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Review

Sentinel node biopsy in breast cancer revisited

Mohammad Omair a, Dhafir Al-Azawi b,c, Gregory Bruce Mann a,b,*aDepartment of Surgery, Royal Melbourne Hospital, University of Melbourne, AustraliabThe Breast Service, Royal Melbourne and Royal Women’s Hospital, Melbourne, AustraliacSt James’s Hospital, Trinity College, Dublin, Ireland

a r t i c l e i n f o

Article history:

Received 15 September 2013

Received in revised form

23 November 2013

Accepted 23 December 2013

Available online 16 February 2014

Keywords:

Breast cancer

Sentinel node biopsy

Review

* Corresponding author. The Breast Service, R393476301.

E-mail address: Bruce.mann@mh.org.au (1479-666X/$ e see front matter ª 2014 RoyalSurgeons in Ireland. Published by Elsevier Lthttp://dx.doi.org/10.1016/j.surge.2013.12.007

a b s t r a c t

The axilla has long been a focus of clinicians’ attention in the management of breast

cancer. The approach to the axilla has undergone dramatic changes over the last century,

from radical and extended radical excisions, through the introduction of sentinel node

biopsy for node negative patients to the current situation where selective management of

those with nodal involvement is being introduced.

The introduction of lymphatic mapping and sentinel node biopsy in the 1990’s has been

key to the major changes that have occurred. In less than 20 years it has moved from a

hypothesis to a situation where it is the default approach to almost all clinically node

negative patients and is being considered in other situations where axillary clearance was

previously considered standard. This article reviews the development and introduction of

sentinel node biopsy, its current uncertainties and limitations, and possible future

developments.

ª 2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and

Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Introduction

Axillary nodal surgery has been an important part of treat-

ment for invasive breast cancer since Halsted and others

demonstrated that a complete axillary dissection as part of

the radical mastectomy resulted in very low rates of loco-

regional recurrence.1 Axillary lymph node status remains an

important prognostic factor and determinant of adjuvant

therapy. The presence and number of involved lymphnodes is

the best indicator of the risk of distant recurrence and death

from breast cancer. The status of axilla has also been

oyal Melbourne and Roy

G.B. Mann).College of Surgeons of Edd. All rights reserved.

historically used to direct the need for and choice of adjuvant

chemo/radiotherapy treatment. Excision of involved axillary

lymph nodes has traditionally been considered essential in

maximizing loco-regional control.2

In the National Surgical Adjuvant Breast Program NSABP

B043 study, patients treated with radical mastectomy, total

mastectomy with axillary radiation and total mastectomy

alone were compared and followed for 25 years, with similar

overall survival in all groups. Axillary surgery or irradiation

was found to lead to significant improvement in loco-regional

control with 5% axillary recurrence, compared to 20% in

population who did not undergo any axillary treatment.

al Women’s Hospital, Suite 12, Parkville 3052, Australia. Tel.: þ61

inburgh (Scottish charity number SC005317) and Royal College of

t h e s u r g e on 1 2 ( 2 0 1 4 ) 1 5 8e1 6 5 159

Notably, the rate of axillary recurrence in the group without

axillary treatmentwas substantially less than the incidence of

axillary nodal metastasis in the group undergoing radical

mastectomy e indicating that not all pathologically involved

nodes are destined to become clinically evident. Despite evi-

dence from the NSABP-B04 of the lack of impact of axillary

dissection on overall survival, it remained a routine part of

surgical management of invasive breast cancer until the

1990s.

Sentinel node biopsy (SNB)

There is significant morbidity associated with ALND (Axillary

lymph node dissection), including seroma formation,

impaired shoulder function, neuropathy and in particular arm

lymphoedema. Some level of lymphoedema was reported by

16%e28% of patients post-operatively.4e6 As the size of breast

cancers diagnosed through screening programs reduced, the

proportion of elective and non-therapeutic axillary lymph

node dissections increased. For every 100 ALNDs in patients

with T1 and T2 tumours, 70 will not contain cancer7 and the

scene was set for a less invasive method of staging the clini-

cally node negative axilla.

The concept of a sentinel node was first introduced by

Cabanas following his work on carcinoma of the penis8 and

then Morton9 developed and demonstrated the accuracy of

lymphatic mapping and sentinel node biopsy in malignant

melanoma. In the early 1990s it was introduced in breast

cancer, with series from Giuliano, Krag and Veronesi10e12

showing that sentinel node biopsy using blue dye and/or

radioisotope was feasible and accurate in patients with clini-

cally node negative breast cancer. Several randomized

controlled trials have compared the difference in morbidity,

recurrence and survival rates between ALND and SNB with

completion ALND when the SLN was found to be involved.

