard until its significance is demonstrated in clinical trials.
COMPLICATIONS
The complications of SLN biopsy in breast cancer patients are

similar to those seen in melanoma patients. There is a minor
Step 3: Pathologic Evaluation of SLN

Pathologic SLN evaluation in breast cancer patients has two
main aspects. The first is intraoperative evaluation of the SLN
when the pathologic status of the node is being used to determine the need for axillary dissection; the second is permanent
evaluation of the nodes to determine whether micrometastatic
disease is present.
Two techniques are commonly employed for intraoperative
evaluation of SLNs: frozen-section analysis and touch-imprint
cytology. Frozen-section histopathology is available in most hospitals, and all surgical pathologists have some experience with it.
This technique has a drawback, however, in that it sometimes
uses up a large portion of the SLN, leaving a remnant that is
insufficient for permanent paraffin-embedded sections. In addition, the sectioning of radioactive nodes on a cryostat raises radiation-safety issues for the pathologists.
Studies of frozen-section techniques of evaluating SLNs for
metastatic breast cancer report false negative rates of 27% and
32%.41,42 When 60 frozen sections are made from each SLN, the

Cytokeratin immunohistochemical staining finds metastatic cells
in 9.4% of breast cancer patients whose SLNs are histologically
negative on routine examination.

3
Table 1SLN Identification by Nodal Basin at Different Injection Sites39,41,50-52,54-95

Injection Location
Nodal Basin
Periareolar/Subareolar
Intradermal/Subdermal
Peritumoral*
Intratumoral
Axilla
92.0% (range, 86%100%)
96.4% (range, 93%100%)
98.4% (range, 94.2%100%)
92.0% (range, 88%96%)
Internal mammary chain
4.9% (range, 0%25.3%)
0.6% (range, 0%4%)
0%
18.4% (range, 13%43%)
Other
0.6% (range, 0%8.4%)
0%
0%
4.3% (range, 0%33.1%)
*28 trials; 5,924 patients.
11 trials; 1,872 patients.
5 trials; 486 patients.
(< 1%) risk of allergic reactions to the blue dye. There is a small
risk of sensory or motor nerve injury or lymphedema whenever
an axillary node procedure is performed; this risk is substantially reduced, though not entirely eliminated, with SLN biopsy.47
With an internal mammary SLN biopsy, there is a risk of pneumothorax from unintended opening of the parietal pleura. This
risk is very small with careful technique, however, and the problem can almost always be corrected by closing the wound around
a rubber catheter inserted through a small stab incision and
removing it at the end of a positive pressure breath given by the
anesthesiologist. Surgical site infections occur in fewer than 1%
of cases, and small seromas occur in about 10%.
OUTCOME EVALUATION
The first report of SLN biopsy in breast cancer, published in

1993, described the use of the gamma-probe localization technique for SLN identification.48 A second report, published the following year, described the use of the vital blue dye technique for
this purpose.49 Since these initial reports, many single-center and
multicenter studies have been published that achieved remarkably
similar results using either or both of these techniques.
The early studies of SLN biopsy tended to use either a radiolabeled tracer or a vital blue dye alone. The first trial in which the
two agents were used together was published in 1996.50 This study
documented an improvement in SLN localization and a 0% false
negative rate, albeit in a small series of patients. Subsequent multicenter trials incorporating larger study groups yielded more reliable indications of the applicability of these techniques to the overall surgical community. In one such study, surgeons from 11
centers performed SLN biopsies and confirmatory axillary dissection in clinically node-negative patients with invasive breast cancer.51 The overall success rate for identifying and removing an SLN
was 93%, the pathologic accuracy rate for predicting the presence
of nodal metastases from the SLNs removed was 97%, and the
pathologic false negative rate was 11.4%. A subsequent multicenter trial, using a combination of blue-dye staining and the gammaprobe technique in most patients, reported an SLN retrieval rate of
88% and a pathologic false negative rate of 7.2%.52 A third trial,
using the gamma-probe technique, reported an SLN retrieval rate
of 87% and a pathologic false negative rate of 13%.53 A fourth, using both blue-dye staining and the gamma-probe technique, reported an SLN retrieval rate of 86% and a pathologic false negative rate of 4%.54
The numerous single-institution reports on SLN biopsy have
made use of a variety of techniques.The technical variable of greatest interest has been the route by which the radiolabeled tracer is
injected into the breast.The routes evaluated include peritumoral
injection (as in the early studies), superficial injection into the dermis of the skin overlying the tumor site, periareolar or subareolar
injection, and, most recently, intratumoral injection.
We have reviewed the literature on the use of different routes of
injection and the associated rates of SLN localization by nodal
basin, node positivity rates, and false negative rates.This review included those studies in which a radiolabeled tracer was used for
SLN identification (either by lymphoscintigraphy or by intraoperative gamma probe localization) and in which the location of the
SLN basins and the pathologic status of the SLNs could be ascertained [see Tables 1, 2, and 3]. Data on 8,951 patients were reviewed.39,41,50-52,54-95 The results of our review indicated that all of
the approaches have acceptable SLN retrieval rates but that the
rates are slightly higher with the more superficial ones (i.e., the dermal, subareolar, and periareolar techniques).There are, however,
significant differences in the locations of the SLN basins identified
with the different methods: with the superficial injection techniques, drainage is essentially confined to the axillary basin, whereas with the deeper injection techniques, as many as 22% of patients
Table 2SLN Pathologic Positive Rates by Nodal Basin at Different Injection Sites39,41,50-52,54-95
Injection Location
Nodal Basin
Periareolar/Subareolar
Intradermal/Subdermal
Peritumoral*
Intratumoral
Axilla
34.0% (range, 21%50%)
35.2% (range, 18.2%51.3%)
26.2% (range, 23.1%42.1%)
37.8% (range, 12.7%43.7%)
Internal mammary chain
21.2% (range, 0%29.2%)
0%
0%
13% (range, 4.2%25.9%)
Other
NA
0%
0%
3.4%

