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Axillary lymph node dissection in early-stage invasive breast cancer: Is it still
standard today?
Bernd Gerber, Kristin Heintze, Johannes Stubert, Max Dieterich, Steffi Hartmann,
Angrit Stachs, Toralf Reimer
Department of Obstetrics and Gynecology, University of Rostock, Suedring 81, 18059
Rostock, Germany
Correspondence Address:
Bernd Gerber, MD, PhD
Department of Obstetrics and Gynecology, University of Rostock,
Suedring 81, 18059 Rostock, Germany
e-mail: bernd.gerber@med.uni-rostock.de
Tel: +49 / 381 / 4401-4500
Fax: +49 / 381 / 4401-4599
Short running head: Axillary lymph node extirpation in early breast cancer
Key words: breast cancer, axillary lymph nodes, dissection, sentinel, prognosis,
metastases
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Responsibilities:
Bernd Gerber
idea, literature search, writing, coordination
Kristin Heintze
literature search, writing, macrometastases
and In which patient is axillary surgery
avoidable?
Johannes Stubert
literature search, writing tumor biology and
do lymph node metastases metastasize?
Max Dieterich
literature search, writing micrometastases
Steffi Hartmann
literature search, writing non-invasive
diagnostics
Angrit Stachs
literature search, writing non-invasive
diagnostics
Toralf Reimer
literature search, reviewing, writing,
coordination
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Abstract
Evaluation of axillary lymph node status by sentinel lymph node biopsy (SLNB) and
complete axillary lymph node dissection (ALND) are an inherent part of breast cancer
treatment. Increased understanding of tumor biology has changed the prognostic and
therapeutic impact of lymph node status. Non-invasive imaging techniques like
axillary ultrasound, FDG-PET or MRI revealed moderate sensitivity and high
specificity in evaluation of lymph node status. Therefore, they are not sufficient for
lymph node staging. Otherwise the impact of remaining micrometastases and even
macrometastases for prognosis and treatment decisions is overestimated.
Considering tumor biology, the distinction of axillary metastases in isolated tumor
cells (ITC, pN0[i+]); micrometastases (pN1mi), and macrometastases (pN1a) is not
comprehensible. Increasing data support the thesis that remaining axillary
metastases neither increase the axillary recurrence rate nor decrease overall
survival. It is doubtful that axillary tumor cells are capable to complete the complex
multistep metastatic process. If applied, axillary metastases are sensitive to systemic
treatment and are targeted by postoperative tangential breast irradiation. Therefore,
the controversy about the clinical relevance of tumor cell clusters or micrometastases
in SLN is a sophisticated but not contemporary discussion. Currently, there is no
indication for axillary surgery in elderly patients with favorable tumors and clinically
tumor-free lymph nodes. Nonetheless, a rational and evidence-based approach to
the management of clinically and sonographically N0 patients with planned breast-
conserving surgery and limited tumor size is needed now.
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Introduction
The axillary lymph node dissection (ALND) with removal and histopathological
examination of at least 10 nodes was an inherent part of surgical treatment of breast
cancer for a considerable time. During the last decade ALND was replaced by
sentinel lymph node biopsy (SLNB) in patients with clinically and sonographically
unsuspicious lymph nodes [1-3]. As a consequence the arm morbidity was reduced
markedly [4]. The SLNB requires estimated costs of 200-250 € per sentinel labeling
and 1,750 € per axillary surgery (Webgrouper DRG Research Group, University of
Muenster, Germany). Due to nationwide mammography screening in most industrial
countries, a greater number of smaller tumors without axillary lymph node
involvement is detected. More than 60% of all primary operable breast cancers do
not have axillary lymph node metastases. This in turn means that even SLNB
represents an overtreatment and is not indicated in the majority of patients. Non-
invasive methods like ultrasound, fluorodeoxyglucose positron emission tomography
(FDG-PET), and magnetic resonance imaging (MRI), have gained more importance
in staging the axillary lymph nodes. With improved insight into primary tumor biology
and metastasis behavior, the relevance of nodal status for adjuvant treatment
decisions is decreasing. Currently, in cases with positive sentinel lymph nodes (SLN)
the need for completion ALND is arguable. Nevertheless, there is an ongoing
discussion about the prognostic impact of isolated tumor cells (ITC, pN0(i+); < 0.2
mm), micrometastases (pN1mi; >0.2 mm to <2.0 mm), and macrometastases (pN1a;
>2.0 mm) in SLNs. The aim of this review was firstly to assess the imaging
techniques in axillary lymph node staging and secondly to evaluate the impact of
pathological lymph node status regarding prognosis and treatment decisions. The
key question to be answered is: Is there a chance to avoid axillary lymph node
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surgery in patients with early breast cancer? This review is not covering the issue of
axillary surgery following primary systemic treatment.
