Acs0306 Lymphatic Mapping And Sentinel Lymph Node Biopsy

© 2004 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
3 BREAST, SKIN, AND SOFT TISSUE 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 priate treatment. The presence of lymph node metastases is the
malignancies treated by U.S. surgeons. In 2003, it was estimat- single most powerful predictor of recurrence and survival in
ed that there were 54,200 new cases of melanoma and 212,600 melanoma patients: 5-year survival is approximately 40% lower
new cases of breast cancer in the United States.1 The incidence in patients who have lymph node metastases than in those who
of melanoma has been rising rapidly in the past few decades, and do not. This finding suggests that many melanoma patients are
the incidence of breast cancer is also likely to keep rising as the likely to benefit from accurate nodal staging.
baby-boomer generation ages.
Over the past 20 years, significant strides have been made in Elective lymph node dissection Until the latter part of
the management of these two diseases from the standpoint of the 1990s, elective lymph node dissection (ELND) was the
both surgical and adjuvant treatment. For both patients with mainstay of the surgeon’s armamentarium for nodal staging of
melanoma and those with breast cancer, adjuvant therapies for melanoma patients. ELND removes clinically negative nodes, as
high-risk lesions have been shown to have a positive impact on opposed to therapeutic node dissections, which are done for
recurrence rates and overall survival. In melanoma, the admin- nodes with gross tumor involvement. Opinions are divided as to
istration of adjuvant interferon alfa-2b to patients with T4 (> 4.0 whether ELND actually extends survival or whether it is solely
mm deep) primary tumors or nodal metastases has led to lower a staging procedure.Two prospective, randomized trials failed to
recurrence rates and longer overall survival.2 In breast cancer, demonstrate better survival in melanoma patients treated with
there is a much more extensive body of experience with adjuvant ELND than in patients undergoing wide local excision (WLE)
chemotherapy and hormone therapy for optimization of survival alone as primary surgical therapy.5,6 Retrospective studies from
in high-risk patients.3,4 In both diseases, the presence or absence large databases, however, suggested that there may be subpopu-
of lymph node metastases is highly predictive of patient outcome lations of patients who do benefit from ELND. The Intergroup
and is the most important prognostic factor for disease recur- Melanoma Trial was the first randomized study to show
rence and cancer-related mortality. Surgical management of the enhanced survival in patient subgroups after surgical treatment
regional lymph nodes will continue to be an important compo- of clinically occult metastatic melanoma.7 The benefit was found
nent of therapy for patients with these malignancies. in patients with melanomas 1.1 to 2.0 mm thick and patients
Progress in the management of regional lymph nodes in mela- younger than 60 years.8
noma and in breast cancer has taken different routes to what is
likely to be the same destination—namely, the use of lymphatic Adjuvant therapy for high-risk melanoma Three
mapping and sentinel lymph node (SLN) biopsy in clinically national prospective, randomized trials sponsored by the
node-negative patients. The development of intraoperative lym- Eastern Cooperative Oncology Group (ECOG) investigated the
phatic mapping and selective lymphadenectomy has made it use of adjuvant interferon alfa-2b in patients with high-risk
possible to map lymphatic flow from a primary tumor to the ini- melanoma.The first trial, ECOG 1684,2 was the impetus for the
tial draining node or nodes (i.e., the SLN or SLNs) in the Food and Drug Administration’s approval of interferon alfa-2b,
regional nodal basin.The pathologic status of the SLN is known in that it was the first study to demonstrate that this agent was
to be concordant with the pathologic status of the nodal basin as an effective adjuvant therapy for patients with high-risk melano-
a whole. Integration of these techniques, along with increasing- ma. Patients eligible for ECOG 1684 had either thick primary
ly detailed and sophisticated pathologic examination of the melanomas (> 4.0 mm thick) or nodal metastases. ECOG 1684
SLN, into the surgical treatment of melanoma and breast can- and a subsequent trial, ECOG 1694,9 reported significant over-
cer offers the potential for more conservative operations, lower all survival benefits for patients receiving adjuvant interferon
morbidity, and more accurate disease staging. 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
Lymphatic Mapping and SLN Biopsy for Melanoma the three ECOG trials, one can make a strong argument that
when the risk of nodal metastases reaches a certain defined level,
RATIONALE
a nodal staging procedure should be performed. Because of the
morbidity associated with a negative ELND, lymphatic mapping
Assessment of Nodal Status and SLN biopsy has become the de facto procedure of choice
There are several established factors for predicting the risk of for nodal staging in melanoma patients.
metastatic disease in melanoma patients. These factors must be
taken into account to ensure that patients are appropriately Lymphatic mapping and selective lymphadenectomy
stratified into different risk groups and hence can receive appro- SLN biopsy in melanoma was first described in 1992 by Morton


