Download Review Sentinel lymph node biopsy in breast cancer

Annals of Oncology 13: 1531–1537, 2002
DOI: 10.1093/annonc/mdf319
Review
Sentinel lymph node biopsy in breast cancer
J. Bonnema* & C. J. H. van de Velde
Leids Universitair Medisch Centrum, Leiden, The Netherlands
Received 4 January 2002; revised 3 June 2002; accepted 18 June 2002
The concept of sentinel lymph node (SLN) biopsy in breast cancer patients is simple, attractive and
rapidly emerging as a new standard of care. Several aspects of the technique of lymphatic mapping, case
selection, pathologic analysis and the finding of micrometastases, and the accuracy of the technique are
important subjects of study and debate in the literature and will be discussed in this review. High
identification rates can be attained by the use of both radioguided and blue dye lymphatic mapping.
Intradermal injection of tracers has reported to be successful, suggesting that dermal and parenchymal
lymphatics drain to the same SLN. Extra axillary drainage is only seen after peri- or intratumoural
injection. SLN biopsy is most widely used for both palpable and non-palpable T1 and T2 tumours, and
limited experience exists for other indications. Accuracy is high only in experienced hands. The impact
of failure of the procedure on regional disease control and survival will be assessed in a trial of the
NSABP (National Adjuvant Breast and Bowel Project). The influence of a positive SLN biopsy with
and without axillary dissection on survival and local control will be studied in trials of the BASO
(British Association of Surgical Oncology), ACOSOG (American College of Surgeons Oncology
Group) and EORTC (European Organisation for Research and Treatment of Cancer). These phase III
trials and related studies on the importance of micrometastases in the SLN will give new insights in the
safety of the SLN procedure and in the importance of treatment of regional lymph nodes in relation to
local disease control and survival.
Key words: breast cancer, case selection, lymphatic mapping, micrometastases, sentinel node biopsy
Introduction
The concept of sentinel lymph node (SLN) biopsy in breast
cancer patients is simple, and therefore appealing. It concerns
the identification and subsequent resection of the initial lymph
nodes (‘sentinel nodes’) upon which the primary tumour
drains. These nodes can be identified by radioguided lymphatic mapping and/or by visualisation of the nodes with vital
blue dyes. The sentinel nodes are those most likely to contain
tumour cells that have spread from the tumour. Histopathological evaluation of these nodes therefore can be an accurate
predictor of other metastases in the same lymph node basin,
and can guide regional and systemic treatment. Axillary node
dissection and its morbidity can be avoided in patients in
whom the sentinel nodes prove to be negative.
The concept is attractive and rapidly emerging as a new
standard of care [1]. Knowledge of theoretical and clinical
issues concerning the SLN procedure has been accumulating
over recent years; however, a number of questions remain
unanswered and are the subject of study and intense debate in
*Correspondence to: Dr J. Bonnema, Leids Universitair Medisch
Centrum, Postbus 9600, 2300 RC Leiden, The Netherlands.
Tel: +3171-526-2309; Fax: +3171-526-6750; E-mail: [email protected]
© 2002 European Society for Medical Oncology
the literature. In this review, some of the most relevant clinical
issues will be discussed.
Technical aspects of lymphatic mapping
A number of techniques for identifying the sentinel node are
applied. Overall, radioisotope mapping of the SLN with the
use of a handheld gammaprobe succeeds more often than blue
dye. Of 39 peer-reviewed pilot studies reporting the results
of SLN biopsy validated by a ‘backup axillary lymph node
dissection (ALND)’ using radioisotope (15 studies) or blue
dye (20 studies) or a combination of both (11 studies), identification rates were 92%, 81% and 93%, respectively, while
false-negative rates were 7%, 9% and 5%, respectively [1].
