Ihab S. Fayeka MD; Fouad A. Saleepa MD; Hany F. Habashyb MD; Alfred E. Namourc MD ; Iman G. Farahatd MD ;Magdy Kotbe MD a: department of surgical oncology - national cancer institute - Cairo university - Egypt. b: department of surgery - Fayoum university hospital - El Fayoum - Egypt. c: department of medical oncology - national cancer institute - Cairo university - Egypt. d: department of surgical pathology - national cancer institute - Cairo university - Egypt. e: department of nuclear medicine - national cancer institute - Cairo university - Egypt. For correspondance contact: drihab74@hotmail.com Kasr el-aini journal of surgery Volume 14, No.1, January 2013

1. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
1
Sentinel lymph node biopsy before neoadjuvant chemotherapy
for clinical axillary node negative breast cancer: impact on
staging.
Ihab S. Fayeka
MD; Fouad A. Saleepa
MD; Hany F. Habashyb
MD; Alfred E. Namourc
MD ;
Iman G. Farahatd
MD ;Magdy Kotbe
MD
a: department of surgical oncology - national cancer institute - Cairo university - Egypt.
b: department of surgery - Fayoum university hospital - El Fayoum - Egypt.
c: department of medical oncology - national cancer institute - Cairo university - Egypt.
d: department of surgical pathology - national cancer institute - Cairo university - Egypt.
e: department of nuclear medicine - national cancer institute - Cairo university - Egypt.
For correspondance contact: drihab74@hotmail.com
Abstact
Background: The ideal timing of sentinel lymph node biopsy (SLNB) is still, by far, a matter
of debate. Meanwhile, several authors reported SLNB after neoadjuvant chemotherapy (NC).
Methods: We evaluated the accuracy and feasibility of SLNB before NC using a combined
procedure (blue dye and radio-labelled detection). Axillary lymph node dissection (ALND) was
performed after completion of NC in patients with breast cancer having clinically node-
negative axillae.
Results: Among the 18 women who had metastatic SLNB (67%) detected before NC, 3
(17%) had additional metastatic node on ALND. While 15 women who had no metastatic
SLNB also had no involved nodes in ALND after NC.
Conclusion: SLNB done before NC is a reliable and accurate diagnostic tool to stage the
clinically negative axillae in breast cancer, permitting to avoid ALND after NC for patients with
negative SLNB.
Introduction
A debate exists as to whether sentinel
lymph node biopsy (SLNB) should be
performed before or after neoadjuvant
chemotherapy (NC) in large breast cancers
in order to obtain a down staging allowing
for breast conservation.1
However
regarding literature review, the accuracy of
SLNB performed after NC is controversial
because of high false negative rates2
and
limited numbers of studies having
performed SLNB before NC.3-10
So, we
report here a study evaluating the role of

2. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
2
SLNB performed before NC in clinically
node-negative breast cancer patients. All
patients underwent a formal ALND
following neoadjuvant chemotherapy to
validate the SLNB findings.
Patients and methods
Patients
Study candidates were patients referred to
the National Cancer Institute (Cairo, Egypt)
and University of Fayoum teaching hospital
(Fayoum, Egypt) for the treatment of
invasive breast cancer. Patients were
included in the study if they had tumor
more than 4 cm in diameter for which a NC
was indicated in order to enhance the
likelihood of breast conservation. A proven
histopathologic diagnosis of invasive breast
cancer was required. Exclusion criteria
included: clinically palpable axillary lymph
node, distant metastasis, and inflammatory
breast cancer, allergy to the isotope used
during the sentinel lymph node mapping.
The protocol consisted to perform a SLNB
before NC and an ALND after NC. All
Patients were informed of the protocol and
a written informed consent was obtained.