and associates,11 who outlined a procedure of intraoperative lym- of nodal metastasis is with respect to the cost and morbidity of
phatic mapping and selective lymphadenectomy in which a vital the procedure.
blue dye was injected into the skin around the site of the primary Patients with intermediate-thickness melanomas (1.0 to 4.0 mm)
melanoma. These investigators showed that the SLN is the first are the ones likely to gain most from SLN biopsy: the risk of nodal
node in the lymphatic basin into which the primary melanoma metastases in the absence of systemic disease is believed to be high-
consistently drains (though not necessarily the closest to the pri- est in this group. In patients with melanomas between 0.76 and 1.0
mary lesion).They harvested the SLN separately from the remain- mm thick, the risk of nodal metastasis is less than 6%, but the pro-
der of the regional nodes, and they found that the pathologic status cedure can certainly be justified in this population on the basis of
of the SLN was highly accurate at predicting the pathologic status its low morbidity. In patients with thin melanomas (< 0.76 mm),
of the entire nodal basin, which was surgically removed in all of the several prognostic factors have been shown to identify higher risk,
patients studied.These findings suggested that melanoma patients including primary tumor depth of Clark level III or higher, ulcera-
could be accurately staged with procedures that were far less ex- tion, the presence of regression, male sex, and axial location.12 Pa-
tensive than complete nodal dissections. tients with thin melanomas and multiple risk factors may be at
high enough risk to warrant SLN biopsy.
PREOPERATIVE EVALUATION
In patients with thick melanomas (> 4.0 mm), the risk of
occult systemic metastases is as high as 70%, and that of occult
Selection of Patients nodal metastases ranges from 60% to 70%. The high risk of sys-
The risk of nodal metastases in melanoma patients depends temic disease was the main reason why ELND was not recom-
on a number of factors, including primary tumor thickness, pres- mended for such patients in the past. Now that these patients
ence of ulceration, primary tumor location, and patient sex. Any have access to effective adjuvant therapy, however, they should
patient with invasive melanoma (Clark level II or higher) is at be offered lymphatic mapping and SLN biopsy as a staging pro-
some risk for nodal metastasis; however, before recommending cedure. Among patients with thick melanomas, those with nega-
SLN biopsy, the surgeon should determine what the relative risk tive nodes survive longer than those with microscopic nodal dis-

Choice of Radiocolloid and Vital Blue Dye for Lymphatic Mapping

Choice of Radiocolloid Choice of Vital Blue Dye
Little work has been done to determine which radiocolloid is best suit- Several vital blue dyes have been investigated with an eye to their poten-
ed to either preoperative or intraoperative mapping. The ideal radiocol- tial applicability to cutaneous lymphatic mapping. Among these are meth-
loid for intraoperative SLN mapping would have small particles (< 100 ylene blue (American Regent, Shirley, NY); isosulfan blue, 1% in aqueous
nm) that are uniformly dispersed, would be highly stable, and would solution (Lymphazurin; United States Surgical Corp., Norwalk, CT); patent
have a short half-life that would not complicate the handling of the blue-V (Laboratoire Guerbet, France); Cyalume (American Cyanamid Co.,
excised specimen. Technetium-99m (99mTc)–labeled compounds, being Bound Brook, NJ); and fluorescein dye. All substances tested were known
gamma emitters, satisfy most of these requirements. In a direct com- to be nontoxic in vivo and were injected intradermally as provided by the
parison between filtered (0.1 µm filter) 99mTc-labeled sulfur colloid (TSC) supplier. In a feline study, patent blue-V and isosulfan blue were the most
and 99mTc-labeled antimony trisulfide colloid (T-ATC), which has a parti- accurate in identifying the regional lymphatic drainage pattern.101 These
cle size of 3 to 30 nm, filtered TSC was transported more quickly to the dyes entered the lymphatics rapidly, with minimal diffusion into the sur-
nodal basin and emitted less radiation to the liver, the spleen, and the rounding tissue. Their bright-blue color was readily visible and allowed easy
whole body.98 Unfiltered TSC contains relatively large particles (100 to identification of the exposed lymphatics.
1,000 nm), and some investigators have found it to migrate more slow- Isosulfan blue has worked extremely well for intraoperative SLN map-
ly from the injection site; however, other investigators have found it to be ping. In some patients with thin skin, the afferent lymphatics can be seen
slow to flow through the first SLN to higher secondary nodes, which is through the skin after the injection of isosulfan blue. In addition, when the
actually an advantage. dye enters the SLN, it stains the node a pale blue, thus clearly distinguish-
A comparison between Tc-labeled human serum albumin (T-HSA), Tc- ing the SLN from the surrounding non-SLNs. The other dyes have largely
labeled stannous phytate, and T-ATC with respect to lymphoscintigram been abandoned as unsatisfactory because they diffuse too rapidly into
quality showed that T-ATC provided the best images for preoperative lym- surrounding tissue and are not retained by the lymphatic channels in suffi-
phoscintigraphy.99 In an animal study comparing T-HSA with TSC, TSC cient concentrations to stain the SLN. The fluorescent dyes fluorescein and
was actually concentrated in the SLN over a period of 1 to 2 hours, where- Cyalume are readily visualized, but a dark room is necessary for optimal
as T-HSA passed rapidly through the SLN.100 As a result, TSC yielded visualization; moreover, because of the diffusion of these dyes into sur-
higher activity ratios at intraoperative mapping, improved the success rate rounding tissue, the background fluorescence is unacceptably high.
of localization, made the technique easier, and thus was a superior reagent Methylene blue is relatively poorly retained by the lymphatic vessels and
for this application. thus stains the SLN too lightly.
The Sydney Melanoma Unit (SMU) prefers the use of T-ATC because this Use of vital blue dyes rarely causes complications but has been asso-
agent seems to have smaller, more uniform particles that rapidly migrate ciated with severe allergic reactions in the literature.19 Blue dye can be
into the lymphatic channels but still are appropriately trapped and retained retained at the primary tumor site for more than 1 year. The color grad-
by the SLN. At SMU, use of T-ATC allows injection of the radiocolloid and ually fades with time; however, the patient can be left with a permanent
imaging to be performed on the day before operation. SMU investigators tattoo if the injected dye is not removed with the wide excision or the
find that hot spots in the regional basin are maintained even when 24 hours lumpectomy. Fortunately, in the head and neck area, where a perma-
have elapsed from the time of injection. The radioactivity in the basin over nent tattoo would be unacceptable, the richness of the cutaneous lym-
the hot spot (i.e., the SLN) is decreased because four half-lives of tech- phatics allows rapid clearance of the blue dye from the skin and sub-
netium have been expended and because some of the radiocolloid has cutaneous tissues. A small amount of residual blue dye may be left
passed through, but the ex vivo activity ratio is not substantially affected. behind after wide excision, but this typically disappears rapidly and
In the United States, T-ATC has been removed from the market and is poses no real problem. All patients report the presence of dye in the
unavailable for clinical use. Currently, TSC (filtered or unfiltered) is the agent urine and stool during the first 24 hours. In some cases, the dye can
favored by most surgeons in the United States. interfere with transcutaneous oxygen monitoring during anesthesia.