Materials and methods
We performed a selective literature search on PubMed database using the search
terms “breast cancer & axillary lymph nodes” and “ultrasound or sonography”, “MRI”
or “PET” and “sentinel lymph node and micrometastases” for the period from January
2002 to February 2011. Activated limits for search were “Female, Clinical Trial, Meta-
Analysis, Randomized Controlled Trial, English”. Contributions to international
congresses on breast cancer in 2009 (SABCS, San Antonio Breast Cancer
Symposium; ECCO, European Cancer Organization; EBCC, European Breast
Cancer Conference) and 2010 (ASCO, American Society of Clinical Oncology) were
included. The treatment recommendations of AGO-Mamma (the Breast Group of the
German Gynecological Oncology Working Group [5]) and the NCCN (National
Comprehensive Cancer Network) Guidelines [6] together with the Cochrane Library
[7] were also considered.
Imaging techniques
The exclusion of lymph node metastases by using non-invasive methods could
reduce the rate of axillary surgery. However, the experience of examiner and period
of availability are crucial for the diagnostic precision and prediction.
Axillary Ultrasound (AUS)
Clinically palpable axillary nodes are widely considered as contraindication to SLNB
in breast cancer. However, various studies have shown that clinical assessment of
axillary lymph nodes alone is inaccurate with a false-positive rate up to 40% [8, 9].
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Among patients with clinically uninvolved axillary lymph nodes, AUS has additional
value in detecting pathological axillary nodes [10, 11]. One third of pathological
involved lymph nodes could predicted preoperatively by ultrasound. AUS combined
with fine needle aspiration (FNA) biopsy of suspicious nodes has shown useful
results to guide preoperative surgical planning [12, 13]. However, the reported
sensitivity for AUS-FNA has varied considerably between different studies [14, 15].
Because of the risk of false-negative results, negative FNA findings are almost
followed by SLNB for confirmation.
According to guidelines, a SLNB is only indicated in patients with histologically
proven invasive breast cancer and clinically and sonographically insuspect lymph
nodes. In a systematic review including 16 studies, in which AUS without palpable
lymph nodes was performed, the node size and the morphology were used as criteria
for positivity [15]. For lymph node size sensitivity varied between 48.8% (95%
confidence interval [CI]: 39.6-58%) and 87.1% (76.1-94.3%) and specificity, between
55.6% (44.7-66.3%) and 97.3% (86.1-99.9%). If lymph node morphology was used
as the criterion for positivity, sensitivity ranged from 26.4% (15.3-40.3%) to 75.9%
(56.4-89.7%) and specificity, from 88.4% (82.1-93.1%) to 98.1% (90.1-99.9%). After
sonographically guided node biopsy, sensitivity varied between 30.6% (22.5-39.6%)
and 62.9% (49.7-74.8%) and specificity was nearly 100% (94.8-100%). More recent
studies confirmed these percentage rates for AUS-FNA showing sensitivities from
53% to 59% and specificities of 100% [16, 17]. AUS-FNA seems to be most useful in
the preoperative assessment of patients with large breast tumors (>2 cm) or with
lymph nodes that appear abnormal.
In conclusion, AUS is moderately sensitive and fairly specific in the diagnosis of
axillary metastatic involvement. These scattered variabilities are the result of the
missing clear criteria for evaluation of axillary lymph nodes by ultrasound. The
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classification of axillary lymph nodes on the basis of cortical thickness (cut-off 2.5
mm) and the appearance of the fatty hilum on sonography was effective for
predicting the presences of metastases in a recent study [18]. In future, addition of
contrast-enhanced color and power doppler ultrasound may improve the sensitivity of
AUS [19]. Malignant lymph nodes showed longer contrast enhancement duration
compared to benign lymph nodes.
FDG-PET
FDG-PET seemed to be an interesting approach as a non-invasive method of staging
the axilla in breast cancer patients. In a meta-analysis, 21 studies for clinical use of
FDG-PET in investigating axillary nodes were graded on methodological quality of
the single studies depending on number and selection of patients, technical details of
examination, pro- or retrospective design, and kind of lymph node biopsy [20]. As
shown in table 1 best quality studies showed a sensitivity, specificity, positive and
negative predictive value of around 80%, whereas in the poorer quality studies the
diagnostic accuracy was higher. However, the variability between study designs has
made it difficult to compare and aggregate the results of these studies. As well,
caution must be exercised when analyzing results from older studies because of the
increased accuracy of the newer scanners [20].
In a current meta-analysis of 25 studies including 2,460 patients a trend to lower
sensitivity (37–85%) in the most recent published and higher quality studies (year
2005-2009 and sample size >25) was detectable, whereas the specificity (84–100%)
remained high [21]. This meta-analysis also indicated that the sensitivity of PET is
not sufficient to detect small metastatic deposits (micrometastases). Interestingly, the
metabolic activity is variable according to the histopathological subtype of breast
cancer. The mean tumor maximum standardized uptake value SUV(max) in lymph
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node metastases of estrogen receptor (ER)-positive, triple-negative and human
epidermal growth factor receptor 2 (HER2)-positive tumors was 6.6, 11.6, and 6.6,
respectively [22].