Preoperative radioactive colloid
mapping of the sentinel node
The day before the surgery a combination
of intradermal and intraparenchymal
radioactive colloid injection and a
lymphoscintigraphy of the breast and the
axilla were done to determine the position
of the sentinel node as previously
described.11
Sentinel lymph node biopsy
Under general anesthesia and 10 min
before incision, 2 ml Patent Blue dye is
injected in subareolar area.11
After an
axillary skin incision sentinel lymph node
dissection was performed by combined
intra-operative gamma probe detection
(Figure 1). All lymph nodes presenting
either blue dye (Figure 2) or radioactive
counts (Figure 1) or both were identified as
sentinel lymph node(s) and removed. All
sentinel lymph nodes were sent individually
for histological examination with
information concerning blue dye uptake
and ex-vivo radioactivity count.
Neoadjuvant chemotherapy
All the patients were assigned to receive
fluorouracil 500 mg/m2
, epirubicin 100
mg/m2
, and cyclophosphamide 500 mg/m2
(FEC) intravenously on day 1 every 21
days for four cycles. Clinical response was
defined by following criteria: (1) complete
response was defined as a total
disappearance of the breast tumor (2)
partial response a 50% or greater reduction
of the product of the two largest
perpendicular dimensions of the breast
mass (3) minor response a less than 50%
reduction of the product of the two largest
perpendicular dimensions of the breast
mass (4) no change in clinical status (5)
progressive disease.12
Axillary lymph node dissection
and breast surgery
Levels I and II axillary lymph node
dissection were systematically performed
four weeks after the end of the NC.13
Mastectomy or lumpectomy ( breast-
conserving surgery ) was performed
according to the clinical response after NC,

3. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
3
the location and the tumor size, the breast
size and the women's wish.
Histology
No intra-operative evaluation was
performed on sentinel lymph node. The
sentinel lymph node was analyzed by serial
sectioning of the whole node after formalin
fixation and paraffin embedding. Every
section of 200 µm was stained with
haematoxylin-eosin and by antibody to
cytokeratin for the detection of
micrometastasis (<2 mm) and isolated
tumor cells (0.2 mm). Axillary lymph node
dissection and tumor were examined
according to the standard procedures.
Complete pathological response was
defined by the complete absence of
residual invasive tumor in the breast or
axillary lymph nodes even if there was
residual carcinoma in situ.14
Statistical analysis
The sentinel lymph node identification rate
and the false negative rate were used to
assess the feasibility of SLNB before NC.
The identification rate was defined as the
proportion of procedures in which a
sentinel lymph node was successfully
identified. The false negative rate was
defined as the proportion of axillary node
dissection-positive cases in which the
sentinel lymph node was negative.
Results
Patients
From August 2006 to january 2011, twenty
seven women with T2 or T3 invasive
breast cancer according to AJCC
classification without palpable axillary
lymph node underwent SLNB before NC
and an ALND after NC.15
The median age
of the patients was 48 years (range 29-66
years). The median clinical tumor size was
45 mm (range 40-70 mm). Characteristics
of the study population were reported in
Table 1.
Sentinel lymph node biopsy
The sentinel lymph node detection was
successfully achieved in all 27 patients.
The median number of axillary sentinel
node removed was 1 (range 1-3). In 15
cases only one sentinel node was removed
(56%); in 7 cases two sentinel nodes were
removed (26%). Three sentinel nodes were
removed for 5 patients (19%). The sentinel
nodes were metastatic in 18 of the 27
patients. All sentinel nodes were
macrometastatic, no micrometastatic cases
were detected.
Neoadjuvant chemotherapy
The planned chemotherapy was completed
in all 27 patients.Complete clinical
response was observed in 11 patients
(41%), partial clinical response in 13
patients (48%) and minor clinical response
in 3 patients (11%). Complete pathological
response was observed in 10 patients
(37%) (Table 2).
Surgical procedure
Fifteen patients (56%) had a mastectomy.