ease.13 Accordingly, some medical oncologists simply observe T4 a b
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
Nodes in
patients who have had large areas of tissue undermining or have Series
undergone reconstruction with a rotational flap or Z-plasty, the SLN
normal lymphatic channels may be disrupted, and such disruption Lt
may render SLN biopsy inaccurate. Nevertheless, there have been Axilla
reports of SLN biopsy being performed successfully after previous Inj
Lt
WLE, which suggests that many of these patients may be salvage- Int Flank
able for accurate nodal staging if their primary tumors have been node
widely excised.14 These patients may have more SLNs in more
regional nodal basins than patients in whom the primary tumor Nodes in
has not been resected with curative intent, but at present, there is Parallel Lt side
no unequivocal evidence that previous WLE of the primary lesion Lt Lat Chest W/M
increases the risk of postoperative nodal relapse.15,16
Figure 1 Lymphatic mapping and SLN biopsy for melanoma.
OPERATIVE PLANNING In-transit nodal areas are identified in 5% of melanoma patients;
this is the reason why preoperative lymphoscintigraphy is per-
formed for primary sites on either the upper or the lower
Positioning and Anesthesia
extremity. In a patient with a melanoma on the left hand (a), the
Patients should be prepared to undergo wide excision of the injection site and the left hand are raised above the head, and
primary melanoma site (where indicated) and SLN biopsy dur- cutaneous lymphatic flow into an epitrochlear node can be seen.
ing the same operative session. Depending on the location of the This in-transit node then emits a lymphatic vessel flowing to the
primary lesion, it may be possible to perform the two procedures left axilla. By definition, the SLN is the first node in the chain
with the patient in a single position; however, it often happens that receives primary lymphatic flow. The epitrochlear node and
any axillary nodes are nodes in series. Hence, the epitrochlear
that the patient must be moved to a different position to afford
node is the SLN and thus is the only node that must be harvested.
the surgeon adequate access to the different locations.The choice In a patient with a primary melanoma on the left flank (b), there
of anesthesia varies, depending on the size and location of the are two separate afferent lymphatics, one leading to an SLN in
wide excision and the likely depth of the SLNs. In selected cases, the left axilla and the other leading to an in-transit node on the
local anesthesia may be appropriate, but for many lesions, gen- left flank. These are nodes in parallel in that they both receive
eral or regional anesthesia is preferable. primary lymphatic flow from the skin site. Hence, the two nodes
are equally at risk for metastatic disease, and both are considered
OPERATIVE TECHNIQUE SLNs and must be harvested.
Although the technical details of lymphatic mapping and SLN
biopsy for melanoma vary from institution to institution, the re-
ported results of the different approaches have been very similar. that are identified [see Figure 1], to allow accurate nodal staging.
Proper performance of these procedures requires close collabora- Lymphoscintigraphy is also useful in that it provides a good esti-
tion between the surgeon, the nuclear radiologist, and the patholo- mate of the number of SLNs the surgeon can expect to find at
gist, with each member playing a critical role in the process. operation.
The timing of tracer injection in relation to the surgical pro-
Step 1: Injection of Radiolabeled Tracer and Lymphoscintigraphy cedure is not critically important. Activity in the SLNs usually
On the day of the procedure, patients report to the nuclear medi- reaches its maximum 2 to 6 hours after injection; waiting longer
cine suite for injection of the radiolabeled tracer and preoperative to carry out the procedure may increase the labeling of sec-
lymphoscintigraphy. It is crucial to have a mechanism in place by ondary nodes.There have, however, been several reports of SLN
which the location of the primary melanoma site and the desired procedures being accurately performed 16 to 24 hours after trac-
dose of the tracer can be reliably communicated to the nuclear radi- er injection.17 Because of the short half-life of technetium (6
ologist. Some melanoma biopsy sites are difficult to locate, particu- hours), delaying procedures for this amount of time may reduce
larly if multiple skin biopsies have already been performed. the radioactivity at the injection site and lower the background
A radiolabeled agent is then selected; the most common interference, but because TSC is retained in the SLN dendritic
choices are technetium-99m(99mTc)–labeled sulfur colloid (TSC) cells, the SLNs can still be easily identified.
and 99mTc-labeled antimony trisulfide colloid (T -ATC) [see Side-
bar Choice of Radiocolloid and Vital Blue Dye for Lymphatic Step 2: Intraoperative Lymphatic Mapping and Identification
Mapping].The dose of the tracer and the volume of the injectate of SLN
are largely determined by the location and size of the primary It is our practice to review the lymphoscintigram when the pa-
tumor site but generally can be kept to 0.5 mCi or less and 1 ml tient arrives in the OR, then evaluate him or her with the gamma
or less, respectively. Injections are made intradermally around probe before deciding on positioning; access to nodal basins may
the circumference of the lesion or biopsy site, and dynamic scans be difficult in certain positions. Probe evaluation begins by defin-
are taken 5 to 10 minutes after injection. The location of the ing the diffusion zone around the primary tumor site, where SLN
SLN can be marked on the skin by the radiologist to assist the identification is not possible.The area between this diffusion zone
surgeon; however, this location may vary slightly with changes in and the possible nodal drainage sites is then mapped for possible
patient position and should therefore be confirmed by the sur- in-transit nodes by means of a systematic but expeditious evalua-
geon with the gamma probe in the operating room. All regional tion for radioactive “hot spots.” The gamma probe is moved in a
basins at risk should be marked, along with any in-transit nodes linear fashion between the diffusion zone and the nodal basin. It is