In conclusion, sensitivity and specifity of PET is comparable to AUS, but because
AUS is less expensive, AUS remains standard of care these days. The combination
of AUS and PET seems to be improved the diagnostic accuracy [23]. The additional
benefit of an assessment of distal metastatic spread provided by PET requires further
investigation [21].
MRI
Breast MRI assessment of breast cancer patients considered for primary surgical
treatment is being used more frequently, especially if breast-conserving surgery
(BCS) is planned. During such assessment, regional lymph nodes are usually
included. Using different contrast agents, sensitivity ranged from 63–100% and
specificity from 56–100% (Tab. 2). Like FDG-PET, contrast-enhanced MRI accuracy
showed a close relationship with histopathologic subtypes of invasive breast cancer
and its limitation in detection of axillary micrometastases [29, 31, 32]. Adding axillary
MRI sequentially after AUS did not significantly improve detection of positive nodes in
AUS-negative cases (false-negative rate of 28% and false-positive rate of 18% for
MRI) [16].
Taken together, all imaging techniques are of high specificity and moderate
sensitivity especially in cases with small lymph node metastases. The value of
combined imaging techniques for improving the diagnostic accuracy should be
considered critically with respect to benefit-cost-ratio.
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In the following we have to discuss three fundamental questions: Firstly, is it really
important to know the nodal status for treatment decisions? Secondly, is there a
chance to avoid axillary surgery in some cases and how can we select these
patients? And thirdly, how is the biological behavior of metastatic involved lymph
nodes left in situ (separated by tumor cluster size)?
Lymph node status for prognosis and treatment decision
Since Halsted first defined the issue of axillary lymph nodes 100 years ago, the
lymph node status is the basis for prognosis and treatment decision in breast cancer
[33]. It is well known that the prognosis declines with increasing number of metastatic
lymph nodes or more precisely, with an increasing lymph node ratio [34, 35]. Larger
breast tumors tended to be associated with a greater number of metastatic involved
axillary lymph nodes than smaller tumors, indicating that a higher number of involved
lymph nodes reflects a longer tumor growth time. In a multivariable logistic regression
analysis the molecular subtypes of breast tumors (luminal, luminal/HER2-positive,
HER2-positive/ER-negative/progesterone receptor (PgR)-negative, and basal-like)
had a predictive effect for nodal involvement (p=0.000001). Using the luminal
subtype as reference, the basal subtype has an odds ratio for axillary lymph node
involvement of 0.53 (95% CI: 0.41-0.69) in a model using core biopsy data [36]. A
Belgian group reported higher likelihood of being lymph node positive for triple-
positive tumors (HER2 positive/ER positive/PgR positive) compared to other
subtypes (56.2 vs. 35.7%) [37]. Patients older than 70 years were more likely to have
positive nodes with increasing age. The effect of age in older women was most
pronounced for small tumors. On the contrary, for very large tumors, the risk of lymph
node involvement even decreased with increasing age [38]. Other studies reported
no increase of lymph node involvement in elderly patients when investigating the
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relationship in pT-strata and adjusting for other prognostic factors. Taken together,
axillary lymph node involvement is the result of different factors and lymph node
status at all does not reflect the aggressive behavior of the tumor correctly [39].
Tumor aggressiveness especially in patient without axillary lymph node involvement
has primarily to do with biological features of the tumor cells from the primary tumor.
Based on this, it seems reasonable that poor outcome depends more on the tumor
biology than on lymph node involvement [40-44]. Gene expression analyses of the
primary tumor indicated that 51% of lymph node-negative tumors and 49% of lymph
node-positive tumors have a poor prognostic signature [45]. The value of gene
expression profiling as a prognostic tool in clinical practice is currently being
evaluated in two large, prospective, randomised studies (TAILORx, MINDACT).
Lymph node status is a good indicator of tumor stage related to the time point of
diagnosis, but it does not reflect the real tumor biology, metastatic behavior as well
as sensitivity to systemic treatment. Extensive characterization of the primary tumor
will be available by gene signatures in future [44-46]. Nevertheless, nodal status is
still an established parameter for treatment decisions in current guidelines. According
to the NCCN guidelines the indication for post-mastectomy radiotherapy in all
patients or for adjuvant chemotherapy in ER-positive/HER2-negative disease is
linked to the number of involved lymph nodes [6].
This adherence to treatment recommendations on the basis of axillary nodal status
was also observed in own previous work. We have shown that the knowledge of
pathologic nodal status influences the indications for postoperative chemotherapy
and post-mastectomy radiotherapy [47]. Re-discussion of postoperative tumor board
records without information regarding axillary lymph node status resulted in adjuvant
treatment recommendations different from the current guidelines in one third of all
cases (72 of 207 patients), especially in carcinomas with present lymphangiosis.
