Validation of axillary sentinel lymph node detection in the staging of early lobular invasive breast carcinoma: a prospective study.
ABSTRACT Previous reports have shown that regional lymph node involvement in patients with early-stage breast carcinoma can be evaluated by resection of axillary sentinel lymph nodes (ASLN). Axillary lymphadenectomy may be unnecessary in the absence of ASLN involvement. In the current study, the authors compared the results of ASLN resection in patients with lobular invasive carcinoma (LIC) with the results from patients with ductal invasive carcinoma (DIC) in terms of detection rates and false-negative rates.
For ASLN detection, technetium 99m sulfur-colloid and patent blue were injected around the tumor. Each patient underwent both ASLN resection and complete axillary lymphadenectomy. Detection rates and false-negative rates were evaluated in patients with LIC and in patients with DIC.
Two hundred forty-three patients with invasive, early-stage breast carcinoma were enrolled in the study (208 patients with DIC and 35 patients with LIC). The median patient age, pathologic tumor size, hormone receptor status, and rates of involved lymph nodes were equivalent for both groups. ASLN detection and false-negative rates did not differ for patients with LIC and patients with DIC.
The ASLN detection rate was not dependent on the pathologic type of invasive carcinoma. Pathologic examination of ASLN in patients with LIC and in patients with DIC predicted axillary lymph node status with the same predictive value in terms of lymph node metastasis. For patients with LIC, ASLN examination overestimated the rate of micrometastasis as diagnosed by immunohistochemical techniques. These results will require confirmation in larger studies.
- SourceAvailable from: Reyhane Hoshyar[Show abstract] [Hide abstract]
ABSTRACT: The perennial flowering plant, saffron crocus (Crocus sativus L.), is the source of the most expensive spice in the world. The dried stigmas of saffron flowers are the source of a natural dye, saffron, which has been used from ancient times for dyeing silk and fabric rugs, and for painting; it also has been used for cooking and in medicine. The yellow compounds present in the dye include crocins, which are 20-carbon water soluble glycosyl derivatives of the carotenoid, crocetin, and the dicarboxylic acid itself. We review the chemistry of these compounds and discuss various applications of saffron as a natural dye. We review in particular the use of saffron or its constituents in histopathologic techniques.Biotechnic & Histochemistry 03/2014; 89(6). · 1.00 Impact Factor
- Expert Review of Endocrinology & Metabolism 05/2008; 3(3):287-290.
- [Show abstract] [Hide abstract]
ABSTRACT: To examine treatment trends in invasive lobular carcinoma (ILC) over the last 15 years and, in particular, to compare rates of recurrence and disease-free survival associated with breast conservation therapy compared with mastectomy. The biologic characteristics of ILC make it difficult to estimate the extent of the disease by either clinical examination or mammography, and can also make it difficult to detect axillary lymph node metastases. Because of this, there has been a bias toward treating ILC with aggressive therapy. Patients with ILC were selected from the National Cancer Data Base (1989-2001) using an extensive set of inclusion and exclusion criteria. A total of 21,596 patients were selected, including 8108 who received breast conservation therapy and 13,488 who received mastectomy. Analysis included demographic characteristics, trends in usage of sentinel lymph node biopsy, rates of local and distant recurrence, and 5-year disease-free survival rates. The use of breast conversation therapy increased almost threefold during the study period. From 1998 to 2001, the use of sentinel node biopsy increased more than twofold in the breast conservation group (an average of 23% in 1998 versus 57% in 2001), compared with limited usage in the mastectomy group (an average of 10% in 1998 versus 23% in 2001). Local recurrence rates were very low and disease-free survival rates were correspondingly high in both treatment groups for all diagnosis years and across all pathologic tumor size/lymph node status designations. Less invasive treatment options are becoming widely used for invasive lobular carcinoma, yielding outcomes equivalent to those seen with more aggressive treatment.Breast Diseases A Year Book Quarterly 04/2006; 17(1):60–61.
Validation of Axillary Sentinel Lymph Node Detection
in the Staging of Early Lobular Invasive Breast
A Prospective Study
Jean-Marc Classe, M.D.1
Delphine Loussouarn, M.D.2
Loı ¨c Campion, M.D.3
Maryse Fiche, Ph.D.2
Chantal Curtet, Ph.D.4
Franc ¸ois Dravet, M.D.1
Raphae ¨lle Pioud, M.D.1
Caroline Rousseau, M.D.5
Isabelle Resche, M.D.5
Christine Sagan, M.D.2
1Department of Oncological Surgery, Rene ´ Gaud-
ucheau Cancer Center, Saint-Herblain, France.