then shifted medial or lateral to the previous line, and the process is allows pathologists to focus their efforts on one node or a small
repeated until the entire area is evaluated. The location of a ra- number of nodes, and this focus has led to a process of ultrastaging.
dioactive hot spot is confirmed by identifying a discrete location Currently employed methods include serial sectioning, immuno-
where the radioactive counts are higher than the counts found in histochemical (IHC) staining for melanoma-associated antigens
the tissue 1 to 2 cm more proximal to the injection site (the back- (e.g., S-100 and HMB-45), and reverse transcriptase polymerase
ground skin count). The counts from the hot spot and the back- chain reaction (RT-PCR) for identification of messenger RNA
ground are recorded.The hot-spot site is marked on the skin to al- (mRNA) transcripts of the enzyme tyrosinase. It is clear that these
low more direct dissection to the SLN. techniques can improve identification of node-positive patients,
Concomitant use of a vital blue dye [see Sidebar Choice of Ra- but it is not yet clear what their prognostic value may be with
diocolloid and Vital Blue Dye for Lymphatic Mapping] is favored respect to determining patient outcome and guiding further ther-
by many surgeons.The blue dye is complementary to the radiola- apy. Additional study in this area is required to resolve this issue.
beled tracer; the combination of the two marking agents improves
COMPLICATIONS
the chances of identifying the SLN and facilitates node retrieval.
The blue dye is injected into the dermis immediately adjacent to Complications of SLN biopsy are quite uncommon. Allergic
the melanoma. For lesions on an extremity, the dye may be inject- reactions to the blue dyes occur in fewer than 1% of patients but
ed along the proximal margin of the lesion or biopsy site; for le- can range in severity from mild urticaria to anaphylaxis; thus, the
sions on other areas, it should be injected circumferentially. The surgical team and the anesthesia team should always be prepared
general recommendation is to wait 5 to 10 minutes after injecting for this uncommon but potentially serious problem.19 Motor
the dye before initiating SLN retrieval. nerve injury is rare. In a series of 30 patients who had head and
To minimize the dissection required for node resection, the inci- neck melanomas with SLN drainage to the parotid region, there
sion for the SLN biopsy should be made through the hot spot were no injuries to the facial nerve when the SLN was removed
identified by the gamma probe.The incision should also be situat- without nerve dissection.20 Similar results have been reported for
ed so that it can be incorporated into a longer incision should the nodes in the posterior triangle of the neck and the spinal acces-
finding of a positive SLN necessitate performance of a completion sory nerve, as well as for axillary nodes and the long thoracic and
lymph node dissection (CLND).The gamma probe is placed in a thoracodorsal nerves. The incidence of wound complications is
sterile sheath and used again after the incision is made to guide fur- quite low (1.7% wound complication rate; 3.0% seroma rate), as
ther dissection. If blue dye was used, the surgeon can visually fol- is the incidence of postbiopsy lymphedema (0.7%). In the Sunbelt
low the blue lymphatic channels to the blue-stained SLN. Melanoma Trial, the complication rate in 2,120 patients under-
An SLN is defined as either (1) the most radioactive node in going SLN biopsy was 4.6%, compared with 23.2% in 444
the basin or (2) a node that either is stained blue or clearly has a patients undergoing CLND.21
blue-stained lymphatic vessel entering it. When an SLN is
OUTCOME EVALUATION
removed, the ex vivo radioactivity count in the node is recorded.
This count is then used as a reference for determining which, if Studies of SLN biopsy in melanoma patients have demonstrat-
any, of the remaining nodes in that basin (some of which may be ed consistently good technical success and high pathologic accu-
potential SLNs) should be removed. In our view, if the radioac- racy with a variety of different techniques. There have been three
tivity count in the hottest remaining node in the basin is less than studies in which SLN biopsy was done with confirmatory CLND
10% of the ex vivo count in the hottest SLN, none of the remain- of all lymph node basins in which SLNs were identified.11,22,23
ing nodes should be considered SLNs, and none should be When the results of these studies are considered together, the
removed.18 Any nodes whose radioactivity counts exceed this pathologic false negative rate for SLN biopsy in clinically node-
10% threshold, however, should be removed. negative melanoma patients is about 6%. The pathologic accura-
A final count of the SLN biopsy bed is then taken to docu- cy rate (i.e., the rate at which the pathologic status of the SLN is
ment that all significantly radiolabeled SLNs have been account- the same as that of the entire nodal basin) is 98%.
ed for and removed. In addition, the tissues are examined for Several trials have prospectively followed patients treated with
blue-stained lymphatic channels or lymph nodes regardless of SLN biopsy and subsequent observation if the SLN was negative.24-27
radioactivity; as noted, blue staining confers SLN status even if These trials reported similar rates of technical success (94%–98%)
the node is not radioactive. Finally, when it appears that all rel- and of node positivity (12% to 16%).The rates of first relapse in the
evant SLNs have been removed, as confirmed by the final bed regional nodes in these patients were similar as well (range, 3.8%–8%;
count, the tissues are palpated for grossly suspicious nodes. Firm mean, 4.4%), a finding that is consistent with the rates of false neg-
tumor-involved nodes with obstructed afferent lymphatics may ative SLNs in the series in which CLND was performed. These
divert lymph flow to non-SLNs, and such diversion is a signifi- studies also found that the pathologic status of the SLNs was the most
cant cause of false negative SLN biopsy results. important predictor of disease-free survival and overall survival, a
Once an SLN is identified, it should be dissected out with as lit- result that further underscores the accuracy of the procedure and
tle trauma to the surrounding tissues as possible. Lymphatic chan- the importance of nodal staging in predicting melanoma outcomes.
nels to the node should be identified and either tied or clipped to The available data suggest that lymphatic mapping is appli-
reduce the risk of postoperative seroma formation. Because the cable to all primary body sites, including the head and the neck
gamma probe can localize SLNs with great accuracy, routine dis- (the most technically demanding sites).17,28 The best results are
section of motor nerves is not required; however, knowledge of the achieved with a combination mapping approach that employs
likely location of the motor nerves is critical for preventing inadver- both a vital blue dye and a radiocolloid. The procedure is associ-
tent injury to these structures during dissection. ated with slightly higher false negative rates in patients with head
and neck melanoma than in those with melanoma of the trunk or
Step 3: Pathologic Evaluation of SLN extremities (10% versus 1% to 2%). Nevertheless, the false nega-
The optimal extent of pathologic evaluation of SLNs in patients tive rates with head and neck melanoma are still low enough to
with melanoma has been the subject of some debate. SLN biopsy justify offering lymphatic mapping to patients—especially given