Veronesi et al.13 prospectively randomized 516 patients with a

similar incidence of positive SNB was noted in both groups

(32.3% and 35.5%). Overall accuracy of SNB was 96.9%, with

sensitivity of 91.2% and the specificity of 100%. Patients who

underwent SNB had less pain and better arm mobility

compared to those having ALND. In the patients who did not

have ALND, there was only one axillary recurrence and short

term survival was the same as the patients who had ALND.

The NSABP B-32 trial of over 5600 patients having SNB fol-

lowed by ALND or SNB alone found that the accuracy of SNB

was found to be 97.1%, with a false negative rate of 9.8%,

which was dependent on tumour location, type of biopsy and

number of sentinel lymph nodes removed. There was an

overall survival of 91.8% in SLNB then ALND group and 90.3%

in the SLNB only group. No statistically significant differences

were observed in local recurrence, overall survival, disease

free survival or regional control between the two groups.14

The multicentre randomized ALMANAC trial of 1031 clini-

cally node negative patients found better quality of life (QOL)

and significantly better arm functioning was found with SNB

(p < 0.003) than standard ALND.15 The Royal Australasian

College of Surgeons (RACS) SNB vs Axillary Clearance (SNAC)

trial16 of around 1000 patients had a strong focus on QOL.

There was a statistically significant increase in arm volume in

ALND group compared to SNB. QOLwas also found to be better

in SNB group with lower rating of arm swelling, symptoms

and dysfunction but not disabilities, with no differences in

oncological outcomes.16

When carried out by an experienced multi-disciplinary

team, a negative sentinel node is strongly suggestive of a

disease free axilla, with a false negative rate of between 5 and

10% and a very high accuracy rate, which depends on the

underlying rate of nodal positivity.17 Consensus guidelines

from ASCO, NCCN and NICE amongst others recommend SNB

for patients with clinically negative lymph nodes.18

SLNB in special circumstances

SLNB in multifocal/multicentric breast cancer

The randomised trials supporting SLNB were conducted on

unifocal small size tumours while large and multicentric

cancers were excluded. Following the success of SLNB the

procedure has been applied to patients with larger, multifocal

and multicentric cancers. In these circumstances SLNB iden-

tification rate was found to be in the region of 91e94.7% and

false negative rate 8.8%.19,20 As the rate of nodal metastasis is

higher in these cancers, the sensitivity, negative predictive

value, and overall accuracy are somewhat lower than for

unifocal smaller cancers.21 Despite this, a low rate of regional

recurrence has been reported when relying on SLNB, sug-

gesting it is reasonable for these patients.22The Royal Aus-

tralasian College of Surgeons’ SNAC2 trial is specifically

assessing the question of SLNB in large and multifocal

cancers.

SLNB in DCIS

Prior to the introduction of SLNB, axillary assessment was

considered unnecessary in patients with DCIS, as the

morbidity of axillary dissection outweighed any benefits. The

lower morbidity of SLNB has changed the risk/benefit anal-

ysis, and the main question relates to which patients with

DCIS on core biopsy should have SLNB as part of their initial

surgery. In a study of 854 patients SLN metastases were

detected in 12 (1.4%) DCIS patients. In 7 cases only micro-

metastases (<2 mm) were diagnosed and in 5 cases macro-

metastases.23 Kurniawan et al. analysed a large group of

patients with DCIS on core biopsy, and found that those with

palpable DCIS, and those with microinvasion on core were

very likely to have invasive cancer on definitive excision.24 Of

the others, patients with mammographic abnormalities

>20 mm, those with mammographic findings other than pure

microcalcification, and those with a long screening interval

were significantly more likely to have invasive cancer in the

excised specimen, and there was a trend for those with high

grade DCIS to be more likely to have invasion. The authors

suggested that SLNB should be used when DCIS is being

treated with mastectomy, when the DCIS is palpable or when

there is microcalcification, and when 2 or more of the other

factors were present.24 Metastasis to the SLN is rare in pure

DCIS, it is more often seen when associated invasive carci-

noma is found on full examination of the resected lesion.25

t h e s u r g e on 1 2 ( 2 0 1 4 ) 1 5 8e1 6 5160

SLNB following neoadjuvant chemotherapy

The initial trials of SLNB excluded patients with locally

advanced tumours and those who received neoadjuvant

chemotherapy. As more neoadjuvant chemotherapy is used,

the role of SLNB in these patients has been controversial.