There is growing evidence that with the use of both methods
in combination—blue dye and radioisotope—very high
identification rates can be reached and fewer SLN may be
missed compared with single-agent mapping [2]. In a multiinstitutional study, injection of blue dyes alone was associated
with decreased identification rates and a trend toward a higher
false-negative rate [3]. The lower false-negative rate in dual
agent tracing was hypothesised to be from the increased
ability to identify multiple sentinel nodes. The same group
demonstrated indeed that the false-negative rate was 14.3%
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when single sentinel nodes were removed, and 4.3% for
patients with more than one SLN removed. A logistic regression analysis of the 1287 SLN biopsy procedures showed that
the use of blue-dye injection alone was the only factor
independently associated with identification of a single SLN
[4]. With the increase of experience, the additional value of
blue dye localisation may decline. The proportion of positive
sentinel nodes identified by blue dye only declined from 12%
to 2% after 2000 SLN procedures using intradermal injected
radioisotope and peritumoural patent blue [5].
Both for isotopes and for blue dyes, different routes of tracer
administration in different combinations have been used [6].
The injection place can be related to either the skin (periareolar, subareolar, intradermal or subcutaneous over the primary
tumour site) or the primary tumour (peritumoural or intratumoural). Groups at most centres inject around the tumour,
but cutaneous methods are increasingly popular [3].
The skin-related methods are based on the hypothesis that
the mammary gland and the overlying skin share the same
lymphatic drainage. This was suggested in studies using peritumoural radioactive tracer injection and intradermal patent
blue injection [7, 8], showing a high concordance in lymphatic
drainage pattern between the two methods. Intradermal injection has the advantage that lymphatic vessel density in the skin
is high, and tracers are cleared more rapidly and can be easily
visualised by lymphoscintigraphy, which distinguishes better
between first and second echelon nodes [9]. Linehan used
unfiltered Tc-99m sulfur colloid injected into a single site in
the skin over the tumour and peritumoural patent blue. There
was a 95% concordance in drainage to the same node and
the identification rate was 100% [2]. Multivariate analysis of
966 consecutive patients treated at the Memorial Sloan Kettering Center confirmed that intradermal injection is associated independently with a higher rate of successful sentinel
node identification [10]. Also, the results of a large study in a
multi-institutional setting of McMasters are in favour of the
dermal isotope injection technique, with an identification rate
of 89.9% and a false-negative rate of 8.3% for peritumoural
isotope injection, and of 98% and 6.5% for the dermal technique, respectively, although the false-negative rates of the
two methods were not significantly different [3].
Subdermal injection over the primary tumour [11, 12] has
also shown good identification rates.
Despite good identification results, other authors state that
these approaches do not provide the certainty that the lymphatics draining the skin or subcutaneous tissue are in all cases
the same as lymphatics draining the tumour, based on anatomic
studies of lymph drainage [6]. There are no randomised
studies comparing the skin related to parenchymal injection
techniques. Although axillary drainage is the principle drainage path of the breast, drainage from any quadrant of the
breast can occur to other lymph node basins [13]. Extraaxillary drainage patterns are reported to be seen only after
peri- or intratumoural radiocolloid injection [14]. The rate of
visualisation of internal mammary nodes is in an average of
6–26% of mapped patients [14, 15]. Other less frequently
(2–7%) identified drainage pathways are to supraclavicular,
intrapectoral or intramammary nodes [6].
The overall and isolated internal mammary node involvement with metastasis is 23% and 5%, respectively, in patients
undergoing SLN biopsy of internal mammary nodes. Cserni
and Pap calculated that for all patients selected for lymphatic
mapping, internal mammary node involvement is <5% overall, and ∼1% for internal mammary node involvement without
axillary disease [14]. Biopsy of internal mammary nodes is
technically demanding, with a successful identification rate of
69% compared with 97% for axillary identification in one
series [15]. An intensive review on the subject of the management of internal mammary node metastases was published by
Klauber-DeMore et al. [16]. Metastases in internal mammary
chain nodes are known to be a prognostic factor, but it is
unknown whether upstaging by internal mammary SLN
biopsy to select patients for adjuvant radiotherapy to the
internal mammary chain will result in better local control or
survival. The use of internal mammary chain SLN biopsy may
have prognostic value when information obtained could
change therapy, as in patients with negative axillary nodes and
a primary tumour that does not select them for adjuvant
systemic treatment (<1 cm). However, the proportion of these
patients is expected to be very small and internal mammary
chain mapping is recommended to be used only in the context
of further studies on these topics in centres that have enough
experience of SLN biopsy [14, 16].