that the only alternative method of obtaining the nodal staging infor- phoscintigraphy may help the surgeon identify SLNs located in
mation is CLND, a procedure that carries a much higher morbidity. 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, par-
Lymphatic Mapping and SLN Biopsy in Breast Cancer ticularly when it is done in conjunction with the breast excision.
RATIONALE OPERATIVE TECHNIQUE

Assessment of Nodal Status Step 1: Injection of Radiolabeled Tracer and Lymphoscintigraphy
In early breast cancer, as in melanoma, the pathologic status of In the United States, the radiocolloid most commonly em-
the regional lymph nodes is the most important predictor of out- ployed for SLN biopsy in breast cancer patients is TSC, which
come. The presence of regional lymph node metastases in breast may be used either unfiltered or filtered (< 220 nm) [see Sidebar
cancer reduces 5-year survival by 28% to 40%.29,30 Prognostic fac- Choice of Radiocolloid and Vital Blue Dye for Lymphatic
tors related to primary tumor characteristics have consistently Mapping]. The 99mTc dose generally ranges from 0.45 to 1.0
been shown to be inferior to nodal status as predictors of disease mCi, and the injectate volume ranges from 4 to 8 ml. TSC is
outcome. In addition, regional lymph node dissection in the setting injected directly into the breast parenchyma in four to eight loca-
of breast cancer is superior to observation and at least equivalent to tions around the primary tumor site or the biopsy cavity.
irradiation for regional disease control in clinically node-negative Because there are fewer lymphatic vessels in the breast parenchy-
patients.31 There is some evidence that adequate regional disease ma than in the dermis, it takes longer for the tracer to be trans-
control may confer a small survival benefit.32 ported in sufficient quantity to the SLNs than it does in the set-
Invasive breast cancer has a relatively high rate of nodal metasta- ting of melanoma. A minimum of 30 minutes is generally neces-
sis in clinically node-negative patients. The risk of metastasis is sary before lymphoscintigraphy is performed or the patient is
clearly related to the size of the primary tumor, but it is significant brought to the OR [see Figure 2].
(15% or higher) even in patients with early (T1a) lesions.33,34 The When the lesion is palpable, injection is guided by the size,
primary nodal drainage basin for the breast is the ipsilateral axilla; shape, and location of the mass.When the lesion is not palpable,
however, drainage to extra-axillary sites (e.g., the internal mamma- injection is guided by ultrasonography or needle-wire localiza-
ry lymph node chain, the supraclavicular nodes, and the intramam- tion. If an excisional biopsy was previously performed, the trac-
mary nodes) is also reported. Other potential sites of lymphatic er should be injected into the breast parenchyma rather than into
drainage notwithstanding, the recommended surgical procedure for the biopsy cavity; it will not diffuse out of the cavity. This is best
evaluating the regional lymph nodes in clinically node-negative done under ultrasonographic guidance. In addition, injections
breast cancer patients has been level I and II axillary lymph node should not be made into the retromammary fat or the pectoral
dissection (ALND). Such dissections are, however, associated with fascia, because doing so would lead to wide diffusion of tracer
a significant risk of long-term morbidity, primarily related to the risk throughout the chest area, which would make nodal identifica-
of lymphedema in the affected arm. For this reason, SLN biopsy tion very difficult.
was developed and investigated as a possible substitute for standard As in melanoma, the timing of SLN biopsy after tracer injection
ALND in the treatment of breast cancer. is not of critical importance. Good results have been obtained with
injection-to-biopsy intervals ranging from 30 minutes to 24 hours.
PREOPERATIVE EVALUATION
The usual recommendation is to wait 1 to 2 hours.
Selection of Patients
All clinically node-negative patients with a diagnosis of inva-
sive 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. SLN
Rt Axilla
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 Inj
breast procedures (e.g., breast reduction, placement of breast Rt breast
implants, or multiple open biopsies) may have significant alter-
ations 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 Upright 40 min Marker View
biopsy, though there is some evidence suggesting that using peri- Pt Ant Arm Outline
areolar injection sites may allow the procedure to be performed Arm Up
accurately in patients with multifocal disease.35 The use of SLN
biopsy in patients who have received preoperative chemotherapy
Figure 2 Lymphatic mapping and SLN biopsy for breast cancer.
has been reported in only a very modest number of cases.36-38
Whereas flow of the radiocolloid to the SLN takes 5 to 10 minutes
OPERATIVE PLANNING for melanoma mapping, it takes 30 to 40 minutes for breast can-
cer mapping. In addition, the primary site is usually closer to the
regional basin in breast cancer than it is in melanoma, and shine-
Positioning and Anesthesia
through from the primary site may be a problem. Invariably, the
Patients should be placed in the supine position, with all lumpectomy or mastectomy is performed first, followed by axil-
potential nodal sites within the operative field. Preoperative lym- lary SLN harvesting.


