Sentinel Lymph Node Mapping in Breast Cancer
Sentinel Lymph Node Mapping in Breast Cancer
Axillary node dissection has long been a
mainstay in the treatment of breast cancer: It provides precise
staging and prognostication, prevents local recurrence in the axilla,
and, in patients with positive nodes, may modestly enhance
survivalall important goals in a disease that responds to
both local and systemic therapy and has a long natural history. To
date, no procedure has proven as effective as axillary lymph node
dissection in accomplishing these goals. Nevertheless, axillary
dissection is a major operation, requires general anesthesia, and
produces long-term morbidity in a small, but significant, minority of patients.
Within the last 2 years, sentinel lymph node (SLN) biopsy (Figure
1) has rapidly emerged as the most exciting development in the
surgical treatment of invasive breast cancer since the advent of
breast conservation. It has the potential to identify those patients
most likely to be helped by axillary dissection (ie, those with
positive nodes) and to spare node-negative patients, who cannot
benefit, from the morbidity of an operation. Undoubtedly, sentinel
lymph node biopsy will rapidly become a standard treatment option for
all patients with early-stage breast cancer and will replace axillary
dissection for many of these patients.
After a brief description of the history of SLN biopsy, this review
will discuss the feasibility and accuracy of the procedure, as well
as some of the technical and clinical issues raised by this new
technology. It will also attempt to answer a key question: Where will
SLN biopsy ultimately fit into the treatment algorithm for breast
cancer in the 21st century?
Most physicians are familiar with Sappeys classic studies of
the lymphatic anatomy of the chest wall, based on mercurial
injection of cadaver specimens. The lymphatics of the chest wall and
breast converge into a few main trunks, which, in turn, drain into
relatively few nodes low in the axilla. These studies formed the
anatomic basis of the complete axillary dissection incorporated into
radical mastectomy by Halsted in the 1890s. The internal mammary
nodes represent an alternative route of lymphatic drainage, but, as
shown in the work of Turner-Warwick and others, receive only a
small fraction of the lymphatic flow of the breast.
The underlying simplicity of the lymphatic anatomy of the breast was
emphasized in subsequent studies using direct lymphangiography.[5,6]
As pointed out by Borgstein and Meijer in a recent comprehensive
overview of the subject, work by Kett et al in 1970 identified a
lymph node (which they called the Sorgius node) that
received the initial drainage of contrast medium from the breast.
The phrase sentinel node must be credited to Cabanas,
who, in 1977 described cannulation of the dorsal lymphatics of the
penis as a means of identifying the first lymph node (sentinel
node) draining penile carcinoma. He noted that the sentinel
node was frequently the only positive node, and proposed that if the
sentinel node were negative, a deep inguinal node dissection might be avoided.
In the 1980s, Morton and colleagues independently developed the
sentinel node concept as an outgrowth of their work mapping the
drainage patterns of cutaneous melanoma with lymphoscintigraphy.
Their classic 1992 study described the intradermal injection of
blue dye into the melanoma site and the identification of a blue
node in the regional nodal basin. Among 237 node basins
studied (with a standard node dissection performed in all cases),
SLNs were identified in 82% of patients. Sentinel lymph node biopsy
correctly predicted regional node status in 99% of successful
procedures and 95% of node-positive cases (38/40).
As recently reviewed by Brady and Coit, 10 groups have since
reported comparable or better results using SLN biopsy (blue dye
and/or radioisotope localization) in melanoma.
The use of SLN biopsy in breast cancer was first reported in 1993 by
Krag et al, who employed radiolocalization, and in 1994 by
Giuliano et al, who employed blue dye. In the study by Krag et
al, isotope identified the SLN in 82% of 22 cases, with 100%
accuracy. In the report of Giuliano et al, blue dye identified the
SLN in 65% of 173 cases, with 96% accuracy.
Since these pioneering reports, 14 groups have published their
results with SLN biopsy for breast cancer, validated in all cases by
a concurrent axillary node dissection. Of the 14 groups, 7 used
isotope localization,[13-19] 3 used blue dye,[20-22] and 4 used a
combination of both methods.[23-26] Table
1 summarizes the results of all 1,564 reported cases.
Success in Identifying the SLN
Regardless of method, SLNs were identified by all of the
investigators in a large majority of cases. The 66% success rate for
blue dye in the initial 1994 report of Giuliano et al may simply
reflect the developmental stage of a new procedure; in this
groups more recent experience, blue dye successfully
identified the SLN in 93% of cases. Overall, radioisotope
localization appears to find the SLN more frequently than does blue
dye, and the combination of isotope plus dye appears to be superior
to isotope localization alone in these pilot studies.