In 4 cases, a mastectomy was performed
to achieve negative margins after a
lumpectomy. Twelve patients (44%) were
treated with lumpectomy. All 27 patients

4. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
4
underwent ALND after NC. An average of
14 additional nodes (range 8-33) were
removed. Among the 9 women who had
negative sentinel lymph node, the average
of additional nodes removed during ALND
was 12 (range 8-23). Among the18 women
with positive sentinel lymph node, the
average of additional nodes removed
during ALND was 15 (range 12-33). Three
patients had remaining axillary metastatic
disease: 1 metastatic node/14 dissected
nodes, 1 metastatic node/15 dissected
nodes, 2 metastatic nodes/12 dissected
nodes,respectively.
Feasibility of sentinel lymph node
biopsy
The identification rate of sentinel lymph
node was 100%. Among the 18 patients
who had metastatic sentinel nodes (67%)
at initial SLNB, 3 (17%) had additional
metastatic lymph nodes on ALND after NC.
Indeed, all patients who had negative
SLNB had also negative ALND (Table 3).
The rate of false negative was 0%.
Discussion
Contrary to the high number of studies
reporting SLNB after NC, very few
investigators have reported the pertinence
of SLNB performed before NC.3-7;9-10
The
original idea of this work was to
systematically perform a combination
procedure for sentinel lymph node
detection and an ALND systematically
done after NC. This idea has not been
systematically performed in previous stud-
ies.3-7;9-10
In the present study, we have
found a high identification rate as well as
no false negative for the application of
SLNB before NC.
Accuracy of SLNB
The major aspect of our study was the
achievement of an ALND in all patients
following the completion of NC. This
attitude may validate the ability of SLNB to
identify the axillary status before NC. In
most previous studies, ALND was not
systematically performed if the SLNB was
negative, precluding any conclusion about
the false negative rate of such a
procedure.3-5,7,9,10
Actually a systematic
ALND after NC allows us to report
important data about the high accuracy of
SLNB in this setting. Among 9 patients who
had no metastasis on SLNB (23%) before
NC, none had metastasis on the ALND
after NC. A potential remark at this stage is
that ALND does not allow differentiation
between patients with true negative SLNB
and those with false negative SLNB
sterilized by chemotherapy. However the
expected rates of non involved axillary
lymph node range from 24% to 41% in
large breast cancers.11,16-18
That is
approaching our own results (23%).
Besides, if NC is known to down stage
tumor-involved lymph nodes, more than
74% of axillary node metastases
histologically confirmed to persist after
NC.3,14,19,20
These arguments are
consistent with our low false negative rate
(0%) for SLNB. Besides, our data suggest
that SLNB performed before NC may spare
a significant proportion of ALND (23%).
Schrenk et al. 2008 had recently proposed
an algorithm for ALND whether SLNB was
positive or negative before NC in clinically
node-negative axilla.10

5. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
5
False negative rate of SLNB
The second important aspect of our study
was the use of a combination procedure
(blue dye and radio-labelled) for sentinel
lymph node detection in all clinically axillary
node-negative breast cancer group.
Primarily, it had been said that the
combination of blue dye and radio-labelled
give the highest sentinel node detection
rates with the lowest false negative rates.21
Nevertheless one of the previous trial, on
SLNB performed before NC, has reported
such lymphatic mapping in one part of the
cohort study.6
Then, it had been shown that
the unsuccessful axillary mapping during
preoperative lymphoscintigraphy was asso-
ciated with positive axillary nodes.22
Yet,
one previous trial has included women with
clinically enlarged axillary lymph nodes at
the time of SLNB.6
In fact, to improve sen-
tinel node detection and reduce false
negative rate, women candidate for SLNB
prior NC must be selected with no clinically
palpable axillary lymph node and the
combination of pre- and intra-operative
sentinel node detection must be performed
for optimal results.21
Timing of SLNB
The ideal time of SLNB in neoadjuvant
setting is still a matter of debate. The major
disadvantages of SLNB performed before
NC are (1) the fact that an additional oper-
ative procedure is done may delay the
beginning of NC, (2) an ALND is performed
after the end of NC for a positive SLNB
even if axillary metastases had been
sterilized by NC.23
By contrast, the major
advantage of post-NC is to provide
information that would allow ALND to be
avoided if SLNB is negative in a more
proportion of women who do axillary
staging performed before NC. In fact, NC is
known to down staging of tumor-involved
lymph nodes. The rate of chemotherapy
sterilization of axillary node metastases
histologically confirmed by fine-needle
aspiration is 20%-26%.3,14,19,20
Nevertheless, if a complete pathologic
response to NC in the axilla has improved
survival,19
thus far no study has
investigated the rate of axillary recurrence
following a pathologic complete eradication
of axillary node metastase after NC for
which no ALND is added. The major
limitation of SLNB performed after NC is a
technical challenge. A recent meta-analysis
including 21 studies report a false negative
rate of 12% (IC 10%-15%).2
This rate
seems unacceptably high according to the
guidelines of the American Society of
Breast Surgeons that recommend a false
negative rate of 5% or less in order to
abandon ALND.21
Lymphatic changes
caused by chemotherapy including nodal
fibrosis, mucin pools or aggregates of
foamy histiocytes may explain the high
false negative rate.24
Consequently, the
application of SLNB after NC is
controversial and does not appear as a
robust method to assess the status of the
axillary basin.