Comment Several alternative routes of tracer injection have
been investigated for SLN biopsy in breast cancer patients, pri-
marily in response to the difficulties sometimes associated with
peritumoral injection (e.g., delayed tracer uptake and wide dif-
fusion 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 local-
ization rates and results in accurate removal of SLNs that reflect
the pathologic nodal status of individual patients. A notable defi-
ciency 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 Figure 3 Lymphatic mapping and SLN biopsy for breast cancer.
deep in the breast parenchyma, separate from the overlying skin, The diffusion zone of radioactivity around the injection site is
that drain to the internal mammary chain. circled on the breast. The hot spot in the axilla is marked (HS)
as well.
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 associ- radioactive SLN below the marked hot spot, the background
ated with peritumoral injection. Intratumoral injection gives the ra- count should be significantly lower than the hot-spot count.
diolabeled tracer access to the deeper lymphatic vessels and identi- Next, after the primary survey and counts have been record-
fies SLN drainage to the extra-axillary nodal sites significantly ed, 5 ml of vital blue dye is injected into the breast parenchyma
more frequently than even peritumoral injection does. around the tumor or the biopsy cavity. The breast is gently mas-
The various tracer-injection methods have not been directly saged for 5 to 10 minutes to enhance transport of the dye to the
compared; thus, at present, the optimal route of injection can SLNs. A small incision is made at the hot-spot location marked
only be inferred by comparing studies from different institutions. on the skin. The gamma probe is placed in a sterile sheath and
The potential importance of the extra-axillary sites is not entire- inserted into the wound, and the “line of sight” to the point of
ly clear, but it appears that these sites may be the sole locations maximal radioactivity, along which dissection proceeds to the
of metastatic disease in as many as 20% of the node-positive hot node or nodes, is identified. During the dissection, the sur-
patients from whom they are removed.39,40 Most patients in geon looks for blue-stained lymphatic channels and nodes [see
whom SLNs are found outside the axilla have additional SLNs Figure 4]. Most of the time, the radiocolloid and the vital blue
in the axillary basin. dye identify the same SLNs. The SLNs are then carefully
Step 2: Intraoperative Lymphatic Mapping and Removal of SLN removed, and the lymphatic vessels entering them are tied off
whenever possible.
Intraoperative mapping of SLNs is done in essentially the Once the SLNs have been excised, the ex vivo radioactivity
same fashion for breast cancer as for melanoma. Our approach count for each one is recorded, as is the presence or absence of
begins by performing a primary survey of the potential nodal blue dye in either the node itself or the lymphatic vessels entering
sites with the handheld gamma detector. First, the radiotracer it.The ex vivo count of the excised node is then used as a guide for
injection-site diffusion zone is defined [see Figure 3]. The points
at which the probe’s audio output peaks are marked circumfer-
entially 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 radioactivi-
ty counts decrease. If there is an SLN beneath the area being eval-
uated, a discrete radioactive hot spot will be identified. The loca-
tion 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 ra- Figure 4 Lymphatic mapping and SLN biopsy for breast cancer.
dioactivity counts over each hot spot are recorded, as well as a A small incision is made in the axilla on the basis of the hot-spot
background count from an area between the hot spot and the in- location. The SLNs identified are both radioactive and stained
jection site, about 2 to 3 cm from the hot spot. If there is indeed a blue.