Accuracy in Predicting Axillary Node Status
Sentinel lymph node biopsy yielded an incorrect result in 2% of all
patients (for an accuracy of 98%) and 5% of node-positive patients
(for a sensitivity of 95%). Although nearly half of the series (7 of
16) reported an accuracy of 100%, these comprise only 23% of the
total number of cases. No diagnostic test is perfect, and the
accuracy of SLN biopsy is probably slightly less than 100%.
Validation of the SLN Hypothesis
As shown in Table 1, the SLN was
the only site of nodal metastasis in 45% (range, 33% to 67%) of all
node-positive cases, strongly supporting the SLN concept. If the SLNs
were examined for micrometastatic disease with enhanced pathology
(serial sectioning, with both hematoxylin and eosin [H&E] and
immunohistochemical [IHC] staining), one might question whether
equally close examination of the nonsentinel axillary nodes would
also find micrometastases, undermining the uniqueness of the SLN as
the true first node. Turner et al have conducted an
elegant histopathologic validation of the SLN hypothesis (Table
2). Among 60 patients whose SLNs were negative on both frozen
and serial sections (using H&E and IHC), all of whom underwent
axillary dissection with serial sectioning of all of the remaining
axillary nodes, only 1 (0.1%) of 1,087 nonsentinel nodes contained tumor.
Because the SLN technology is evolving rapidly, variation in
technique is widespread, and anecdote rather than controlled
observation has been the rule. Nevertheless, all of those who perform
SLN biopsy would agree that it is a multidisciplinary procedure
requiring close collaboration among nuclear medicine (for
institutions using radiolocalization), surgery, and pathology. A
summary of some pertinent technical issues relevant to each specialty follows.
Localization of the SLN represents a new challenge for the specialty
of nuclear medicine, with requirements quite different from those of
solid organ imaging. The behavior of injected radiocolloids is
largely a function of particle size and interstitial pressure. The
largest particles (> 200 nm) simply remain at the injection site,
and the smallest (< 5 nm) rapidly disperse into the bloodstream.
Particles between 5 to 10 nm in size rapidly enter the lymphatics but
spread into numerous nodes. Sentinel lymph node localization depends
on a small fraction of the injected isotope dose (perhaps 1%)
migrating consistently to relatively few regional nodes, and optimal
particle size is probably between 10 and 200 nm.
Interstitial pressure, which must be elevated for lymphatic uptake of
particles to occur, is related to both route (intradermal vs
intramammary) and volume of injection: Lymphatic uptake of isotope
may be greater with either a high-pressure intradermal injection or a
high-volume intramammary injection. American investigators have used
technetium-99m sulfur colloid,[11,18,23,25] while European studies
have employed technetium-99m colloidal albumin.[13-17,24,26] The
particle size in technetium-99m sulfur colloid preparations is
particularly subject to wide variation; this may be reflected in the
somewhat less consistent results reported for radiolocalization in
the American literature.
One might assume that intramammary injection of isotope, as was done
in the studies from America and Holland,[11,14-18,23-25] would most
accurately emulate the lymphatic drainage of a breast cancer.
Interestingly, in the two series from Milan,[13,16] lymphatic mapping
based on a subdermal injection of isotope over the tumor site was
equally successful and accurate in predicting axillary node status.
The dermal and parenchymal lymphatics of the breast may simply drain
to the same SLN.
Investigators using technetium-99m sulfur colloid typically inject
0.3 to 1.0 mCi in a volume of 4 mL of normal saline around the tumor
(or biopsy site) 1 to 4 hours prior to operation,[11,18,23,25,26]
whereas those using technetium-99m colloidal albumin inject 0.1 to
1.6 mCi either subdermally or into the breast about 24 hours in
advance of surgery.[13-17,24] Filtration of technetium-99m sulfur
colloid prior to injection produces greater uniformity of particle
size, and has become standard practice in lymphatic mapping for
melanoma. The smaller particles rapidly traverse the lymphatic
vessels and regional nodes, helping to identify anomalous patterns of
lymphatic drainage on preoperative lymphoscintigraphy.