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However, this finding is the result of guidelines which are mostly based on elderly
studies with nodal status as an in- or exclusion criterion. More recent studies have
confirmed the effectiveness of chemotherapy and trastuzumab even in high risk,
node-negative patients [48, 49].
Engel et al. reported 15 reasons to stop axillary surgery entirely [50]. This paper was
hypothesis generating in 2006 without changing current surgical practice. The
author’s discussion is based on the hypothesis that locoregional and distant
metastases develop over time from disseminated tumor cells that originate from the
primary and not from the lymph nodes. The current pros and contras for axillary
lymph node status and associated treatment decisions are summarized in table 3
using some arguments published by Engel et al..
Definition of patient subgroups without any axillary surgery
SLNB is a minimal invasive procedure with the same oncologic safety as ALND and
low (but not zero) morbidity [51-53]. Therefore, SLNB is suggested to be an optimal
approach to reduce the morbidity by the assessment of axillary status in clinically
node-negative breast cancer. But the indication for SLNB in all clinically node-
negative patients is questionable because at least 70% of these patients are
pathologically tumor-free in the axillary nodes. Two randomized trials investigated the
use of ALND versus no axillary surgery in elderly patients [54, 55]. A third trial
randomized patients without any axillary surgery to no axillary treatment versus
axillary radiotherapy (ART) [56]. The results of all three studies showed a very low
rate of axillary recurrences, even in the arms without axillary surgery, and
comparable disease-free and overall survival (Tab. 4).
In an observational study with 671 consecutive patients, aged >70 years, and a
clinically tumor-free axilla, 172 received and 499 did not receive axillary dissection.
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After a median follow-up of 15 years, there was no significant difference in breast
cancer mortality between the axillary and no axillary clearance groups. Ipsilateral
axillary recurrence rate was zero in the axillary dissection group and relatively low in
the no axillary dissection group: 5.8% overall and 3.7% for pT1 patients [57]. These
axillary recurrence rates in the non-operated group were much lower than the rate of
pathological nodal involvement in the axillary dissection group (33.7% pN+ overall
and 29% pN+ for pT1 patients). The authors concluded, that due to a very low
cumulative incidence of axillary recurrence in elderly patients with BCS both, SLNB
and ALND can be avoided. Axillary dissection should be restricted to the small
number of patients who will later develop apparent axillary disease.
Axillary recurrence is rare, although four-times more common in younger women
(<40 years) than in older patients (50-60 years) [58]. Current NCCN guidelines
consider the performance of ALND as optional in patients who have particularly
favorable tumors, in patients for whom the selection of adjuvant systemic therapy is
unlikely to be affected, for the elderly, or those with severe comorbid conditions [6].
There is no clear statement in the NCCN guidelines in which patients the SLNB can
be avoided.
ART has been used instead of or in addition to axillary sampling or ALND. In 2004,
Louis-Sylvestre et al. published results of a prospective randomized trial comparing
lumpectomy plus ART versus lumpectomy plus ALND (n=658; median follow-up 180
months; 21% node-positive in the ALND group) [59]. Overall survival rates were
identical in both groups, recurrences in the axillary nodes were less frequent in the
ALND group (1% versus 3%, p=0.04). As an alternative to completion ALND for
SLNB positive patients, ART has been suggested [60]. This concept is undergoing
prospective evaluation by the EORTC trial, “After Mapping of the Axilla: Radiotherapy
versus Surgery?” (AMAROS) [61]. The trial is full recruited, but definitive data will not
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be available for years. ART in the setting of no prior axillary surgery has generally
been associated with less morbidity than that seen with ALND. The incidence of
morbidity after SLNB combined with ART has not been well characterized [62].
In situ left metastatic involved axillary lymph nodes and prognosis
Macrometastases
SLNB trial arms with immediate conventional ALND showed false-negative rates up
to 9.8% regarding accuracy of SLNB [2, 63]. Even after ALND of level I and II, up to
30% of positive lymph nodes remain in the axilla, 15% of these present as 'skip
metastases' [64, 65]. Rudenstam et al. reported nodal involvement in 28% of the
patients who had axillary dissection [54]. Isolated lymph node recurrences are rare
(<2%) in patients with BCS and lymph node-positive disease [58, 66, 67].
The presentation of the prospective, multicentric ACOSOG Z0011 trial at the ASCO
Congress 2010 was a landmark for the discussion about surgical options in pN+
patients after SLNB. According to the protocol, nearly 900 patients with clinically T1-2
cN0 cM0 breast cancer and BCS with metastatic involved sentinel nodes (routine
hematoxylin and eosin [H&E] detected) were randomized to no further axillary
dissection or completion ALND [68]. Targeted enrollment was 1,900 women, but the
trial closed earlier due to lower than expected accrual and event rates. Both arms
were comparable with respect to pathological tumor size, grading, histological tumor
type, hormone receptor status and systemic treatment. After a median follow up of
6.3 years there were no significant differences between SLNB alone and SLNB plus
ALND arms concerning 5-year local recurrence rate (1.6% versus 3.1%), 5-year
disease-free survival (83.9% versus 82.2%), or 5-year overall survival (92.5% versus
91.8%). The local axillary recurrence rate was 0.9% for SLNB alone and 0.5% for
SLNB+ALND [68, 69]. Because all patients were treated with opposing and
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tangential field irradiation, a local effect on the axilla could not be excluded
completely, however it seems very unlikely in this dimension [58, 66].