From this point of view, one may chose to inject superficially (intradermally) if the aim of lymphatic mapping is to
reveal only axillary sentinel nodes to avoid axillary dissection
in node-negative patients. Peri- or intratumoural injection is
more accurate at performing staging of other nodal basins
such as internal mammary chain nodes or staging of deep
tumours, which may not share the same lymphatic pathway as
the skin [6].
There is a wide variation in the isotope techniques used concerning choice and dosage of isotope, carrier, particle size,
timing of injection, and definition of a successful result. The
general similarity of outcome despite high variations in
technique indicates that SLN biopsy is a generally robust procedure. However, the optimum technique remains to be established.
Lymphoscintigraphy can be very helpful to localise SLN
pre-operatively, especially when lymph node basins other
than the axilla need to be explored. However, for axillary
identification of SLN, its additional value above handheld
gammaprobe identification has been discussed, as two studies
demonstrated no additional benefit of lymphoscintigraphy for
SLN identification in the axilla [17, 18].
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Case selection
Most of the reported experience with SLN biopsy includes
patients with clinical stage T1–2N0 [1]. The procedure seems
equally accurate for T1 and T2 tumours [19, 20]. Experiences
with sentinel node procedures of T3 tumours are limited, but
seem to be associated with increased false-negative rates [21].
It has been hypothesised that if lymphatics and lymph nodes
become progressively infiltrated with tumour cells, alternative
pathways of lymph drainage may occur, or the nodes may no
longer be able to retain tumour cells and the sentinel nodes
will not be visualised during lymphoscintigraphy [9]. Clinically suspicious non-SLNs were present in >50% of falsenegative SLN biopsy procedures in the Memorial Sloan Kettering Cancer Centre, and careful intraoperative palpation of
the axilla is therefore an essential component of SLN biopsy
procedure, especially when a high chance of nodal involvement is suspected [1]. Any suspicious nodes should be
removed for histopathological evaluation [22].
SLN biopsy has been used in patients with ductal carcinoma
in situ (DCIS). In a group of 87 patients with pure DCIS
lesions, Pendas found 5 patients (6%) with SLN metastasis.
Routine haematoxylin–eosin (H&E) staining detected the
metastasis in two of these five patients and immunohistochemistry (IHC) detected it in all five patients. Four patients
had high-grade DCIS and one patient had a 9.5 cm lesion of
low-grade DCIS. ALND was performed in all five patients
and the SLN were the only nodes found to harbour metastases
[23]. In another study of 76 patients with high-risk DCIS, nine
patients (12%) had positive SLNs and seven out of nine were
positive for micrometastases only. Six patients out of nine had
a completion axillary dissection, and one of the patients with a
SLN micrometastasis had an additional positive node on
routine H&E sectioning. Of 31 patients with DCIS with
microinvasion, three (10%) had positive SLN and two out of
three were positive for micrometastases only [24]. However,
there is no consensus about the indication of SLN biopsy for
DCIS. The significance of micrometastases in the sentinel
node from a true DCIS is questioned by DCIS experts [25]. In
a series of 103 cases of DCIS, treated between 1974 and 1992
with negative nodes on routine sections, additional serial step
sections and immunohistochemistry increased the number of
lymph node metastases to 12 (12%), all of which were
micrometastases. Clinical follow-up revealed 12% recurrence,
none of which involved the micrometastasis-positive group
[26].
The results regarding the use of SLN biopsy after neoadjuvant chemotherapy are inconsistent and based on small
numbers. Fernandez et al. [27] and Nason et al. [21] found
false-negative rates of 22% and 33% in 36 and 33 mapped
patients, respectively, while in other studies better results
were reported, with no false-negatives in 33 mapped patients
[28], zero in 29 mapped patients [29] and three in 43 mapped
patients [30]. SLN biopsy can be used without surgical
removal of the tumour before neo-adjuvant chemotherapy in
order to guide the choice for locoregional treatment after completion of the systemic treatment. In the setting of advanced
disease, SLN biopsy may play a role in estimating the
response to neoadjuvant chemotherapy [31].