In our experience performing SLN radiolocalization for breast cancer
at Memorial Sloan-Kettering Cancer Center, we have noted a higher
failure rate with filtered than with unfiltered technetium-99m sulfur
colloid. Therefore, we continue to use an unfiltered preparation,
as initially recommended by Krag et al.[11,18] In contrast, Albertini
et al have reported good results with filtered technetium-99m
Lymphoscintigraphy is a well-established component of lymphatic
mapping for melanoma. It identifies anomalous patterns of lymphatic
drainage, which, in turn, directly alter the surgical approach. This
examination is probably less useful on a routine basis in breast
cancer, where the primary focus is the axilla. Management of the 14%
of patients who demonstrate internal mammary drainage is a new,
The surgeons objective is simply to find the SLN as
consistently as possible. Each failed localization will result in an
axillary dissection that might not otherwise have been necessary.
Debate centers on which method is best to accomplish this objective:
isotope, blue dye, or both? Table 1
suggests that all three approaches work.
With isotope, as first described by Krag et al, the surgeon uses
a handheld gamma probe intraoperatively to find the axillary hot
spot(s) corresponding to the SLN(s) and removes hot node(s)
until the axillary background radiation count falls below a defined
threshold level . With blue dye, as described by Giuliano et al,
the surgeon identifies blue lymphatic vessels exiting the tail of the
breast and traces them to a blue-stained SLN in the axilla, removing
all blue nodes. All blue and/or hot nodes are removed and submitted
for pathologic examination.
Early in the surgeons experience, SLN biopsy is best validated
by the performance of a backup axillary dissection (as part of a
formalized protocol) after removal of the SLN. The learning curve for
this procedure varies from institution to institutions and surgeon to
surgeon. At present, it is impossible to specify exactly how many
procedures should be done with validation before SLN biopsy can be
performed as a stand-alone procedure.
In our experience performing more than 800 SLN biopsies at Memorial
Sloan-Kettering, we have found that failed SLN localizations diminish
but do not altogether disappear with experience; the results of other
investigators (Table 1) support
this impression. We advocate the combined use of isotope and blue dye
for SLN biopsy (Figure 2): Although
80% of SLNs were found by both isotope and dye, 10% were found by
isotope alone, and 10% by blue dye alone. This additive effect of
isotope and blue dye was first noted by Albertini et al, and was
confirmed by our initial experience and that of Barnwell et al.
The surgeons greatest concern in undertaking SLN biopsy is that
the SLN will prove to be falsely negative. False-negative SLN
biopsies (like failed SLN localizations) also diminish over time. Our
experience suggests that about half of all falsely negative SLN
biopsies will occur within the first 10 cases performed by each surgeon.
No studies have specifically addressed the relative value of isotope
and blue dye in finding the positive SLN. However, our experience
suggests that while most positive SLNs will be found by both isotope
and blue dye, a small fraction (perhaps 10%) will be found by either
isotope or blue dye alone. Although others have achieved excellent
results with a single modality (Table 1),
the reliability of SLN biopsy in our hands would have been
undermined by reliance on a single localization technique.
The most crucial element in SLN biopsy is enhanced pathologic
analysis of the SLN. Reporting on the early experience with melanoma,
Gershenwald et al found that 4.1% (10/243) of patients with
negative SLNs (by routine single-section pathologic examination)
later developed a local relapse in the undissected nodal basin.
Reanalysis of the negative SLNs in these 10 patients
(with serial sections and IHC stains) demonstrated that 80% were, in
Thus, an increasing number of investigators performing SLN biopsy for
breast cancer have relied on serial sectioning of the SLN, with both
H&E and IHC staining of each section. The IHC technique uses
antibodies to cytokeratin and, thus, identifies epithelial cells that
are presumed to represent metastases from the breast (Figure
3). Although no authors have reported the occurrence of a
falsely positive SLN in breast cancer, benign rests of
epithelial cells (typically melanocytes) in the subcapsular area of a
lymph node may occasionally be mistaken for metastasis; we have
encountered 1 such case in our first 600 SLN biopsies.
Reverse transcriptasepolymerase chain reaction (RT-PCR)
technology has the exciting potential to identify metastases even
smaller than those found by IHC, but thus far has proven to be
problematic in the study of SLNs from breast cancer patients. First,
since breast cancer has no unique marker (such as tyrosinase for
melanoma), the analysis must depend on nonspecific epithelial cell
products. As a result, there is no way to be certain that the
amplified gene product obtained was expressed specifically by a tumor
cell within the node.
In addition, the level of expression at which a result is defined as
positive or negative is somewhat arbitrary and allows considerable
latitude in the interpretation of results. Thus, RT-PCR for SLN
analysis in breast cancer remains investigational at present.