Studies of the accuracy and feasibility of SLNB after neo-

adjuvant chemotherapy suggest that the rate of false negative

may be higher.26,27 In a study of 3746 patients with clinically

node negative T1eT3 breast cancer underwent SLNB, Hunt

et al. showed that SLN identification rates were 97.4% in the

neoadjuvant group and 98.7% in the surgery first group

(p ¼ 0.02). In this study the false negative rates were similar

between groups e 5.9% in neoadjuvant vs 4.1% in the surgery

first group (p ¼ 0.39), with the conclusion that SLN surgery

after chemotherapy is as accurate for axillary staging as SLN

surgery prior to chemotherapy.28

A systematic review of 27 studies including 2148 patients

found inadequate evidence to recommend SLNB as a routine

procedure followingneoadjuvant chemotherapy (sensitivity of

90% and false negative rate of 10.5%).29 If neoadjuvant

chemotherapy is used to downstage tumours in patients with

positive axillary lymph nodes, many surgeons continue to

recommend axillary dissection following chemotherapy even

if there is a clinical response in the nodal disease, however

SLNB may be appropriate for those with negative axillary

assessment at presentation. In a meta-analysis of 21 studies

Xing et al. found that SLNB is a reliable tool for planning

treatment after neoadjuvant chemotherapy.30 The results of

the multicentre ACOSOG Z1071 trial were presented in the

2012 San Antonio Breast Cancer Symposium by Judy Boughey,

and showed that in certain breast cancer patients who had

positive axillary lymph nodes prior to neoadjuvant chemo-

therapy, SLNBhad a false negative rate of 13%. Forty percent of

the patients in whom an SLN could be identified had negative

nodes after chemotherapy. Depending on how this is inter-

preted, itmay provide a less invasive option for those patients.

Preoperative assessment of axilla

The introduction of SNB meant that a number of patients

require two operations to complete axillary staging and sur-

gical management. This led to the investigation of a variety of

techniques for pre- or intraoperative assessment of the

sentinel node.

Physical examination alone is not reliable, with high false

positive (25e40%) and false negative (27e32%) rates.31e35 Pre-

operative imaging with US, magnetic resonance imaging

(MRI)36 and FDG-PET37 have been investigated, with US being

the most widely used.

US can detect changes in the size, shape and contours of

lymph node, also changes in the cortical morphology and

texture that is suggestive of metastases.38e42 The two most

important criteria to determine the positivity of nodes is the

cortical thickness (>3 mm) and the morphology (a rounded

shape, hypoechogenicity, obliteration of the hilum and lobu-

lation).43 Some studies found using the combination of size

and morphological criteria to give better results.44

The combination of US and fine needle aspiration cytology

in patients with breast cancer was first introduced by Bon-

nema.45 Specificity of 100%and sensitivity from80 to 91%have

been reported,46 depending on definitions. In general, preop-

erative assessment is much better at detecting macro-

metastatic rather than micrometastatic disease. When the

findings are positive, the patient undergoes ALND without

havingSLNB,whichmayreduce thenumberof surgeries.45,47,48

Further studies have indicated higher sensitivity of US FNA

with higher grade or size of the primary cancer and extensive

nodal involvement. Krishnamurthy et al.49 found 100%

detection rate for US FNA with >2 positive lymph nodes, 93%

of all those with metastatic size >0.5 cm and just 44% with

metastatic <0.5 cm. Bauruah et al.50 found that the sensitivity

was 15% in patients with grade 1 cancer compared to 43%with

grade 3 cancer. Diepstraten et al. in a recent meta-analysis of

preoperative US found that approximately 50% ofwomenwith

axillary involvement can be identified preoperatively. Some

25% of US FNA negative axillae had a positive SNB.51

Intraoperative assessment of SLNB

Intraoperative frozen section analysis of the SLN is used

during surgery in many centres.52,53 The sensitivity of intra-

operative frozen section analysis for identifying SLN metas-

tases has been reported to vary from 44% to 95%,4e17 with

most series reporting in the range of 60%e75%. Invasive

lobular carcinoma may be more difficult to interpret, yet

Horvath et al. showed no differences in sensitivity and spec-

ificity between invasive lobular and invasive ductal carci-

noma.54 Touch imprint cytology of axillary sentinel nodes has

also been used with similar sensitivities to frozen section.

Depending on local expertise some centres found it to be

feasible and a reliable method for evaluating axillary nodes.55

More recently intraoperative molecular analysis using RT-PCR

has been reported, and many centres in the UK are using it.

