Download Sentinel Lymph Node Mapping in Breast Cancer

Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
Sentinel Lymph Node Mapping in Breast Cancer
Review Article [1] | January 01, 1999 | Breast Cancer [2]
By Hiram S. Cody III, MD [3]
Sentinel lymph node (SLN) biopsy is a rapidly emerging treatment option for patients with
early-stage invasive breast cancer and a clinically negative axilla. In the era of mammographic
detection, SLN biopsy has the potential to eliminate axillary dissection for the enlarging cohort of
breast cancer patients who are node-negative. Using radioisotope, blue dye, or both methods,
experienced surgeons can successfully localize SLNs in more than 90% of cases. The effects of
isotope and blue dye may be additive. Sentinel lymph node biopsy reliably predicts axillary node
status in 98% of all patients and 95% of those who are node-positive. The operation is best learned
under a formalized protocol in which a backup axillary dissection is performed to validate the
technique during the surgeon’s early experience. Enhanced pathologic analysis, including serial
sections and immunohistochemical (IHC) staining, is an essential element of the procedure. In
experienced hands, SLN biopsy has less morbidity and greater accuracy than conventional axillary
dissection. [ONCOLOGY 1(13):25-34, 1999]
Introduction
xillary 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 survival[1]—all 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.
A
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?
Historical Background on SLN Biopsy
Most physicians are familiar with Sappey’s classic studies of the lymphatic anatomy of the chest
wall,[2] 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.[3] The internal mammary nodes represent an
alternative route of lymphatic drainage, but, as shown in the work of Turner-Warwick[4] 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[7] in a recent
comprehensive overview of the subject, work by Kett et al[6] 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,[8] who, in 1977 described cannulation of
the dorsal lymphatics of the penis as a means of identifying the first lymph node (“sentinel node”)
Page 1 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
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[9] 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] 10 groups have since reported comparable or better
results using SLN biopsy (blue dye and/or radioisotope localization) in melanoma.
Overview of SLN Biopsy in Breast Cancer
The use of SLN biopsy in breast cancer was first reported in 1993 by Krag et al,[11] who employed
radiolocalization, and in 1994 by Giuliano et al,[12] 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[12] may simply reflect
the developmental stage of a new procedure; in this group’s more recent experience,[20] 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[27] 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.
Technical Issues Related to SLN Biopsy
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.
Nuclear Medicine
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.
Page 2 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
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.[10] 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.[28] Therefore, we continue to use an unfiltered preparation, as initially recommended
by Krag et al.[11,18] In contrast, Albertini et al[23] have reported good results with filtered
technetium-99m sulfur colloid.
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[25] is a new, unresolved problem.
Surgery
The surgeon’s 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,[11] 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,[12] 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 surgeon’s 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,[23] and was confirmed by our initial
experience[25] and that of Barnwell et al.[26]
The surgeon’s greatest concern in undertaking SLN biopsy is that the SLN will prove to be falsely
Page 3 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
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.
Pathology
The most crucial element in SLN biopsy is enhanced pathologic analysis of the SLN. Reporting on the
early experience with melanoma, Gershenwald et al[29] 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 fact, positive.
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 transcriptase–polymerase 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.
Patient Selection
In general, patients selected as candidates for SLN biopsy have had T1 or T2 invasive breast cancers
and clinically negative axillary nodes. Some specific issues related to patient selection are the
following:
Palpable Axillary Nodes—In general, patients with clinically positive axillae have been excluded
from SLN biopsy. Reactive nodes that appear post-biopsy are not a contraindication.
Previous Surgical Biopsy—Although some investigators have avoided performing SLN biopsy in
patients who have had a previous excisional biopsy,[13,14,16,23] others (ourselves included) have
observed equal success with SLN localization regardless of the prior biopsy method.[17,18,25,26] A
very large biopsy cavity, especially in the upper outer quadrant of the breast, has the potential to
extensively disrupt the lymphatics on which the accuracy of SLN biopsy depends. Therefore, we
agree entirely with Ollila and Giuliano[30] in discouraging SLN biopsy in this setting, where we have
observed a disproportionate number of our failed and false-negative procedures.