According to these findings the German AGO Breast Group has adapted the current
guidelines in March 2011. The completion ALND is not longer recommended (only
“+/-“ grade of recommendation) in patients with positive sentinel nodes and: cT1/2,
cN0, less than three sentinel nodes involved, BCS plus tangential breast irradiation,
and no alternative ART [5]. The ACOSOG Z0011 data are supported by a
retrospective SEER database analysis (1998-2004) including 26,986 patients with
positive sentinel nodes [70]. Among those, 4,425 (16.4%) underwent SLNB alone,
and 22,561 (83.6%) underwent SLNB with completion ALND. Contrary to the Z0011
study, the SEER analysis was not restricted to BCS (21.2% with total mastectomy in
the SLNB alone arm). At a median follow-up of 50 months, there were no statistically
significant differences in overall survival between patients with SLNB alone versus
complete ALND.
Of 97,314 patients from the US National Cancer Database who underwent SLNB and
who had nodal metastases, 20.8% underwent SLNB alone, and 79.2% underwent
SLNB with complete ALND [71]. In patients with macroscopic nodal metastases and
a median follow-up of 63 months, there was a non-significant trend towards better
outcomes for complete ALND compared to SLNB alone: axillary recurrence HR=0.58
(95% CI: 0.32-1.06) and overall survival HR=0.89 (95% CI: 0.76-1.04). A randomized
controlled trial with 30 years follow-up indicated that clearing the internal mammary
or axillary lymph nodes has no impact on long-term survival [72]. Moreover, tumor
location affects the frequency of lymph node metastases but not the survival. Janni et
al. showed that 25.8% of patients with a tumor in the medial quadrant of the breast
have axillary lymph node metastases compared with 35.5% of patients with a lateral
localized breast tumor [73]. Despite the 10% difference, survival time was similar for
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both tumor locations. There is no additional survival advantage in clearing level III of
the axilla compared with clearing restricted to levels I and II [74].
The Memorial Sloan-Kettering Cancer Center (MSKCC) developed nomograms to
predict the likelihood of a positive sentinel node or finding additional positive non-
sentinel nodes in patients with involved SLNs [75, 76]. The nomograms are a
statistical approach for calculation metastatic axillary risk by combining different
histopathologic factors (plus age, which is incorporated in the sentinel nomogram)
and are available online (www.mskcc.org/mskcc/html/15938.cfm). Although the first
published MKSCC nomogram for patients with positive SLN has been validated by
numerous centers, clinicians were unlikely to change their surgical plan based on
nomogram results [77]. Additionally, this model seems not reliable predictive for
positive non-SLN in cases with micrometastatic positive SLN [78].
Micrometastases
The SLN is the most likely site of regional metastasis, and gives pathologists the
opportunity to concentrate detection techniques on one or a few lymph nodes. The
use of step sectioning and immunohistochemistry for SLN analysis results in a higher
detection rate of micrometastases (International Union Against Cancer classification:
pN1mi, >0.2 mm to <2.0 mm) and isolated tumor cells (pN0(i+), <0.2mm) [79-81].
Pathologists should follow published recommendations for the management of SLN
[2, 82, 83].
Breast cancer micrometastases have lower tumor proliferation rates and
angiogenesis than breast cancer macrometastases [84]. These characteristics may
explain a discrimination of micro- and macrometastases. The distinction between
pN1mi and pN0(i+) depends on 0.1 mm. Why should 0.1 mm in tumor cluster size
determine different prognosis? Any tumor spread to axillary lymph nodes indicates
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that the tumor cells are able to metastasize. Therefore the meaningfulness of
distinction between pN1mi and pN0(i+) and also pN1a must be challenged [85].
Tan et al. reported a significant decreased disease-free and overall survival for
pN0(i+) patients (HR=1.7 [95% CI: 1.0-2.9]) compared to pN0(i-) in a retrospective
analysis with 17.6 years follow-up [86]. Many studies confirmed that the occurrence
of pN1mi and pN0(i+) depends on the tumor biology and the location of
micrometastases (sinusal versus parenchymal) [66, 87-94]. However, the clinical
relevance and therapeutic implications of pN1mi and pN0(i+) in the SLN remain a
matter of debate.