The one step nucleic acid amplification (OSNA) whereby the

detection of CK19 mRNA using the transcription-reverse

transcription concerted reaction (TRC) test as found in many

studies and in a multicentre trial to be an accurate and rapid

method for detection of SLN metastasis and can be applied as

an intraoperative molecular diagnosis in breast cancer pa-

tients.56,57 Layfield reviewed the topic of intraoperative

assessment of sentinel nodes and concluded that molecular

techniques have significant potential.58

Subsequently, a NICE committee report suggested that

intraoperative analysis of sentinel lymph nodes using the RD-

100i OSNA system had considerable advantages over tradi-

tional histopathology testing and had the potential to reduce

both clinical complications, and patient anxiety and distress

and therefore recommended its use (NICE 7th August 2013).

Micrometastases and isolated tumour cells

The introduction of SNB has allowed pathologists to focus

attention on fewer nodes. The use of step sectioning and

immunohistochemical (IHC) analysis with antibodies to

cytokeratin has resulted in upstaging in approximately

t h e s u r g e on 1 2 ( 2 0 1 4 ) 1 5 8e1 6 5 161

10e20% of patients who might otherwise have had a negative

SLN with the detection of micrometastasis (0.2e2.0 mm) and

isolated tumour cells and cluster of tumour cells (<0.2 mm).59

The prognostic significance of isolated tumour cell or

micrometastases is questionable. The NSABP B32 study

showed that IHC-detected metastases in SLNB were an inde-

pendent prognostic variable, however the magnitude of the

difference in outcome at 5 years was small (1.2%). These data

do not indicate a clinical benefit of additional evaluation,

including immunohistochemical analysis, of initially negative

sentinel nodes in patients with breast cancer.60 Importantly

the MIRROR study from the Netherlands showed a definite

advantage of adjuvant treatment for patientswith early breast

cancer whose SLN showed isolated tumour cells or

micrometastasis.61

Predicting non-SNBmetastasis after positive SNB

A recommendation to perform a completion nodal dissection

when the sentinel node is involved is based on the knowledge

that other lymph nodes might be involved. Various studies

have identified pathological features associated with the

incidence of non-sentinel lymph node involvement after a

positive SNB. These include age, primary tumour-related

factors (type, size, grade, lymphovascular invasion (LVI) and

hormone receptor status) and node related factors (method of

detection, size of metastasis, extracapsular extension, num-

ber of positive sentinel lymph nodes and number of negative

sentinel lymph nodes).62e72

A number of nomograms have been developed to accu-

rately predict the likelihood of non-SLNmetastasis.73 Van Zee

et al. from Memorial Sloan-Kettering Cancer Center (MSKCC)

proposed the first nomogram in 2003.70 Parameters were

identified after a multivariate logistic regression analysis of a

retrospective group of patients. Several studies from variety of

centres across have attempted to validate the MSKCC nomo-

gram, with an ROC ranging in between 0.71e0.86,69,74e80 with

two studies reporting a poorer performance.79,80 Other no-

mograms have also been developed, which include Tenon

model,68 Cambridge model62 and Stanford model.81

Reports of the outcomes of patients with involved sentinel

nodesmanagedwith selective axillary dissection indicate that

such nomograms can be valuable clinically.82

Future role of completion ALND in sentinellymph node (SLN) positive patients

Validation that axillary metastasis are limited to the SN in

60e70% of patients overall, and in 90% for low volume

involvement (micrometatstasis/ITC), raised the possibility of

selective completion dissection. The infrequency of axillary

recurrence in patients having SNB alone, compared to the

number of patientswith presumedundissected disease (based

on the known false negative rate) indicated that a substantial

proportion did not progress to clinically relevant disease.20

Series of cases emerged where patients with involved SN

either chose, or were recommended, to omit the completion

ALND, with no apparent detriment to their oncological

outcomes.30e33 Despite this, there was no high-level evidence

on the safety of omitting completion ALND, a retrospective

review of SEER data suggested that removal of regional lymph

nodes, even if they were interpreted as negative, have a sur-

vival advantage83 and the main randomized study addressing

the question of the need for a completion ALND closed early

having failed to meet its accrual targets. The presentation and

publication of the American College of Surgeons Oncology

Group (ACOSOG) Z0011 study34,35 has provoked controversy

around the world regarding the extent to which this is a

practice-changing study.

ACOSOG Z0011 was designed as a non-inferiority study

comparing completion ALND to no further axillary treatment

in patients with limited sentinel node involvement who were

to undergo whole breast RT after breast conservative surgery.