Intraductal Carcinoma—Since axillary node metastasis occurs in fewer than 1% of patients with
ductal carcinoma in situ (DCIS), most patients with DCIS do not require any axillary surgery. The
exception may be patients with DCIS and a mass, in which the presence of invasion cannot be ruled
out absolutely prior to surgery.
Microinvasive Cancers—Axillary metastasis occurs in patients with microinvasive cancers but does
so very infrequently (probably in < 5% of such patients). Sentinel lymph node biopsy is ideal in this
setting, particularly in younger patients, in whom the decision of whether to recommend systemic
therapy hinges entirely on the biopsy result.
Histologically Favorable Tumors—Patients with tubular, medullary, or colloid cancers are all less
likely to be node-positive than are patients with invasive duct cancers of comparable size.
Consequently, SLN biopsy is ideal for these groups.
Large Tumors—In our initial experience,[25] SLN biopsy was more accurate in patients with T1
tumors (45/46; 98%) than in those with T2 cancers (10/12; 83%). This difference may simply reflect
Page 4 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
the greater likelihood of node-positivity in patients with larger tumors.
Our subsequent experience suggests that SLN biopsy is falsely negative in a relatively fixed
percentage of node-positive patients, and that, with experience, this fraction falls to about 5%. This
corresponds quite well with the overall false-negative rate of 5% (ie, sensitivity of 95%) noted for all
of the published series to date (Table 1). Reassuringly, no authors have yet reported a false-negative
SLN biopsy for a breast cancer < 1.0 cm, and, by current standards, almost all patients with tumors ≥
1 cm receive systemic adjuvant therapy regardless of nodal status.
Multicentric tumors raise the possibility of identifying the “wrong” SLN and, in general, should be
excluded from SLN biopsy. Exceptions may be tumors that are relatively contiguous, or tumors that
contain a small invasive lesion within an extensive in situ component. In these settings, the isotope
and/or dye injections would be administered near the invasive lesion.
Patients Needing Mastectomy—Sentinel lymph node biopsy is just as feasible in patients
undergoing a mastectomy as in those having breast conservation, as long as the extent of the
invasive portion of the tumor is relatively well-defined.
Unexpectedly Extensive Cancers—In some patients, tumors that appear to be small on
mammography prove, on wide excision, to have an unexpectedly extensive invasive component (as
may be the case with some invasive lobular cancers) and require either reexcision or mastectomy. In
these cases, a negative SLN result should be regarded cautiously, and a conventional axillary
dissection should be considered as part of the second procedure.
In an effort to define and standardize criteria for case selection, the National Comprehensive Cancer
Network (NCCN), a consortium of 16 US cancer centers, has recently modified its breast cancer
treatment guidelines to include SLN biopsy (Table 3), incorporating many of the considerations
discussed above. As SLN biopsy is rapidly integrated into both clinical practice and randomized trials,
consistency in case selection and technique will assume increasing importance.
Treatment Algorithm for SLN Biopsy
At Memorial Sloan-Kettering Cancer Center, our current approach to SLN biopsy involves the use of
both isotope and blue dye lymphatic mapping. Based on our initial study,[25] patients with T1 breast
cancers are candidates for SLN biopsy alone if the SLN is negative, while most patients with T2
cancers still undergo a planned axillary dissection at the time of SLN biopsy.
The morning of surgery, patients are taken to the Department of Nuclear Medicine, where they
receive 0.1 to 0.3 mCi of unfiltered technetium-99m sulfur colloid (CIS-US Inc., Bedford, MA) injected
either into the breast parenchyma (adjacent to the tumor) or intradermally (overlying the tumor). A
lymphoscintigram is then taken to visualize the sites of lymphatic drainage. A negative
lymphoscintigram does not preclude successful radiolocalization at surgery.