Limitations
Our study has some limitations such as the
small number of patients included in the
analysis. Moreover, the dissected axillary
nodes were not analyzed with the same
pathological protocol as for SLNB. A recent
study has shown that serial sectioning and
use of IHC on dissected axillary nodes

6. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
6
allow the detection of micrometastases or
isolated tumoral cells in 21% of patients
originally staged as node-negative with the
standard procedure.25
Interestingly, such
occult metastases have been shown to be
prognostically significant.25
Nevertheless
this pilot study confirms the pertinence of
SLNB performed before NC and might
benefit the patient by reducing the
morbidity of axillary staging by ALND.
These findings remain to be confirmed in a
larger cohort before any clinical
recommendation can be made.
Conclusion
Contrary to the limited number of studies
that report SLNB before NC, we
systematically performed a combination
procedure for sentinel lymph node
detection before NC and an ALND after NC
in a homogeneous cohort study without
clinically palpable axillary lymph node. We
report a high identification rate and no false
negative results. SLNB is a reliable and
accurate diagnostic tool to stage the
clinically negative axillae in breast cancer
before NC and to predict the pre-
therapeutic axillary lymph node status.
Moreover, SLNB performed before NC may
spare a significant proportion of patients
with locally advanced breast cancer the
morbidity of an axillary lymph node
dissection. Further studies with larger
patient number are needed to confirm
these findings and put them into clinical
use.
References
1. Fisher B, Bryant J, Wolmark N,
Mamounas E, Brown A, Fisher ER,
Wickerham DL, Begovic M, DeCillis A,
Robidoux A, Margolese RG, Cruz AB Jr,
Hoehn JL, Lees AW, Dimitrov NV, Bear
HD. Effect of preoperative chemotherapy
on the outcome of women with operable
breast cancer. J Clin Oncol 1998;16:2672-
85.
2. Xing Y, Foy M, Cox DD, Kuerer HM,
Hunt KK, Cormier JN. Meta-analysis of
sentinel lymph node biopsy after
preoperative chemotherapy in patients with
breast cancer. Br J Surg 2006;93:539-46.
3. Cox CE, Cox JM, White LB, Stowell
NG, Clark JD, Allred N, Meyers M,
Dupont E, Furman B, Minton S. Sentinel
node biopsy before neo-adjuvant
chemotherapy for determining axillary
status and treatment prognosis in locally
advanced breast cancer. Ann Surg Oncol
2006; 13:483-90.
4. Ollila DW, Neuman HB, Sartor C,
Carey LA, Klauber-Demore N. Lymphatic
mapping and sentinel lymphadenectomy
prior to neoadju-vant chemotherapy in
patients with large breast cancers. Am J
Surg 2005;190:371-5.