There is no restriction for using SLN biopsy in non-palpable
tumours. Techniques may vary but the most minimally invasive approach is percutaneous imaging-guided (stereotactic or
sonographic guidance) diagnosis of the primary tumour, and
removal of the tumour and sentinel lymph nodes in one
session. A single surgical procedure is then possible in 82%
(164 out of 200) of carcinomas [32]. Peritumoural injection of
radioisotope or blue dye can be guided using the wire needle
localisation. If breast cancer is diagnosed with excisional
biopsy, no influence of excision volume or tumour location on
the identification rate or false-negative rate of SLN was
reported in one series of 181 excised tumours [33]. Large
upper quadrant biopsy cavities may preclude accurate staging
by disruption of the axillary lymphatics [1]. There are a
number of patient categories (male patients, elderly patients,
patients with multifocal tumours and those requiring profylactic operations) where SLN biopsy has only been used to a
limited extent and literature on this subject has not yet been
widely published.
Multifocal tumours are an exclusion criterion for performing SLN biopsy in most centres. Satisfying results in small
numbers [19] of such patients have been described [34].
SLN biopsy has been shown to be successful in a small
group of 16 male patients treated at the Memorial Sloan
Kettering Cancer Center. Mean tumour size was 1.3 cm, and
SLNs were identified in 15 out of 16 patients (93.75%). There
were 10 patients with negative nodes, of whom six had a mean
of 5.7 additional nodes removed, all of which were negative
[35].
Increasing patient age affects successful lymphatic mapping.
Not only are fewer sentinel nodes found, they are also found
less frequently [36]. Krag suggested that this was secondary to
the progressive replacement of the parenchyma of the lymph
nodes by fat [37]. A higher false-negative rate has not been
found [38], but the reported numbers are small.
In patients selected for prophylactic mastectomy, SLN
biopsy has been used as a diagnostic procedure as the mastectomy precludes the subsequent option of SLN biopsy in case an
unsuspected carcinoma is found. Of 57 patients treated using
these procedures, four (7%) experienced a significant change
in their surgical management: in two patients carcinoma was
found in the breast but they had negative sentinel nodes, and
another two had positive sentinel nodes by immunohistochemistry with no tumour in the breast. These latter patients
subsequently underwent a complete axillary dissection and no
additional metastatic nodes were found [39].
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Pathological analysis and micrometastases
In the past, many authors have reported finding micrometastases that were not found by routine section of the lymph
nodes, but were identified only by serial sectioning and
immunohistochemical staining. The increased yield of serial
sectioning with haematoxylin–eosin (H&E) staining has been
reported as ranging from 7% to 33% [40]. The Ludwig Breast
Cancer Study Group showed that micrometastatic nodal
disease, which was present in 9% of cases (detected by serial
sectioning and H&E staining), affected both disease-free
survival and overall survival after 6 years of follow-up [41]. A
recent update of the same patient population confirmed that
occult lymph node metastases detected using H&E and also
IHC were associated with worse disease-free and overall
survival in post-menopausal women [42].
The major disadvantages of introducing this approach in
clinical practice were cost and labour implications in processing all axillary lymph nodes through serial sectioning. The
SLN biopsy offers the possibility of examining lymph nodes
in great detail without these drawbacks [43].
Histopathological evaluation by taking step sections at
regular intervals increases the percentage of metastases found
in SLNs by ∼10% [44]. The exact number of step sections and
step size needed to reveal all metastatic foci in one node is
unknown and methods differ between centres, but a section
interval of 0.25 mm is proposed as a practical and accurate
approach [45, 46].