One to two hours post-injection, patients are taken to the operating room, where 4 mL of isosulfan
blue dye is injected into the breast parenchyma adjacent to the tumor site. Within 5 to 10 minutes,
the axilla is explored through a small transverse incision while the patient is under local anesthesia
coupled with intravenous sedation (or general anesthesia if a mastectomy is planned). Guided by
both a handheld gamma probe and direct visualization for blue dye staining, the surgeon removes all
blue and/or hot sentinel nodes.
In one-third of cases, a single SLN is found; the median number of SLN identified is two. The SLN is
submitted for frozen-section examination, and, if this is positive, an immediate axillary node
dissection is performed.
If the frozen-section analysis is negative, the remainder of the node is embedded. Sections are taken
from three levels within the node and stained using both H&E and IHC for cytokeratins (CAM5.2 and
AE1:AE3; Becton Dickinson Immunocytometry Systems, San Jose, California). About 3% of patients
with a negative frozen-section examination will have positive results on permanent sections.
If either the H&E or IHC stain reveals tumor cells, the patient is returned to surgery for an axillary
dissection. All patients with positive SLNs are treated conventionally as axillary node-positive cases
and receive systemic chemotherapy and/or tamoxifen (Nolvadex) as appropriate.
Specific Clinical Issues
With respect to any medical intervention, the procedure requires justi-fication, and the results
demand interpretation. This is certainly true of SLN biopsy. Indeed, this technology raises at least as
many questions as it answers. A discussion of some specific issues follows.
How Should the Predictive Value of SLN Biopsy Be Explained to Patients?
The results of SLN biopsy may be presented in terms of sensitivity ([true positive]/[true positive +
false negative]), false-negative rate ([false negative]/[true positive + false negative]), or accuracy
Page 5 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
([true positive + true negative]/[total patients]). All of these values are summarized in Table 1. Since
most breast cancer patients present with a known tumor size and an unknown axillary node status,
accuracy will be of greatest relevance to them. Patients want to know, “For a breast cancer of my
size, how likely is SLN biopsy to yield an incorrect result?”
Table 4 gives estimates of the accuracy of SLN biopsy based on tumor size, using the expected rate
of axillary node involvement and assuming false-negative rates of both 10% (which might be
expected early in one’s experience) and 5% (reflecting the published experience summarized in
Table 1). These estimates should always be compared with the inaccuracy of conventional axillary
dissection, which is well documented in the literature but very seldom discussed with patients. In
three large series,[31-33] conventional single-section pathologic analysis of axillary nodes failed to
identify prognostically significant micrometastatic disease in 9% to 24% of cases.
Is There an Upper Tumor Size Limit Beyond Which SLN Biopsy Loses its Validity?
Assuming that the false-negative rate for SLN biopsy does not vary with tumor size, the procedure
may prove to be less accurate for large tumors, simply because the risk of node involvement
increases with tumor size. However, there may be circumstances (ie, old age or serious
comorbidities) in which the advantage to the patient of avoiding axillary dissection outweighs the
very small risk of leaving residual nodal disease in the axilla.
What is the Risk of Axillary Relapse After a Negative SLN Biopsy?
No recurrences in the intact axilla have yet been reported in breast cancer patients after a negative
SLN biopsy. The axillary recurrence rate for breast cancer is unlikely to be as high as the 4.1% rate
observed (at 35 months’ follow-up) in the early SLN experience with melanoma.[29]
Enhanced pathologic analysis, effective systemic therapy, and (for patients undergoing breast
conservation) the possibility of a radiotherapy effect on the low axilla all act to minimize axillary
relapse in the small percentage of patients whose SLN biopsy is falsely negative. Although the
axillary recurrence rate will not be 0, it may actually prove to be comparable to the < 1% rate seen
after conventional axillary dissection.
Are Axillary Micrometastases Prognostically Significant?
Serial sectioning and IHC stains can demonstrate micrometastatic disease with striking clarity. It is
tempting to believe that these micrometastases are too small to be of any significance, and the older
literature on this subject is contradictory. The 1990 Ludwig study[31] convincingly demonstrates
otherwise. Among a cohort of 921 patients who were axillary node–negative on routine single section
pathologic analysis, 9% were found to be node-positive on serial sections and had a 5 year
disease-free survival that was 15% worse than those who were “truly” node-negative.