5. Van Rijk MC, Nieweg OE, Rutgers
EJT, Oldenburg HS, Olmos RV,
Hoefnagel CA, Kroon BB. Sentinel node
biopsy before neoadjuvant chemotherapy

7. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
7
spares breast cancer patients axillary
lymph node dissection. Ann Surg Oncol
2006;13:475-9.
6. Schrenk P, Hochreiner G, Fridrik M,
Wayand W. Sentinel node biopsy
performed before preoperative
chemotherapy for axillary lymph node
staging in breast cancer. Breast J
2003;9:282-7.
7. Jones JL, Rhei E, Gadd MA, Howard-
Mcnatt, Hughes KS, Lesnikoski BA,
Christian RL, Rabban JT, Kaelin C,.
Smith BL. Predictive value of sentinel
lymph node biopsy prior to neoadjuvant
chemotherapy in clinically node negative
breast cancer. American Society Clinical
Oncology. Annual Meeting. 2004.
8. Jones JL, Zabicki K, Christian RL,
Gadd MA, Hughes KS, Lesnikoski BA,
Rhei E, Specht MC, Dominguez FJ,
Smith BL. A comparison of sentinel node
biopsy before and after neoadjuvant
chemotherapy: timing is important. Am J
Surg 2005;190:517-20.
9. Sabel MS, Schott AF, Kleer CG,
Merajver S, Cimmino VM, Diehl KM,
Hayes DF, Chang AE, Pierce LJ. Sentinel
node biopsy prior to neo-adjuvant
chemotherapy. Am J Surg 2003;186:102-5.
10. Schrenk P, Tausch C, Wolfl S,
Bogner S, Fridrik M, Wayand W. Sentinel
node mapping performed before
preoperative chemotherapy may avoid
axillary dissection in breast cancer patients
with negative or micrometastatic sentinel
nodes. Am J Surg 2008;196:176—83.
11. Lelievre L, Houvenaeghel G,
Buttarelli M, Brenot-Rossi I, Huiart L,
Tallet A, Tarpin C, Jacquemier J. Value
of the sentinel lymph node procedure in
patients with large size breast cancer. Ann
Surg Oncol 2007;14:621-6.
12. Miller AB, Hoogstraten B, Staquet M,
Winkler A. Reporting results of cancer
treatment. Cancer 1981;47:207-14.
13. Berg JW. The significance of axillary
node levels in the study of breast
carcinoma. Cancer 1955;8:776-8.
14. Kuerer HM, Sahin AA, Hunt KK,
Newman LA, Breslin TM, Ames FC,
Ross MI, Buzdar AU, Hortobagyi GN,
Singletary SE. Incidence and impact of
documented eradication of breast cancer
axillary lymph node metastatses ' before
surgery in patients treated with
neoadjuvant chemotherapy. Ann Surg
1999;230:72-8.
15. Edge SB, Compton CC. The American
Joint Committee on Cancer: the 7th edition
of the AJCC cancer staging manual and
the future of TNM. Ann Surg Oncol. 2010
Jun;17(6):1471-4.
16. Schule J, Frisell J, Ingvar C,
Bergkvist L. Sentinel node biopsy for
breast cancer larger than 3 cm in diameter.
Br J Surg 2007;94:948-51.
17. Bedrosian I, Reynolds C, Mick R,
Callans LS, Grant CS, Donohue JH,
Farley DR, Heller R, Conant E, Orel SG,
Lawton T, Fraker DL, Czerniecki BJ.
Accuracy of sentinel lymph node biopsy in
patients with large primary breast tumors.
Cancer 2000;88:2540-5.
18. Chung MH, Ye W, Giuliano AE. Role
for sentinel lymph node dissection in the

8. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
8
management large (> or = 5 cm) invasive
breast cancer. Ann Surg Oncol
2001;8:688-92.
19. Hennessy BT, Hortobagyi GN,
Rouzier R, Kuerer H, Sneige N, Buzdar
AU, Kau SW, Fornage B, Sahin A,
Broglio K, Singletary SE, Valero V.
Outcome after pathologic complete
eradication of cytologically proven breast
cancer axillary node metastases following
primary chemotherapy. J Clin Oncol
2005;23:9304-11.