The use of immunohistochemistry for detection of tumour
cells in nodes negative according to H&E staining remains
controversial. Detection of occult micrometastases is of prognostic significance for the presence of metastases in nonsentinel nodes. In 93 patients whose sentinel node metastases
were <2.0 mm, 24 (26%) had non-SN metastases, which
included seven macroscopic, six H&E microscopic and 11
IHC metastases. The majority (63%) of the 101 patients with
SLN macrometastases had non-SLN metastases. Multivariate
analysis demonstrated that the size of the SLN metastasis,
extranodal hilar tissue invasion, tumour size and peritumoural
lymphatic vascular invasion were correlated with the presence
of non-SLN metastases [47]. In another study, also using IHC
for both SLNs and non-SLNs, patients with a single positive
SLN and patients with metastases <1 mm2 in the SLN had
significantly less non-SLN involvement than patients with
more than one positive node (40% compared with 78%,
respectively) and patients with macrometastases (27% and
49%, respectively) [48]. In the whole group of SLN-positive
patients, ∼50% had metastases in non-SLNs at subsequent
ALND [49]. However, in the group of patients with a positive
SLN, no subset of patients could be identified conclusively
without SLN metastases.
The benefit of the completion axillary lymphadenectomy in
patients with (micro)metastases in SLNs is unknown and
questionable because of the controversial role of locoregional
control for survival and the effect of adjuvant systemic
therapy and radiotherapy on residual disease in the axilla.
Trial Z0011 of the American College of Surgeons Oncology
Group (ACOSOG) addresses the clinical importance of the
metastases in the non-SLN, and the impact of ALND for SLNpositive patients on survival. In this trial, women with T1 and
T2 N0M0 breast cancer and a positive SLN were randomised
between ALND or observation of the axilla [50]. Primary end
point is overall survival, and secondary end points are surgical
morbidities and distant disease-free survival.
An ongoing European EORTC trial called AMAROS (After
Mapping of the Axilla Radiotherapy Or Surgery) has been
designed to determine the effectiveness of axillary radiation in
comparison to ALND and the associated morbidity of both
treatment modalities [51].
Once these trials have been concluded, it will be established
whether SLN biopsy alone or SLN biopsy followed by radiotherapy provide the same therapeutic benefits as ALND but
without the surgery-associated morbidity.
The influence of the upstaging of patients by finding micrometastases with thorough examination of SLNs on overall survival by the wider use of adjuvant chemotherapy is unknown.
Immunohistochemistry detects metastases in 12–29% of
patients with T1a/1b tumours who are node negative on H&E
staining, and may be used to recommend adjuvant systemic
therapy only because of these micrometastases [52]. The
ACOSOG Z0010 trial is a prospective evaluation of the significance of bone marrow and SLN micrometastases in SLNnegative patients processed using H&E [50]. In previous
studies, the presence of bone-marrow micrometastases was
associated with shorter relapse-free and overall survival, but
was not an independent prognostic factor in multivariate
analysis after a median follow-up of 12.5 years [53].
Reverse transcriptase–polymerase chain reaction of mRNA
only expressed in cancer cells has even more potential to detect
single groups of cancer cells, but there are still methodological
problems, and the clinical significance of single cells that
escape extensive histopathological investigation remains to be
established [45].
Accuracy of SLN biopsy
The success of SLN biopsy is hampered by false-negative
procedures: the wrong node may be removed and nodes
containing metastases may remain unrecognised in patients.
This can be detrimental because it may adversely affect local
control, and result in understaging of the patient and underestimation of the need for adjuvant systemic treatment.
False-negative biopsies have a complex aetiology with
patient- and tumour-related factors, such as re-routing of
lymphatic flow by tumour blockage of the lymph node and
variability in lymph flow, and also with non-patient-related
factors such as pathologist sampling error and surgeon inexperience [22]. The last factor has been well recognised in the
literature. It has been documented that there is a definite
1535
learning curve for the procedure. Results representing the mean
of five surgeons’ experiences in a one-centre setting indicate
that 23 and 53 cases are required to achieve success rates of
90% and 95%, respectively, in identifying the sentinel node
[54]. McMasters published the results of the largest prospective multi-institutional study to date, on 2148 patients with
SLN biopsies performed by 226 surgeons. They showed that
SLN identification rate and false-negative rates were significantly improved after the completion of 20 cases per surgeon
[38]. However, skills are not only related directly to the number
of procedures performed, but also appear to be related to the
technical skills of the surgeon. Initial experiences published
by Krag and colleagues of 11 surgeons participating in a multicentre study showed that the success rates differed significantly among the participating surgeons. One surgeon had
a minimum of a 79% identification rate, but a false-negative
rate of 7% after 43 procedures, while another surgeon had a
maximum of a 98% identification rate but a false-negative rate
of 27% after 51 procedures [37]. Guidelines for successful
implementation of the SLN biopsy have been published and
include: the use of a formalised protocol, patients being fully
informed, backup axillary dissection to validate the early
experience, and audits of individual and institutional results
[55, 56]. However, in a survey of 1000 randomly selected surgeons in the United States, a marked variation in the number
of SLN biopsies validated before performing SLN biopsy
was found: 28% of respondents performed ≤10 procedures
with subsequent ALND before performing SLN biopsy alone
[57]. The same was found in The Netherlands, where 43% of
surgeons who had done <10 SLN biopsies felt themselves
competent enough to omit ALND [58].