Two other large studies from France[32](1992; 229 patients) and Australia[33] (1993; 343 patients)
show similar results for patients whose micrometastases were found by IHC. Although these
micrometastases may not carry the same prognostic weight as does gross nodal disease, both the
surgeons and medical oncologists at our institution currently recommend systemic adjuvant
treatment to almost all SLN-positive patients.
Do Patients With Negative Frozen Sections But Positive H&E or IHC Stains Require
Axillary Dissection?
In approximately half of SLN-positive patients, the SLN is the only positive node (Table 1). In our first
500 cases, we have found that, among patients whose SLN was positive on either frozen section or
H&E, about 40% had residual disease found at axillary dissection. Among those whose SLN was
positive only on IHC, about 10% had residual disease. Because these data are based on relatively
few (N = 126) node-positive cases, our current practice is to recommend axillary dissection for
almost all SLN-positive patients. A future goal is to develop specific criteria to identify SLN-positive
patients in whom axillary dissection may not be necessary.
How Should an Internal Mammary SLN Be Managed?
In our initial experience with SLN biopsy, routine preoperative lympho-scintigraphy identified internal
mammary drainage in 14% of patients.[25] Positive internal mammary nodes carry a prognostic
weight equal to that of positive axillary nodes, and 10% to 20% of axillary node–negative T1 breast
cancer patients will have internal mam-mary node metastases.[34,35] This high-risk group will
remain unidentified by current standards of practice and will receive no systemic treatment at all if
their cancers are < 1.0 cm.
Although internal mammary SLN biopsy is possible, both blue dye and radiolocalization are made
difficult by the proximity of the breast injection site to the interspace containing the SLN. Our current
practice is to consider internal mammary SLN biopsy for medially placed tumors < 1.0 cm, if either
lymphoscintigraphy or the intraoperative gamma probe suggests internal mammary drainage of
isotope.
Page 6 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
Clinical Trials of SLN Biopsy
Sentinel lymph node biopsy will be incorporated increasingly into clinical trials, either as a surrogate
for conventional axillary dissection or to examine aspects of the procedure itself. To ensure reliable
results nationwide, the SLN biopsy technique must be standardized, with validation on a site-by-site
basis, defining acceptable levels both for successful SLN localization (at least 90%) and for
false-negative procedures (perhaps 5% of node-positive cases).
Table 5 summarizes four major multicenter trials of SLN biopsy that are either proposed or actively
accruing patients.[36] The most ambitious of these trials is Giuliano’s two-part study, sponsored by
the American College of Surgeons Oncology Group. Collectively, these four trials have the potential
to define the significance of SLN and bone marrow micrometastases detected only by IHC, to
determine whether axillary dissection is really necessary in patients whose SLN is positive by H&E,
and to establish the accuracy of SLN biopsy in the community hospital setting.
Conclusions
The Fisher hypothesis,[37] familiar to all oncologists, has been the dominant conceptual model for
breast cancer over the last 30 years. It proposes that the spread of breast cancer is not mechanistic
and orderly; that regional lymph nodes are not simple filters, but rather, are indicators of a
host-tumor relationship; that occult systemic metastases occur frequently and early in the tumor’s
natural history; and that local control and survival are therefore unrelated. This thesis is always
presented as a major theoretical advance over the anatomic Halstedian model,[3] which formed the
basis of breast cancer surgery throughout most of the 20th century.
In fact, the Halsted and Fisher hypotheses represent the two poles of a dichotomy that has always
been artificial. Neither by itself is sufficient to explain breast cancer’s broad spectrum of clinical
behavior, and yet the SLN concept simultaneously demonstrates the truth of both.
In deference to Dr. Halsted, SLN biopsy clearly shows that the spread of breast cancer to regional
nodes is anatomically defined, predictable, and orderly. A single SLN is involved surprisingly often,
and a negative SLN predicts a negative axilla with remarkable accuracy.