Patients with T1 or T2 tumours and 1 or 2 involved sentinel

nodes without gross extranodal extension were eligible. Its

planned accrual was 1900, but it closed early on the advice of

the DSMCwith 891 patients enrolled due to slow accrual and a

low event rate. There was no significant difference in either

regional recurrence or disease free survival between the two

arms. Five year overall survival was 91.8% in the ALND arm

and 92.5% in the SNB alone arm with axillary recurrence rates

of 0.5% and 0.9% respectively.

The investigators concluded from these results: “Among

patients with limited SNmetastatic breast cancer treatedwith

breast conservation and systemic therapy, the use of SNB

alone compared with ALND did not result in inferior

survival.”35

Translation of the results of ACOSOG Z0011 into practice

has varied around the world. A number of major US cancer

centres have altered their practice, but many surgeons and

MDTs have beenmore cautious. There have been a number of

concerns raised, some relating to the fact that the study did

not meet its accrual targets, others to the nature of patients

actually taking part in the study (as opposed to those who

were potentially eligible for the study), and others to the

extent of other therapies the patients in the study received.

Statistical analysis suggests that with the results found in

the study of 891 patients, it is next to impossible that even if

the trial had accrued its planned 1900 patients that SNB alone

would have been found to be inferior. It is therefore appro-

priate to conclude that, in the group studied, the authors’

conclusions are correct. It is critical to note that the patients

participating in the study were not a true reflection of the

group who were potentially eligible. Around 70% of the can-

cers were T1, 82% ER positive, 40% had micrometastatic dis-

ease in the SN and 96% received some form of adjuvant

systemic therapy. 27% of completion ALND specimens con-

tained additional nodal disease. Thus it was effectively a study

of heavily treated low risk patients. The requirement for all

patients to receive adjuvant radiotherapy suggests that the

therapeutic effect of RTwas considered potentially important.

Details on the extent of radiotherapy actually received by

patients in the study are seen by some as important to

assessing the generalizability of the ACOSOG Z0011 study

results.

Confirmation that not all patients with involved SNs

require completion axillary dissection came from the IBCSG

B23 study,84 that randomized over 900 patients with

t h e s u r g e on 1 2 ( 2 0 1 4 ) 1 5 8e1 6 5162

micrometastases to completion ALND or not. This study

included about 10% of patients withmastectomy, and showed

no clinically significant differences in oncological outcomes.

It is important to note that in the MIRROR study, the

regional recurrence rate was 5.6% at 5 years for those with

micrometastases not receiving further axillary treatment, 1%

in those receiving ALND, and 0 in those receiving axillary RT. A

doubling in tumour size, high grade and negative hormone

receptor status were strongly and significantly associated

with increased regional recurrence rate, although there large

confidence intervals around these factors. This study raises a

precautionary note about doing to further axillary treatment if

no systemic therapy is being considered.61

The AMAROS trial randomized SLN positive patients with

cT1-2N0 breast cancer having breast conservation or mas-

tectomy to axillary clearance or axillary radiotherapy. There

were no significant differences at 5 years in disease free (86.9%

vs 82.7%; P ¼ 0.1788) or overall survival (93.3% vs 92.5%;

P¼ 0.3386) withmore lymphoedema in the surgery group (28%

vs 14%).85 Analysis of adjuvant systemic therapy in the two

arms of the AMAROS trial was analysed, suggesting that

absence of knowledge regarding the extent of nodal involve-

ment appears to have no major impact on the administration

of adjuvant systemic therapy.86

However, the results of AMAROS, and those of the NCIC

MA20 study that suggest patients with node positive breast

cancer treated with additional regional nodal irradiation have

improved disease free survival,87 indicate that further anal-

ysis and clinical trials will be needed to precisely define the

role and nature of regional therapy in patients with positive

sentinel nodes.

Summary

Axillary management has rapidly evolved in the last 20 years.

For some 90 years after Halsted’s seminal publication, com-

plete axillary dissection was standard for most patients with

invasive breast cancer. Since the early 1990’s, sentinel node

biopsy has been developed, proven and widely introduced for

the management of most clinically node negative patients. A

variety of techniques can be used for pre- or intraoperative

assessment of the sentinel node, and mathematical models

can predict the likelihood of non-sentinel nodal involvement.

The current key question is identification of patients with

involved sentinel nodes who either do or do not require

further axillary treatment. While the findings of Z0011 trial

question the role of ALND after positive SNB, further evidence

is required before the optimal management of various groups

of patients with involved sentinel nodes can be considered

resolved.

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