20. Rouzier R, Extra JM, Klijanienko J,
Falcou MC, Asselain B, Vincent-
Salomon A, Vielh P, Bourstyn E.
Incidence and prognostic significance of
complete axillary downstaging after primary
chemotherapy in breast cancer patients
with Tl to T3 tumors and cytologcally
proven axillary metastatic lymph nodes. J
Clin Oncol 2002;20: 1304-10.
21. Lyman GH, Giuliano AE, Somerfield
MR, Benson AB 3rd, Bodurka DC,
Burstein HJ, Cochran AJ, Cody HS 3rd,
Edge SB, Galper S, Hayman JA, Kim TY,
Perkins CL, Podoloff DA,
Sivasubramaniam VH, Turner RR, Wahl
R, Weaver DL, Wolff AC, Winer EP.
American Society of Clinical Oncology
guideline recommendations for sentinel
lymph node biopsy in early-stage breast
cancer. J Clin Oncol 2005 ;23:7703-20.
22. Rossi Brenot, Houvenaeghel G,
Jacquemier J, Bardou VJ, Martino M,
Hassan-Sebbag N, Pasquier J.
Nonvisualization of axillary sentinel node
during lymphoscintigraphy: is there a
pathologic significance in breast cancer? J
Nucl Med 2003;44:1232-7.
23. Newman EK, Sabel MS, Nees AV,
Schott A, Diehl KM, Cimmino VM, Chang
AE, Kleer C, Hayes DF, Newman LA.
Sentinel lymph node biopsy performed
after neoadjuvant chemotherapy is
accurate in patients with documented
node-positive breast cancer at
presentation. Ann Surg Oncol
2007;14:2946-52.
24. Newman LA, Pernick NL, Adsay V,
Carolin KA, Philip PA, Sipierski S,
Bouwman DL, Kosir MA, White M,
Visscher DW. Histopathologic evidence of
tumor regression in the axillary lymph
nodes of patients treated preoperative
chemotherapy correlates with breast
cancer outcome. Ann Surg Oncol
2003;10:734-9.
25. Tan LK, Giri D, Hummer AJ,
Panageas KS, Brogi E, Norton L, Hudis
C, Borgen PI, Cody HS 3rd. Occult
axillary node metastases in breast cancer
are prognostically significant: results in 368
node-negative patients with 20-year follow-
up..J Clin Oncol 2008;26:1803-9.

9. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
9
Table 1: Patients Characterestics
Patients n=27
Age (Years)
≤50
>50
16 (59%)
11 (41%)
Clinical Stage (TNM)
c T2
c T3
14 (52%)
13 (48%)
Tumor histology
Invasive ductal carcinoma
Invasive lobular carcinoma
Medullary carcinoma
24 (89%)
2 (7.3%)
1 (3.7%)
Tumor grade
Grade I
Grade II
Grade III
4 (15%)
17 (63%)
6 (22%)
Receptor status
ER-PR +ve
ER-PR -ve
19 (70%)
8 (30%)
HER2/neu overexpression 6 (22%)
Table 2: Pathological results (clinical and histological) and types of surgery
Patients n=27
SLNB
Involved
Not involved
18 (67%)
9 (23%)
Clinical response to NC
Complete
Partial
Minor or No response
11 (41%)
13 (48%)
3 (11%)
ALND
Involved
Not involved
3 (11%)
24 (89%)
Type of breast surgery
Mastectomy
Consevative
15 (56%)
12 (44%)
Histologic response to NC
Complete
Partial (residual tumor)
9 (33%)
18 (67%)

10. Kasr el-aini journal of surgery Volume 14, No.1, January 2013
11
Table 3: Concordance between histological analysis of SLNB before NC and ALND
after NC
Non metastatic
SLNB n=9
Metastatic
SLNB n=18
Total n=27
Non metastatic ALND 9 (100%) 15 (83%) 24
metastatic ALND 0 3 (17%) 3