2Department of Histopathology, Centre Hospitalier
Universitaire, Ho ˆpital G. et R. Laennec, Saint-Her-
3Department of Biostatistics, Rene ´ Gauducheau
Cancer Center, Saint-Herblain, France.
4Unit 463, National Institute of Health and Medical
Research, Nantes, France.
5Department of Nuclear Medicine, Rene ´ Gauduch-
eau Cancer Center, Saint-Herblain, France.
Address for reprints: Jean-Marc Classe, M.D., Ser-
vice Chirurgie Oncologique, Site Ho ˆpital Nord, Bd.
J. Monod, 44805 Saint-Herblain, France; Fax:
(011) 33 240679759; E-mail: jm-classe@nantes.
Received July 16, 2003; revision received Novem-
ber 28, 2003; accepted December 3, 2003.
BACKGROUND. Previous reports have shown that regional lymph node involvement
in patients with early-stage breast carcinoma can be evaluated by resection of
axillary sentinel lymph nodes (ASLN). Axillary lymphadenectomy may be unnec-
essary in the absence of ASLN involvement. In the current study, the authors
compared the results of ASLN resection in patients with lobular invasive carcinoma
(LIC) with the results from patients with ductal invasive carcinoma (DIC) in terms
of detection rates and false-negative rates.
METHODS. For ASLN detection, technetium 99m sulfur-colloid and patent blue
were injected around the tumor. Each patient underwent both ASLN resection and
complete axillary lymphadenectomy. Detection rates and false-negative rates were
evaluated in patients with LIC and in patients with DIC.
RESULTS. Two hundred forty-three patients with invasive, early-stage breast car-
cinoma were enrolled in the study (208 patients with DIC and 35 patients with LIC).
The median patient age, pathologic tumor size, hormone receptor status, and rates
of involved lymph nodes were equivalent for both groups. ASLN detection and
false-negative rates did not differ for patients with LIC and patients with DIC.
CONCLUSIONS. The ASLN detection rate was not dependent on the pathologic type
of invasive carcinoma. Pathologic examination of ASLN in patients with LIC and in
patients with DIC predicted axillary lymph node status with the same predictive
value in terms of lymph node metastasis. For patients with LIC, ASLN examination
overestimated the rate of micrometastasis as diagnosed by immunohistochemical
techniques. These results will require confirmation in larger studies. Cancer 2004;
100:935–41. © 2004 American Cancer Society.
KEYWORDS: breast carcinoma, lobular carcinoma, ductal carcinoma, sentinel lymph
node, axillary lymphadenectomy.
of the most important prognostic indicators in invasive breast carci-
noma.1,2The treatment of operable, invasive, early-stage breast car-
cinoma involves axillary lymphadenectomy, which is particularly
valuable in the choice of adjuvant therapy.3This surgical procedure
causes local morbidity, resulting in lymphocele, pain, limited shoul-
der movement and upper limb lymphedema.4Axillary sentinel lymph
node (ASLN) resection is an alternative to lymphadenectomy.5The
morbidity related to ASLN resection is significantly less compared
with the morbidity related to axillary lymphadenectomy.6–8A de-
tected ASLN free of metastatic involvement indicates that the other
xillary lymph node status, as determined by histologic examina-
tion of axillary lymph nodes draining the breast, is currently one
© 2004 American Cancer Society
lymph nodes of the axilla also may be considered free
of metastatic involvement, so that lymphadenectomy
ASLN can be detected with peritumoral injection
of lymphotropic products (stains and/or isotopes) that
map the regional lymph network of the tumor. The
best results are obtained by combining a staining
method (patent blue) with isotopes labeled with tech-
The main criteria for the success of the ASLN
technique are the detection rate and the false-negative
rate. The detection rate is an indirect indicator of
detection failure, in which case axillary lymphadenec-
tomy must be required, involving a particular risk of
axillary morbidity.13A false-negative result corre-
sponds to a finding of a metastasis free ASLN with
metastatic involvement of other axillary lymph nodes.