In deference to Dr. Fisher, SLN biopsy (through enhanced pathologic analysis) demonstrates that
occult micrometastases occur more frequently than conventional techniques of axillary dissection
would suggest, and that these occult metastases are significant predictors of systemic relapse. A
surprising proportion of “node-negative” patients have micrometastatic disease, and through SLN
biopsy have been correctly identified as candidates for systemic treatment.
Sentinel node biopsy is an ingenious, simple, and accurate technique. It cannot explain the
remarkable heterogeneity of breast cancer. What it can do, with minimal morbidity, is to define with
a new level of precision where an individual cancer lies on that broad biological spectrum.
Acknowledgment: The author wishes to thank Arnold D. K. Hill, MCH, FRCSI, Laura
Liberman, MD, and Jeffrey A. Boyd, PhD, for their assistance in the preparation of this
manuscript, and the Tow Foundation and Liz Claiborne Foundation for their
philanthropic support of sentinel node mapping at Memorial Sloan-Kettering Cancer
Center.
References:
1. Petrek JA, Blackwood MM: Axillary dissection: current practice and technique. Curr Probl Surg
32:259-323, 1995.
2. Sappey PC: Anatomie, Physiologie, Pathologie des Vesseaux Lymphatiques Consideres chez
l’Homme et les Vertebres. Paris, A. Delahaye and E. Lecrosnier, 1885.
3. Halsted WS: The results of operations for the cure of cancer of the breast performed at the Johns
Hopkins Hospital from June 1889 to January 1894. Johns Hopkins Hosp Rep 4:297-350, 1894.
4. Turner-Warwick RT: The lymphatics of the breast. Br J Surg 46:574-582, 1959.
Page 7 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
5. Halsell JT, Smith JR, Bentlage CR, et al: Lymphatic drainage of the breast demonstrated by vital
dye staining and radiography. Ann Surg 162:221-226, 1965.
6. Kett K, Varga G, Lukacs L: Direct lymphography of the breast. Lymphology 1:3-12, 1970.
7. Borgstein P, Meijer S: Historical perspective of lymphatic tumour spread and the emergence of the
sentinel node concept. Eur J Surg Oncol 24:85-89, 1998.
8. Cabanas R: An approach for the treatment of penile carcinoma. Cancer 39:456-466, 1977.
9. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic
mapping for early stage melanoma. Arch Surg 127:392-399, 1992.
10. Brady MS, Coit DG: Sentinel lymph node evaluation in melanoma. Arch Dermatol 133:1014-1020,
1997.
11. Krag DN, Weaver DL, Alex JC, et al: Surgical resection and radiolocalization of the sentinel lymph
node in breast cancer using a gamma probe. Surg Oncol 2:335-340, 1993.
12. Giuliano AE, Kirgan DM, Guenther JM, et al: Lymphatic mapping and sentinel lymphadenectomy
for breast cancer. Ann Surg 220:391-401, 1994.
13. Veronesi U, Paganelli G, Galimberti V, et al: Sentinel node biopsy to avoid axillary dissection in
breast cancer with clinically negative lymph-nodes. Lancet 349:1864-1867, 1997.
14. Pijpers R, Hoekstra OS, Collet GJ, et al: Impact of lymphoscintigraphy on sentinel node
identification with technetium-99m-colloidal albumin in breast cancer. J Nucl Med 38:366-368, 1997.
15. Roumen RMH, Valkenburg JGM, Geuskens LM: Lymphoscintigraphy and feasibility of sentinel
node biopsy in 83 patients with primary breast cancer. Eur J Surg Oncol 23:495-502, 1997.
16. Galimberti V, Zurrida S, Zucali P, et al: Can sentinel node biopsy avoid axillary dissection in
clinically node-negative breast cancer patients? Breast J 7:8-10, 1998.
17. Borgstein PJ, Pijpers R, Comans EF, et al: Sentinel lymph node biopsy in breast cancer: Guidelines
and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 186:275-283, 1998.