3
Table 3False Negative SLN Identification

Rates at Different Injection Sites39,41,50-52,54-95
Evaluable Patients (No.)
False Negative Rate
Peritumoral*
3,909
6.0%
Intradermal/subdermal
1,734
6.5%
Periareolar/subareolar
19
0%
Intratumoral
126
5.2%
Injection Location

patients.
5 trials; 669
are found to have nodal basins outside the axilla. Approximately

16% to 21% of the extra-axillary SLNs will be found to have
metastatic disease if removed. The clinical ramifications of these
findings are that some patients may be understaged if the extra-axillary sites are not evaluated, and such understaging may affect the
recommendations for systemic adjuvant therapy.What impact this
possibility might have on tumor recurrence rates and patient survival is unknown at present; to resolve the uncertainty would require a large prospective, randomized trial.
To date, the only prospective, randomized trial of SLN biopsy in
breast cancer is that of Veronesi and coworkers.96 In this trial, a total of 516 evaluable patients were randomly assigned to undergo
either SLN biopsy with confirmatory axillary dissection (257 patients) or SLN biopsy with axillary dissection done only if the
biopsy yielded positive results (259 patients). At a median followup point of 46 months, no significant survival differences were reported, and there were no regional nodal recurrences in either
arm. Admittedly, the study size was quite small. Other, larger trials
that will have greater statistical power to evaluate the safety of SLN
biopsy when completed are the National Surgical Adjuvant Breast
and Bowel Project (NSABP) B32 trial and the American College
of Surgeons Oncology Group (ACOSOG) Z0010 trial. Another
ongoing study is the ACOSOG Z0011 trial, the aim of which is to
evaluate the effectiveness of SLN biopsy as the sole surgical procedure in patients with pathologically positive SLNs.
Training and Credentialing
Credentialing criteria for new operative procedures have traditionally been under the jurisdiction of local hospital credentialing
committees. When new technology becomes available, adequate
training is essential, both to ensure that surgeons can perform the
new procedures competently and to address medicolegal liability
concerns. The American College of Surgeons (ACS) has a committee (the Committee on Emerging Surgical Technology and Education) that monitors this activity. With some new techniques
(e.g., laparoscopic cholecystectomy and image-guided breast biopsy), hospitals have required surgeons to attend formal training
courses and to have their first cases proctored by surgeons with experience in the new technique before they are allowed to perform
the procedure on their own.
National organizations continue to struggle with the problem of
educating and credentialing surgeons to perform new procedures.
This problem takes on increasing urgency as medicolegal issues

proliferate, as other specialists begin to move into areas once generally considered to be the domain of surgeons (e.g., radiologists
performing breast biopsies), and as new technical developments
promise to revolutionize surgical care. In an effort to address this
problem as it bears on lymphatic mapping, the ACS, in association
with the Moffitt Cancer Center, initiated a program designed to
investigate how best to train teams (comprising surgeons, nuclear
medicine physicians, radiologists, and pathologists) in the new
technology. This formal training course is a 2-day session composed of didactic lectures, live surgery (including extensive surgeon-audience interaction during the procedure), and a hands-on
laboratory.The program offers mentoring of initial cases as registrants go back to their institutions, maintains national registries on
the Internet so that different experiences can be compared, and, finally, facilitates the participation of other university and community physicians in national protocols. Further information may be
obtained from the Center for Minimally Invasive Surgical Techniques (888-456-2840; www.slnmapping.org). Participation in
programs such as this one provides a certain degree of protection
against medicolegal risk as new technology and procedures are introduced.
Another avenue of training that has been available to surgeons
is participation in clinical trials such as the NSABP B32 trial.
Previous experience with SLN biopsy is not a requirement for
participation in this trial, and all participating surgeons are
required to undergo a training process to gain experience with
the procedure and familiarity with the specifics of the protocol.
The techniques used in this trial represented a combination of
common methods designed to maximize the efficacy of the procedure. The training phase included distribution of a detailed
training manual, the opportunity to view a video of the procedure, and a site visit by a protocol-designated core trainer to
explain the specifics of the procedure.
Radiation Exposure Guidelines and Policies
The amount and type of radioactivity injected in the course of

lymphatic mapping and SLN biopsy are relatively limited.
Typically, from 0.4 to 1.2 mCi of 99mTc is injected. This agent is
a pure gamma emitter with a short half-life (6 hours); thus, the
risks of potentially harmful beta radiation are avoided. The total
radiation dose used is quite smallonly about 5% of that used
in common nuclear scanning techniques (e.g., bone scans). It
has been estimated that a maximum of 0.45 Gy could be
absorbed at the injection site. Of hospital workers, the surgeon is
exposed to the highest levels of radiation. A study from Walter
Reed Army Medical Center found that the hands of surgeons
performing lymphatic mapping and SLN biopsy were exposed
to an average of 9.4 + 3.6 mrem per operation.97 Therefore, on
the basis of skin dosage recommendations set by the Nuclear
Regulatory Commission, a surgeon would have to perform more
than 5,000 SLN procedures a year to incur more than the minimal level of risk.
The low risk notwithstanding, proper handling of radioactive
specimens is recommended. All such specimens should be handled as little as possible for at least 24 to 48 hours and should be
appropriately labeled. Each institution performing these procedures should develop guidelines for handling and processing
specimens in accordance with their own institutions radiation
safety policies.

3

6
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Lymphatic Mapping and Sentinel Lymph Node Biopsy 1