This situation can lead to inadequate treatment and
may reduce the chances for recovery.13The false-neg-
ative rate can be evaluated accurately only by con-
comitant performance of the ASLN technique and
complementary axillary resection.14This two-fold sur-
gical procedure corresponds to the learning curve.15
Many previously published studies evaluated the
parameters that influence the success rate of ASLN de-
tection, such as tumor size,16breast location,17injection
site of lymphotropic tracers,18delay between injections
of lymphotropic tracers, and surgical resection of breast
carcinoma.19The pathologic subtype of the primary tu-
mor rarely has been studied as a parameter affecting the
results of ASLN detection. Lobular invasive carcinoma
(LIC), which was described first by Foote and Stewart in
1941, is characterized by the growth of small, round,
bland-looking, noncohesive tumor cells in a dispersed,
desmoplastic stroma.20The ill-defined pattern of LIC,
i.e., scattered noncohesive cells producing a poorly pal-
pable tumor, raises questions regarding the feasibility
and accuracy of lymph node staging with the sentinel
lymph node technique. The accuracy of ASLN detection
in patients with LIC is of particular interest in view of
increasing rates of LIC incidence since 1977, specifically
among women age ? 50 years, due to the specific risk of
hormone replacement therapy.21,22The objective of the
current study was to evaluate whether the ASLN tech-
nique is feasible and accurate in patients who have LIC
compared with patients who have ductal invasive carci-
noma (DIC) in terms of detection rates and false-nega-
MATERIALS AND METHODS
Between June 14, 1999 and January 30, 2003, a pro-
spective series of 243 patients who were treated for
invasive breast carcinoma underwent ASLN resection
and complementary axillary lymphadenectomy in our
center. This was a consecutive series of patients who
were enrolled in the learning curves of each surgeon of
our institute, consistent with inclusion and exclusion
The inclusion criteria were a preoperative diagno-
sis of LIC or DIC by fine-needle aspiration or core
needle biopsy, clinical tumor size ? 3 cm (T0, T1, T2
? 3 cm), an axilla clinically free of pathologic lymph
nodes (N0), and an operable breast tumor. Exclusion
criteria were pregnancy, lack of a preoperative diag-
nosis, a histologic subtype other than LIC or DIC, and
previous tumor excision or neoadjuvant chemother-
The radiodetection method used unfiltered, techne-
tium 99m-labeled rhenium sulfide colloids (Nanocis?
kit) injected superficially within the parenchyma
around the tumor. An activity of 30–40 megabecque-
rels (MBq) in 2 ? 0.1 mL of physiologic serum was
used when the injection was made 1 day before sur-
gery, and activity of 20–30 MBq in 2 ? 0.1 mL of
physiologic serum was used when it was made the
morning before surgery. The intraoperative detection
protocol for each patient included successive counts
for background and for each ASLN.
Colorimetric detection involved peritumoral in-
jection of 2 mL of patent blue under general anesthe-
sia. The surgical technique was comprised of breast
tumorectomy followed by ASLN detection and then a
complementary functional axillary lymphadenectomy
of the first two Berg levels.
Definition of the ASLN
The ASLN was defined by intraoperative detection of a
number of counts per second that was at least twice
the number of counts for background and/or for blue
lymph node staining.
Each ASLN was cut into 10 4-?m sections. Standard
hematoxylin-phloxine-saffron (HPS) staining was per-
formed on Levels 1, 4, and 7. In the absence of metas-
tasis or micrometastasis detected on these first sec-
performed at the three intermediary levels. Microme-
tastasis was defined as a metastasis that measured
? 0.2 cm in greatest dimension. For each lymph node
obtained by lymphadenectomy, a 4-?m section was
cut from each block and stained with HPS, and no IHC
labeling was performed. No intraoperative histopatho-
logic examination was performed.
936CANCER March 1, 2004 / Volume 100 / Number 5
Definition of the detection rate
The detection rate was defined as the number of pa-
tients with an ASLN that was isolated relative to the
total number of patients included in the study.
Definition of the false-negative rate
The false-negative rate was defined as the ratio of 1)
the number of patients who had an ASLN that was
detected and was not involved, but who had involved
non-ASLNs, to 2) the number of patients with an iso-
lated ASLN who showed lymph node involvement,
whether sentinel or not (1/2).
The chi-square test was used, with an ? risk of 5%, to
compare detection rates and false-negative rates.
Characteristics of the Population
Patient characteristics are shown in Table 1. The two
populations did not differ statistically with regard to
mean age, breast tumor site, clinical or pathologic
tumor size, and hormone receptor status. The histo-
logic grade of LIC consistently was Grade 2 (Table 1).
Results for resected lymph nodes are shown in Table
2. The mean number of resected lymph nodes and the
numbers of patients with involved lymph nodes were
equivalent for patients with DIC and patients with LIC.