a b 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 perma-
nent histopathologic evaluation. In comparison, touch-imprint cy-
tology consumes much less time and tissue, is far more accurate
(false negative rate, 0.8%),44 and does not contaminate the cryo-
stat. It has also been applied to the evaluation of lumpectomy mar-
gins [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 cyto-
keratin staining to detect tumor cells in touch-imprint or frozen-
section 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 sec-
tioning of the nodes with routine hematoxylin-eosin (H&E)
Figure 5 Lymphatic mapping and SLN biopsy for breast cancer. staining, (2) cytokeratin IHC staining [see Figure 6], and (3)RT-
In touch-imprint cytology, slides are touched to tissue from a PCR detection of mRNA transcripts specific for epithelial cells.
“hot” specimen, and cells on the section or the margin are exfoli-
Each of these techniques is more sensitive in detecting tumor
ated onto the slide for cytologic preparation. Shown are (a) per-
cells in the SLNs than routine H&E analysis of bivalved nodes.
manent histology of an infiltrating ductal carcinoma extending
down to an inked margin and (b) a touch preparation demonstrat- There is, however, some controversy surrounding their use, cen-
ing bizarre malignant cells from the sampling of the margin. The tering on the clinical relevance of a positive result. Some of these
advantages of this technique are that the entire margin can be techniques (i.e., IHC and RT -PCR) are sensitive enough to identify
sampled and that tissue is not lost in the cryostat. single tumor cells in SLNs, but it is not clear whether such indi-
vidual cells are actually capable of forming metastases. In the
current staging system for breast cancer, metastases large
determining the completeness of radioactive SLN removal. As in enough to be seen on H&E sections are the benchmark for nodal
melanoma, if the remaining radioactivity in the nodal basin is more staging. Metastases 2 mm in size or larger are known to have a
than 10% of that in the hottest node removed, there may be SLNs negative impact on survival45; however, it is not certain that the
still in place that should be sought out and, if found, removed. If same can be said of smaller metastatic lesions. In 1999, the
the residual radioactivity in the nodal basin is less than 10% of that College of American Pathologists issued a consensus statement
in the hottest node, the remaining nodes should not be removed. recommending that the staging of SLNs be based on routine his-
These guidelines apply equally to SLN biopsy in extra-axillary lo- tologic evaluation of the nodes cut at approximately 2 mm inter-
cations. The remaining nodes in the nodal basin should also be vals.46 Routine use of cytokeratin IHC staining should not be
evaluated for blue staining of the nodes themselves or of the lym- adopted as standard until its significance is demonstrated in clin-
phatic channels entering them; any nodes meeting these criteria ical trials.
should be removed and labeled as SLNs.
COMPLICATIONS
Finally, before the SLN procedure is completed, the remain-
ing nodes in the basin should be palpated. If a firm, hard tumor- The complications of SLN biopsy in breast cancer patients are
replaced node is identified, it should be removed and categorized similar to those seen in melanoma patients. There is a minor
as an SLN. As in melanoma, the presence of a tumor-replaced
node can increase the risk of a false negative SLN biopsy.
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 deter-
mine 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 hos-
pitals, 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 addi-
tion, the sectioning of radioactive nodes on a cryostat raises radi-
ation-safety issues for the pathologists. Figure 6 Lymphatic mapping and SLN biopsy for breast cancer.
Studies of frozen-section techniques of evaluating SLNs for Cytokeratin immunohistochemical staining finds metastatic cells
metastatic breast cancer report false negative rates of 27% and in 9.4% of breast cancer patients whose SLNs are histologically
32%.41,42 When 60 frozen sections are made from each SLN, the negative on routine examination.


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

Injection Location
Nodal Basin
Peritumoral* Intradermal/Subdermal† Periareolar/Subareolar‡ 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. 5 trials; 669 patients.

(< 1%) risk of allergic reactions to the blue dye. There is a small of nodal metastases from the SLNs removed was 97%, and the
risk of sensory or motor nerve injury or lymphedema whenever pathologic false negative rate was 11.4%. A subsequent multicen-
an axillary node procedure is performed; this risk is substantial- ter trial, using a combination of blue-dye staining and the gamma-
ly reduced, though not entirely eliminated, with SLN biopsy.47 probe technique in most patients, reported an SLN retrieval rate of
With an internal mammary SLN biopsy, there is a risk of pneu- 88% and a pathologic false negative rate of 7.2%.52 A third trial,
mothorax from unintended opening of the parietal pleura. This using the gamma-probe technique, reported an SLN retrieval rate
risk is very small with careful technique, however, and the prob- of 87% and a pathologic false negative rate of 13%.53 A fourth, us-
lem can almost always be corrected by closing the wound around ing both blue-dye staining and the gamma-probe technique, re-
a rubber catheter inserted through a small stab incision and ported an SLN retrieval rate of 86% and a pathologic false nega-
removing it at the end of a positive pressure breath given by the tive rate of 4%.54
anesthesiologist. Surgical site infections occur in fewer than 1% The numerous single-institution reports on SLN biopsy have
of cases, and small seromas occur in about 10%. made use of a variety of techniques.The technical variable of great-
est interest has been the route by which the radiolabeled tracer is
OUTCOME EVALUATION
injected into the breast.The routes evaluated include peritumoral
The first report of SLN biopsy in breast cancer, published in injection (as in the early studies), superficial injection into the der-
1993, described the use of the gamma-probe localization tech- mis of the skin overlying the tumor site, periareolar or subareolar
nique for SLN identification.48 A second report, published the fol- injection, and, most recently, intratumoral injection.
lowing year, described the use of the vital blue dye technique for We have reviewed the literature on the use of different routes of
this purpose.49 Since these initial reports, many single-center and injection and the associated rates of SLN localization by nodal
multicenter studies have been published that achieved remarkably basin, node positivity rates, and false negative rates.This review in-
similar results using either or both of these techniques. cluded those studies in which a radiolabeled tracer was used for
The early studies of SLN biopsy tended to use either a radiola- SLN identification (either by lymphoscintigraphy or by intraoper-
beled tracer or a vital blue dye alone. The first trial in which the ative gamma probe localization) and in which the location of the
two agents were used together was published in 1996.50 This study SLN basins and the pathologic status of the SLNs could be ascer-
documented an improvement in SLN localization and a 0% false tained [see Tables 1, 2, and 3]. Data on 8,951 patients were re-
negative rate, albeit in a small series of patients. Subsequent multi- viewed.39,41,50-52,54-95 The results of our review indicated that all of
center trials incorporating larger study groups yielded more reli- the approaches have acceptable SLN retrieval rates but that the
able indications of the applicability of these techniques to the over- rates are slightly higher with the more superficial ones (i.e., the der-
all surgical community. In one such study, surgeons from 11 mal, subareolar, and periareolar techniques).There are, however,
centers performed SLN biopsies and confirmatory axillary dissec- significant differences in the locations of the SLN basins identified
tion in clinically node-negative patients with invasive breast can- with the different methods: with the superficial injection tech-
cer.51 The overall success rate for identifying and removing an SLN niques, drainage is essentially confined to the axillary basin, where-
was 93%, the pathologic accuracy rate for predicting the presence as with the deeper injection techniques, as many as 22% of patients

Table 2—SLN Pathologic Positive Rates by Nodal Basin at Different Injection Sites39,41,50-52,54-95

Injection Location
Nodal Basin
Peritumoral* Intradermal/Subdermal† Periareolar/Subareolar‡ 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%
† ‡ §
*28 trials; 5,924 patients. 11 trials; 1,872 patients. 5 trials; 486 patients. 5 trials; 669 patients.