Although the sentinel node procedure has been proven to be
valid in numerous studies, all studies report a definite number
of false-negative procedures. The percentage of patients with
false-negative results cannot be calculated using the total
number of patients, as the majority of patients with T1 and T2
tumours are node-negative and SLN biopsy cannot be falsenegative in these cases. The false-negative rate is defined as
the number of false-negative procedures divided by the sum of
the true-positive and false-negative procedures. Sensitivity is
defined as the complement of it: the number of true positives
divided by the sum of the true positives and false negatives.
Obviously, sensitivity (and its associated confidence interval)
depends only on the fraction of node-positive patients. In a
meta-analysis of 18 phase I/II studies on 2500 sentinel node
biopsies with backup axillary dissection assessing the validity
of the technique, only studies with >50 node-positive patients
were used [59]. Sensitivity ranged from 83% to 100% and
pooled sensitivity was 91% (95% confidence interval = 89%
to 93%). These authors concluded that SLN biopsy is a safe
substitute of ALND. However, the possibility that ALND is
not a perfect standard for comparison is also considered, as it
may carry some risk for false-negativity for nodal disease on
its own [59]. The extent of the overestimation of sensitivity by
the use of conventional ALND (with routine H&E examination of one or two sections of each node) as a control for the
SLN procedure in one-arm studies has been calculated by Roy
and colleagues [60]. The true sensitivity declined from 94% to
85%, and the true negative predictive value declined from
97% to 91%, with 10% of true node-positive cases missed by
SLN biopsy and ALND.
The influence of inaccuracy of SLN biopsy on axillary
recurrence and survival is a complex matter and is currently
unknown. It will be influenced by the benefits of the procedure, such as more adequate pathological nodal staging,
against the pitfalls of understaging patients, omitting adjuvant
therapy and failure to treat regional disease. Factors determining these figures are patient selection, the numbers of expected
positive nodes and the wider use of adjuvant chemotherapy in
node-negative patients.
There have been three follow-up studies of SLN-negative
patients without subsequent treatment of the axilla. All have a
short follow-up but demonstrate a low level of regional recurrence of 0% in 67 patients after a median of 39 months [61],
0% in 285 patients after a median of <24 months [62], and 1%
in 100 patients after a median follow-up of 24 months [63].
The influence of SLN biopsy on regional disease control
and quality of life will be addressed in the ALMANAC (Axillary Lymphatic Mapping Against Nodal Axillary Clearance)
trial of the British Association of Surgical Oncology (BASO).
Patients with clinically negative axillary nodes are randomised between SLN biopsy, followed by axillary surgical
treatment only in cases of a positive sentinel node and conventional axillary surgical treatment [64]. In the National Adjuvant Breast and Bowel Project (B-32 trial) of the National
Cancer Institute, patients in the United States with clinically
negative axillary nodes will be randomised between SLN
biopsy followed by ALND, and SLN biopsy followed only
by ALND in cases of a positive SLN on H&E staining. All
negative sentinel nodes will be processed by immunohistochemistry in a blinded evaluation [65].
These trials should provide the final proof that sentinel node
biopsy is equivalent to ALND in regional disease control and
patient survival.
At the consensus conference on the role of SLN biopsy in
carcinoma of the breast in April 2001 (Philadelphia, USA),
surgeons were strongly encouraged to perform SLN biopsy
within the context of one of the ongoing American and European clinical trials [66].
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