A recent meta-analysis including 297,533 patients from 58 studies published
between 1977 and August 2008 divided patients into three categories according to
the method of pathological assessment of the lymph nodes: cohort studies with
single-section examination (n=285,638 patients), occult metastases studies with
retrospective examination of negative lymph nodes by step sectioning and/or
immunohistochemistry (n=7,740 patients), and SLNB studies with intensified work-up
of the sentinel but not of the non-SLN (n=4,155 patients) [95]. In the cohort studies,
axillary lymph node metastases of 2 mm or less in diameter were associated with
poorer overall survival (HR=1.44, 95% CI: 1.29-1.62), occult metastases were
associated with poorer 5-year disease-free survival (RR=1.55, 95% CI: 1.32-1.82)
and overall survival (RR=1.45, 95% CI: 1.11-1.88), although these endpoints were
not consistently assessed in multivariable analyses. SLNB studies are limited by
small patient numbers, SLNB alone or complete ALND in pN1mi and/or pN0(i+),
different systemic treatments, and short follow-up.
As shown in table 5, nine of 12 studies reporting survival outcome, demonstrate no
associations between occult metastases and overall survival. The MIRROR study
(Micrometastases and Isolated tumor cells: Relevant and Robust or Rubbish) has
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found pN0(i+) and also pN1mi to be indicators of poor prognosis compared to pN0
[89]. The MIRROR-trial is also a retrospective cohort study including only patients
with favorable tumor characteristics for whom adjuvant systemic treatment was not
indicated according to the Dutch treatment guidelines. ITCs or micrometastases in
regional lymph nodes were associated with a reduced 5-year rate of disease-free
survival among patients who did not receive adjuvant therapy (HR 1.5 [95% CI: 1.15-
1.94] for ITC and HR 1.56 [95% CI: 1.15-2.12] for pN1mi). In patients with ITC or
micrometastases who received adjuvant therapy, disease-free survival was
significantly improved as compared with the node-positive, no-adjuvant-therapy
cohort [89].
A recent study showed that the actual rate of positive non-SLNs for patients with SLN
micrometastases or ITCs who underwent completion ALND was significantly less
than that predicted by the MSKCC nomogram [104]. The rate of axillary recurrence
for included 116 patients with stage I to III breast cancer was negligible, regardless of
the extent of axillary staging. The NSABP trial B-32 investigated the clinical
significance of occult metastatic disease in selected sentinel nodes – primary
pathologically negative [96]. Occult metastases were detected in 15.9% of 3,887
patients: 11.1% with ITC clusters, 4.4% with micrometastases, and 0.4% with
macrometastases. Occult metastases were an independent prognostic variable;
however, the magnitude of the difference in overall survival at 5 years was small
(94.6% with and 95.8% without detectable metastases). The authors conclude, that
identification of occult metastases does not appear to be clinically useful for patients
with newly diagnosed disease in whom systemic therapy can be recommended on
the basis of the characteristics of the primary tumor.
Do lymph node metastases metastasize?
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The key question, whether regional lymphatic metastases can further metastasize to
distant organs like the liver, lung or bone or not, is currently unanswered [105]. The
process of metastatic spread is highly complex involving more than 250 genes,
multiple mutations and cell evolutions, and is organotropic [105-109]. Metastatic
spread of tumor cells to regional lymph nodes via lymphatic vessels is not a passive,
but a highly complex active process with specific interaction of tumor cells and
lymphatic tissue [110]. If radio-labeled tumor cells are injected into the afferent nodal
lymphatic vessel, they rapidly appear in the efferent lymphatic vessel and the
thoracic duct, showing, that the lymph node is not only a simple cell-filter [111].
Metastasis to lymph nodes is positively correlated to enhanced peritumoral
lymphangiogenesis, which results from expression of vascular endothelial growth
factor (VEGF)-C. VEGF-C binds to the VEGF receptor (VEGFR)-3 on lymphatic
endothelial cells and induces lymphangiogenesis [112, 113]. High levels of VEGF-C
and VEGFR-3 are not only associated with an increase of lymph node metastasis but
also with poor overall survival without affecting the growth of the primary tumor.
VEGF-C-induced lymphangiogenesis in SLN promotes tumor metastasis spread to
distant sites [114, 115]. These results implicate the possibility of further metastasis to
distant organs from the lymph nodes via the thoracic duct. According to the soil and
seed hypothesis of Paget the fate of a circulating tumor cell is also strongly controlled
by the organ of metastasis resting upon complex cell-cell and cell-matrix interactions.