Table 3—False Negative SLN Identification proliferate, as other specialists begin to move into areas once gen-
Rates at Different Injection Sites39,41,50-52,54-95 erally 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
Injection Location Evaluable Patients (No.) False Negative Rate problem as it bears on lymphatic mapping, the ACS, in association
with the Moffitt Cancer Center, initiated a program designed to
Peritumoral* 3,909 6.0%
investigate how best to train teams (comprising surgeons, nuclear
Intradermal/subdermal† 1,734 6.5% medicine physicians, radiologists, and pathologists) in the new
technology. This formal training course is a 2-day session com-
Periareolar/subareolar‡ 19 0%
posed of didactic lectures, live surgery (including extensive sur-
Intratumoral§ 126 5.2% geon-audience interaction during the procedure), and a hands-on
† ‡ § laboratory.The program offers mentoring of initial cases as regis-
*28 trials; 5,924 patients. 11 trials; 1,872 patients. 5 trials; 486 patients. 5 trials; 669
patients. trants go back to their institutions, maintains national registries on
the Internet so that different experiences can be compared, and, fi-
nally, facilitates the participation of other university and communi-
ty physicians in national protocols. Further information may be
are found to have nodal basins outside the axilla. Approximately
obtained from the Center for Minimally Invasive Surgical Tech-
16% to 21% of the extra-axillary SLNs will be found to have
niques (888-456-2840; www.slnmapping.org). Participation in
metastatic disease if removed. The clinical ramifications of these
programs such as this one provides a certain degree of protection
findings are that some patients may be understaged if the extra-ax-
against medicolegal risk as new technology and procedures are in-
illary sites are not evaluated, and such understaging may affect the
troduced.
recommendations for systemic adjuvant therapy.What impact this
Another avenue of training that has been available to surgeons
possibility might have on tumor recurrence rates and patient sur-
is participation in clinical trials such as the NSABP B32 trial.
vival is unknown at present; to resolve the uncertainty would re-
Previous experience with SLN biopsy is not a requirement for
quire a large prospective, randomized trial. participation in this trial, and all participating surgeons are
To date, the only prospective, randomized trial of SLN biopsy in required to undergo a training process to gain experience with
breast cancer is that of Veronesi and coworkers.96 In this trial, a to- the procedure and familiarity with the specifics of the protocol.
tal of 516 evaluable patients were randomly assigned to undergo The techniques used in this trial represented a combination of
either SLN biopsy with confirmatory axillary dissection (257 pa- common methods designed to maximize the efficacy of the pro-
tients) or SLN biopsy with axillary dissection done only if the cedure. The training phase included distribution of a detailed
biopsy yielded positive results (259 patients). At a median follow- training manual, the opportunity to view a video of the proce-
up point of 46 months, no significant survival differences were re- dure, and a site visit by a protocol-designated core trainer to
ported, and there were no regional nodal recurrences in either explain the specifics of the procedure.
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 Radiation Exposure Guidelines and Policies
and Bowel Project (NSABP) B32 trial and the American College The amount and type of radioactivity injected in the course of
of Surgeons Oncology Group (ACOSOG) Z0010 trial. Another lymphatic mapping and SLN biopsy are relatively limited.
ongoing study is the ACOSOG Z0011 trial, the aim of which is to Typically, from 0.4 to 1.2 mCi of 99mTc is injected. This agent is
evaluate the effectiveness of SLN biopsy as the sole surgical proce- a pure gamma emitter with a short half-life (6 hours); thus, the
dure in patients with pathologically positive SLNs. risks of potentially harmful beta radiation are avoided. The total
radiation dose used is quite small—only about 5% of that used
in common nuclear scanning techniques (e.g., bone scans). It
Training and Credentialing
has been estimated that a maximum of 0.45 Gy could be
Credentialing criteria for new operative procedures have tradi- absorbed at the injection site. Of hospital workers, the surgeon is
tionally been under the jurisdiction of local hospital credentialing exposed to the highest levels of radiation. A study from Walter
committees. When new technology becomes available, adequate Reed Army Medical Center found that the hands of surgeons
training is essential, both to ensure that surgeons can perform the performing lymphatic mapping and SLN biopsy were exposed
new procedures competently and to address medicolegal liability to an average of 9.4 + 3.6 mrem per operation.97 Therefore, on
concerns. The American College of Surgeons (ACS) has a com- the basis of skin dosage recommendations set by the Nuclear
mittee (the Committee on Emerging Surgical Technology and Ed- Regulatory Commission, a surgeon would have to perform more
ucation) that monitors this activity. With some new techniques than 5,000 SLN procedures a year to incur more than the min-
(e.g., laparoscopic cholecystectomy and image-guided breast biop- imal level of risk.
sy), hospitals have required surgeons to attend formal training The low risk notwithstanding, proper handling of radioactive
courses and to have their first cases proctored by surgeons with ex- specimens is recommended. All such specimens should be han-
perience in the new technique before they are allowed to perform dled as little as possible for at least 24 to 48 hours and should be
the procedure on their own. appropriately labeled. Each institution performing these proce-
National organizations continue to struggle with the problem of dures should develop guidelines for handling and processing
educating and credentialing surgeons to perform new procedures. specimens in accordance with their own institution’s radiation
This problem takes on increasing urgency as medicolegal issues safety policies.


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