The resected ASLN results are shown in Table 3. The
number of patients for whom an ASLN was the only
involved lymph node did not differ statistically be-
tween patients with DIC and patients with LIC. The
relative proportion of patients who had micrometas-
tasis detected by IHC was greater for patients who had
Clinical Characteristics of the Population of 243 Patients
No. of patients
Mean ? SD age (yrs)
Clinical size of tumor
T2 (? 3 cm)
Median ? SD pathologic tumor
Pathologic tumor grade (SBR)
Hormone receptor status
Not defined (ER or PR)
56 ? 10
57 ? 10NS
1.8 ? 10.3 2.1 ? 12.7NS
DIC: ductal invasive carcinoma; LIC: lobular invasive carcinoma; SD: standard deviation; NS: not
ILQ: internal lower quadrant; UEQ: union of external quadrants; ULQ: union of internal quadrants;
UUQ: union of upper quadrants; ULQ: union of lower quadrants; SBR: Scarff–Bloom–Richardson; ER:
estrogen receptor; PR: progesterone receptor.
Pathologic Results for All Lymph Nodes (Including Axillary Sentinel
(n ? 208
(n ? 35
Mean ? SD no. of
No. of patients with
9.5 ? 3.4 9.8 ? 3.7NS
85 (40.8) 11 (31.4)NS
DIC: ductal invasive carcinoma; LIC: lobular invasive carcinoma; SD: standard deviation; NS: not
Pathologic Results for Axillary Sentinel Lymph Nodes
(n ? 208
(n ? 35
Mean ? SD no. of ASLN
No. of patients with involved
No. of patients with ASLN the
only involved lymph node(s)
No. of patients with
micrometastasis into ASLN
Micrometastasis detected with
2.2 ? 1.2 2.0 ? 0.93 NS
73/194 (35.6)10/33 (30.3)NS
43/73 (60.5)5/10 (50)NS
DIC: ductal invasive carcinoma; LIC: lobular invasive carcinoma; ASLN: axillary sentinel lymph nodes;
NS: not significant; HPS: hematoxylin phyloxin saffron; IHC: immunohistochemistry.
ASLN in Lobular Invasive Breast Carcinoma/Classe et al.937
LIC compared with patients who had DIC, although
the difference was not statistically significant.
The detection rates are shown in Table 4. The detec-
tion rate for ASLN was 94.3% in patients with LIC and
93.2% in patients with DIC. Detection rates were
equivalent between patients with LIC and patients
False Negative Rate
The false-negative rates are shown in Table 5. The
false-negative rates did not appear to differ for pa-
tients with LIC and patients with DIC.
The objective of the current study was to determine
the feasibility and accuracy of the ASLN technique in
LIC compared with DIC. Conservative surgical treat-
ment, involving breast tumor excision and axillary
lymphadenectomy combined with radiotherapy, is in-
dicated for both patients with LIC and patients with
DIC, and the outcomes for patients with both sub-
types are similar in terms of local recurrence and
survival.23–25Sentinel lymph node principles are two-
fold: the detection of a sentinel lymph node and the
ability of this lymph node to represent accurately the
pathologic status of the other regional lymph nodes.
ASLN Detection and Preoperative Diagnosis
The first step in the ASLN technique is to inject lym-
photropics, assuming that a preoperative diagnosis of
invasive carcinoma has been made. Preoperative di-
agnosis, using fine-needle aspiration or biopsy, is par-
ticularly difficult in patients with LIC.26Whether sur-
gical biopsy involving excision of the primary breast
tumor is required for diagnostic accuracy of ASLN
detection is controversial.
Detection Rate and Histologic Subtype
Our results for the ASLN detection rate did not differ
between patients with LIC and patients with DIC
(94.3% vs. 93.2%). In previously published studies, the
ASLN detection rate for patients with LIC was equiv-
alent5,13or marginally lower27compared with the rate
for patients with DIC. The particular pathologic struc-
ture of LIC does not appear to influence the ASLN
Accuracy of Staging and Histologic Subtype
The main risk of the ASLN technique is that breast
carcinoma staging may be underestimated. Failure to
detect a metastatic axillary lymph node may compro-
mise the patient’s chances for recovery. To date, few
studies have considered the impact of pathologic sub-
typeon ASLN detection
Beechey-Newman, in an important review of the main
historic series of ASLN detection for early breast car-
cinoma, did not consider it necessary to separate re-
sults for DIC and LIC.28The false-negative rate in our
series did not differ between patients with LIC and
patients with DIC (9% vs. 7.6%; not significant). In
previously published studies, axillary staging with
ASLN resection was equivalent to that of axillary
lymphadenectomy both for favorable (tubular, med-
ullary, and colloid) histologic subtypes and for unfa-
vorable (ductal, lobular, and unspecified) histologic
subtypes.29The accuracy of ASLN in predicting axil-
lary status was 100% in a series of 105 patients with
False-negative evaluation requires both ASLN de-
tection and axillary lymphadenectomy.31This two-
fold procedure corresponds to a learning curve (for
which only 10–20 patients are recommended).15,32
The median false-negative rate is 5–10%.33Accurate
evaluation of the false-negative rate requires a large
group of patients with both ASLN detection and
results. For example,
Detection rate of Axillary Sentinel Lymph Nodes in Ductal Invasive
Carcinoma and Lobular Invasive Carcinoma
DIC: ductal invasive carcinoma; LIC: lobular invasive carcinoma; NS: not significant.