Key players in lymph node metastasis are the chemokines CXCL12 and CCL21,
produced by the lymphatic tissue. They are attractants for tumor cells which express
the chemokine receptors CXCR4 or CCR7 [110]. High expression of these receptors
is associated with higher incidence of lymph node metastasis in breast cancer
patients [116, 117]. A significant number of patients show discordant quantitative
expression of molecular markers between primary and nodal disease indicating a
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organotropy [118]. This concept of organ site specificity corroborates the hypothesis,
that lymph node metastases do not further spread or if they do only into lymph nodes
down stream the metastatic one. The lack of lung metastases in patients with a
palliative peritoneo-venous shunt in cases of malignant ascites impressively
emphasizes this hypothesis [119]. But as a result of genetic instability, metastases
that are initially of clonal origin, continuously acquire a genetic heterogeneity which
could result in metastatic transformation of some cells, that permit a further spread to
distant sites [119]. However, animal studies with inhibition of lymph node metastases
are inconsistent and do not clearly confirm the hypothesis of a “metachronous
seeding” [120].
It is widely accepted that also small tumors could early spread to distant sites.
Micrometastases have occurred in 20-40% of carcinomas in the absence of other
detectable signs of spread [88, 121]. Micrometastases as well as the number of
circulating tumor cells are associated with the incidence of distant metastases as well
as with the overall survival of breast cancer patients [122-124]. For patient’s
prognosis, these parameters of tumor spread could be more relevant than the
likelihood of a metastasis from lymph nodes [125, 126]. Therefore we need effective
treatment strategies for these probably stem cell like tumor cells [127-130]. In
conclusion, there is increasing doubt, that lymph node metastasis are able to
metastasize. The life threatening effect of lymph node metastases is overestimated.
Conclusion:
Increasing data suggest that surgical management of the axilla by SLNB or ALND
has no influence on recurrence-free and overall survival in all breast cancer patients.
However, sample size and length of follow-up are substantially different between
cited studies, so that definitive conclusions can not be made. Case reports suggest
20
that patients with axillary metastases alone after SLNB, who had undergone delayed
ALND, have no prognostic disadvantage. With the exception of the ACOSOG Z0011
trial, there are no data from large randomized clinical trials that support or refuse this
hypothesis. There is high evidence to avoid any axillary surgery in elderly patients
with favorable tumor biology (older than 60 years, pT1, G1-2, hormone sensitivity, no
clinically and sonographically involved axillary lymph nodes).
It might be academically interesting to discuss about micrometastases and
immunohistochemically detected tumor cells or tumor cell clusters in the SLN. On the
other hand, we urgently need to initiate randomized clinical trials to avoid any axillary
surgery in most patients with breast cancer and no clinically considerable enlarged
axillary lymph nodes. As the ACOSOG Z0011 trial has shown, patients can be
motivated to participate in randomized trials with restricted axillary surgery.
Nonetheless, a rational and evidence-based approach to the management of
clinically and sonographically N0 patients with planned BCS and limited tumor size is
needed now. Risk estimates using the MSKCC nomogram to predict likelihood of
SLN metastases may be helpful for the decision regarding pro or contra axillary
surgery outside from clinical trials. In patients with BCS without any axillary surgery
an additional regional treatment effect can be expected by postoperative external
beam radiotherapy because traditionally defined tangential breast fields include the
majority (60%-90%) of level I lymph nodes [62].
Surgeons, radiologists, and pathologists should work together to avoid unnecessary
axillary surgery. There is an urgent need for simple but reproducible and validated
sonographic criteria to categorize patients as cN0/iN0 (imaging N0) correctly in the
preoperative setting. Future studies should also include patients with total
mastectomy and favorable tumor biology to prove the value of axillary clearance for
local recurrence and survival rates. It took some decades to replace the radical
21
Halsted theory by new paradigms including BCS. Similarly, the performance of
axillary surgery has to be questioned.
22
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Tab. 1: Diagnostic accuracy of FDG-PET in staging axillary nodes. Summarized
results of a meta-analysis [20].
Quality of
Study*
Number
of Studies
/ Pts.
Sensitivity
(%)
Specificity
(%)
Positive
Predictive
Value (%)
Negative
Predictive
Value (%)
A (best)
3 / 675
78
85
80
84
B
4 / 222
67
89
82
78
C
8 / 207
96
84
78
97
D (poor)
6 / 167
78
99
99
76
* depending on number and selection of patients, technical details of examination,
pro- or retrospective design, method of lymph node biopsy.
Tab. 2: Diagnostic accuracy of MRI in staging axillary nodes.
Author
Number
of pts.
Sensitivity
(%)
Specificity
(%)
Positive Predictive
Value (%)
Negative Predictive
Value (%)
Harada (2007)
[24]
33
86
97
91
96
Stadnik (2006)
[25]
10
100
80
80
100
Murray (2002)
[26]
47
100
56
38
100
Michel (2002)
[27]
20
82
100
100
-
Memarsadeqhi
(2006) [28]
22
100
98
98% accuracy
Suzuma
(2002) [29]
62
91
100
91% accuracy
Stets
(2002) [30]
9
63
86
75% accuracy
40
Tab. 3: Reasons for and against knowledge of lymph node status for treatment
decisions.