18. Krag DN, Ashikaga T, Harlow SP, et al: Development of sentinel node targeting technique in
breast cancer patients. Breast J 4:67-74, 1998.
19. Offodile R, Hoh C, Barsky SH, et al: Minimally invasive breast cancer staging using lymphatic
mapping with radiolabeled dextran. Cancer 82:1704-1708, 1998.
20. Giuliano AE, Jones RC, Brennan M, et al: Sentinel lymphadenectomy in breast cancer. J Clin Oncol
15:2345-2350, 1997.
21. Guenther JM, Krishnamoorthy M, Tan LR: Sentinel lymphadenectomy for breast cancer in a
community managed care setting. Cancer J Sci Am 3:336-340, 1997.
22. Flett MM, Going JJ, Stanton PD, et al: Sentinel node localization in patients with breast cancer. Br J
Surg 85:991-993, 1998.
23. Albertini JJ, Lyman GH, Cox C, et al: Lymphatic mapping and sentinel node biopsy in the patient
with breast cancer. JAMA 276:1818-1822, 1996.
24. Borgstein PJ, Meijer S, Pijpers R: Intradermal blue dye to identify sentinel lymph node in breast
cancer. Lancet 349:1668-1669, 1997.
Page 8 of 9
Sentinel Lymph Node Mapping in Breast Cancer
Published on Cancer Network (http://www.cancernetwork.com)
25. O’Hea BJ, Hill ADK, El-Shirbiny A, et al: Sentinel lymph node biopsy in breast cancer: Initial
experience at Memorial Sloan-Kettering Cancer Center. J Am Coll Surg 186:423-427, 1998.
26. Barnwell JM, Arredondo MA, Kollmorgen D, et al: Sentinel node biopsy in breast cancer. Ann Surg
Oncol 5:126-130, 1998.
27. Turner RR, Ollila DW, Krasne DL, et al: Histologic validation of the sentinel lymph node
hypothesis for breast carcinoma. Ann Surg 226:271-278, 1997.
28. Linehan DC, Hill ADK, Tran KN, et al: Sentinel lymph node localization in breast cancer: unfiltered
isotope is superior to filtered (abstract). SSO Cancer Symposium, p 51, 1998.
29. Gershenwald JE, Colome MI, Lee JE, et al: Patterns of recurrence following a negative sentinel
lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 16:2253-2260, 1998.
30. Ollila DW, Giuliano AE: Intraoperative lymphatic mapping and sentinel lymphadenectomy using
isosulfan blue dye. Breast Diseases 8:297-300, 1998.
31. International (Ludwig) Breast Cancer Study Group: Prognostic importance of occult axillary lymph
node micrometastases from breast cancers. Lancet 335:1565-1568, 1990.
32. DeMascarel I, Bonichon F, Coindre JM, et al: Prognostic significance of breast cancer axillary
lymph node micrometastases assessed by two special techniques: Reevaluation with longer
follow-up. Br J Cancer 66:523-527, 1992.
33. Hainsworth PJ, Tjandra JJ, Stillwell RG, et al: Detection and significance of occult micrometastases
in node-negative breast cancer. Br J Surg 80:459-463, 1993.
34. Veronesi U, Cascinelli N, Bufalino R: Risk of internal mammary lymph node metastases and its
relevance on prognosis of breast cancer patients. Ann Surg 198:681-684, 1983.
35. Cody HS, Urban JA: Internal mammary node status: A major prognosticator in axillary
node-negative breast cancer. Ann Surg Oncol 2:32-37, 1995.
36. McNeil C: Four large studies aim to resolve sentinel node debate. J Natl Cancer Inst 90:729, 1998.
37. Fisher B: Laboratory and clinical research in breast cancer: A personal adventure: The David A.
Karnofsky memorial lecture. Cancer Res 40:3863-3874, 1980.
Source URL:
http://www.cancernetwork.com/review-article/sentinel-lymph-node-mapping-breast-cancer-0
Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/breast-cancer
[3] http://www.cancernetwork.com/authors/hiram-s-cody-iii-md
Page 9 of 9