Contra
Pro
Tumor biology is more important than
nodal status regarding prognosis and
treatment
Treatment mismatch if node status is
unknown (especially in ER-positive,
HER2-negative disease)
Any axillary surgery increases costs
and morbidity
dose-dense and/or dose-intense
chemotherapy in patients with 4 or more
involved lymph nodes
Axillary recurrences are very seldom,
even in node positive patients
Resection of metastases as a potential
source of distant metastases
Delayed surgery of involved lymph
nodes is without overall survival
disadvantages
Tumor volume reduction
Nodal status as an indicator for or
against radiotherapy after mastectomy
Distant metastasis even in pN0 patients
Seldom axillary metastases in patients
with medial tumor location,
pN for staging, study inclusion and
comparison of outcome necessary
Systemic treatment acts also in axillary
lymph node metastases
There is no evidence that lymph node
metastases are able to metastasize
Leaving involved lymph nodes in situ
does not increase axillary recurrences
or metastasis
Tab. 4: Prospective randomized clinical trials comparing axillary lymph node
dissection versus no axillary surgery. Veronesi et al. randomized patients with
no axillary surgery to none further treatment versus radiotherapy of the axilla.
Pts.
N
Follow
-up (mo)
Axillary
recurrences
DFS
OAS
Rudenstam
(2006) [54]
>60 y, pT1-2*
cN0,
473
78
0.9 vs 2.5%
67% vs 66%
p=.7
75% vs 73%;
p=.8
Martelli
(2005) [55]
>65 y, pT1
cN0, Tam
219
60
0 vs 1.8%
95% both
p=.9
96% both
p=.9
Veronesi
(2005) [56]
>45 y, Tumor
<1.2 cm, cN0,
435
63
0.5 vs 1.5%
97 vs 95%
p=.19
99 vs 97%
p=.23
* 42% pts. with tumors >2 cm, y = years, mo = months
DFS = disease-free survival
OAS = overall survival
41
Tab. 5: Summary of studies reporting outcome (follow-up >24 months) of
patients (case numbers >150) with isolated tumor cells pN0(i+) and
micrometastasis pN1mi (International Union Against Cancer classification, >.2 mm
to <2.0 mm) in sentinel lymph node (SLN)
Author
Study design
Accrual period
N
Follow-up
Conclusions
Weaver
(2011)
[96]
prospective,
multicenter
1999-2004
3,887
95.6 mo
Occult metastases (11.1% pN0(i+), 4.4% pN1mi, 0.4%
pN1a) in initial negative SLNs have a small, but
significant impact on DFS, DMFS, and OAS
Maaskant-Braat
(2011) [97]
population-based
1996-2006
6,803
50 mo,
36 mo for
pN0(i+)
pN1mi or pN0(i+) in the SLNB did not convey any
significant OAS difference compared with pN0 pts.
(discrimination between pN1mi and pN0(i+) since 2003)
Langer
(2009) [80]
prospective cohort
1998-2002
150
77 mo
No significant differences for OAS, LRR, and DMFS
between pN0 and pN1mi groups
de Boer
(2009) [89]
population-based
before 2006
2,707
5.1 y
pN(i+) and pN1mi status were associated with reduced
5y-DFS in cases without adjuvant therapy
Montagna
(2009) [98]
prospective cohort
1997-2002
3,158
6.3 y
Among SLNB group, no difference in outcome between
pts. with pN0 or minimal lymph node involvement (ITC,
micrometastasis 0.2-1 mm, micrometastasis 1-2 mm)
Reed
(2009) [92]
prospective,
multicenter
1996-2005
1,259
4.9 y
pN1mi, but not pN0(i+), was associated with additional
positive nodes (27%) and with increased distance
recurrence rate
Gobardhan
(2009) [99]
prospective cohort
1999-2007
703
40 mo
Risk of distant metastases higher in patients with pN1mi
than in pN0 group, but no significant differences in DFS
or OAS between pN0 and pN1mi
Tan (2008) [86]
retrospective
1976-1978
368
17.6 y
Clear trend toward worse outcome (DFS, BCSS) with
increasing tumor cluster size in the lymph nodes
Cox
(2008) [100]
retrospective review
1997-2004
2,381
1.5-2.1 y
Poorer OAS/DFS for pts. with pN1mi compared with pN0
pts.; additional axillary disease in 9.3% of pts. with
pN0(i+)
Nagashima
(2006) [101]
prospective cohort
1999-2004
375
30 mo
No difference in DMFS between pN0 and pN1mi pts.
Imoto (2006)
[102]
retrospective cohort
1998-2000
165
73 mo
No difference in 6y-DFS between pN0(i+)/pN1mi group
and pN0 pts.
Fan (2005) [103]
retrospective
1997-2002
390
31.1 mo
No difference in LRR between pN0 and pN1mi pts.
OAS = Overall survival, DMFS = Distant metastases-free survival, DFS = Disease-free
survival; BCSS = Breast cancer-specific survival, pts. = patients; LRR = Local recurrence
rate; mo = months; y = years; ITC = isolated tumor cells