False-Negative Rates for Ductal Invasive Carcinoma and Lobular
A: No. patients with no ASLN involved
and no sentinel nodes involved
B: No. patients with ASLN detected
and lymph nodes involved, sentinel
False-negative rate (%)
DIC: ductal invasive carcinoma; LIC: lobular invasive carcinoma; NS: not significant; ASLN: axillary
sentinel lymph nodes.
aFalse-negative rate ? A/B.
bThe number of patients who had an axillary sentinel lymph node detected that was negative and who
had at least 1 involved lymph node after undergoing axillary dissection (DIC, 73 ? 6; LIC, 10 ? 1).
938 CANCER March 1, 2004 / Volume 100 / Number 5
lymph node metastasis. This requirement is particu-
larly difficult to fulfill for LIC, which is a rare histologic
subtype, representing 15% of breast invasive carcino-
The false-negative rate tends to increase in pro-
portion to the risk of axillary lymph node metastasis.
In the current series, axillary lymph nodes were in-
volved in 11 of the 35 patients with LIC (31.4%) and in
85 of the 208 patients with DIC (40.8%) (difference not
statistically significant). The impact of the LIC or DIC
subtype on the risk of lymph node involvement re-
mains debatable.35In a recent multiparameter analy-
sis, Velanovich and Szymanski showed that LIC was
not an independent predictor of lymph node involve-
ment compared with DIC.36In the current series, the
proportion of patients in whom the ASLN was the only
involved lymph node was approximately the same for
patients with DIC and patients with LIC (43 of 71
patients vs. 5 of 10 patients; difference not statistically
Tumor size is the main criterion for lymph node
metastasis.37In the current series, pathologic tumor
size was nearly the same for patients with LIC and
patients with DIC (2.1 mm vs. 1.8 mm). In fact, tumor
size still is the main accurate predictor of lymph node
involvement, even for tumors that measure ? 2 cm,
which represents the main validated indication for
ASLN resection.38For large tumors, the accuracy of
ASLN detection is controversial, because the false-
negative rate is too high.39Large, advanced tumors
appear to constitute a contraindication for lymphatic
mapping.40In the multicenter validation study of the
ASLN technique reported by Krag et al., the mean
tumor size was 1.9 ? 1.3 cm.5Thus, tumor size ap-
pears to be the main tumor characteristic predicting
lymph node involvement, even in patients who have
ASLN metastasis of LIC.29
The pathologic characteristics of LIC, such as the
lack of stromal reaction, are consistent with the clin-
ical difficulties in evaluating tumor size.3In a previ-
ously published series that made a comparison be-
tween 2155 patients with DIC and 217 patients with
LIC, clinical under evaluation was more frequent for
the patients with LIC (statistically significant differ-
ence; P ? 0.05).41It was found that the median clinical
size of LIC was greater compared with the median
clinical size of DIC.42Mammographic diagnosis of LIC
provides a high rate of misestimation,43whereas ul-
trasonography or magnetic resonance imaging is use-
ful for preoperative characterization.44,45
The pathologic grade may be associated with
lymph node metastasis.46In our series, Grade 2 tu-
mors were more frequent in patients with LIC (P
? 0.0001). LIC more frequently is a low-grade tumor
and rarely is a Grade 3 tumor.47The validity of grading
lobular invasive carcinoma requires further evalua-
The accuracy of ASLN resection for determining
lymph node metastasis in patients with LIC is debat-
able. In fact, the particular biology and cell growth of
this tumor make it difficult to identify lymph node
metastases.48In a series of 50 patients with LIC that
was classified as lymph node negative, metastases
were detected by IHC in 12 patients (24%).48Many
lymph node metastases from LIC, especially occult
metastases, are missed by conventional histologic
analysis, but not by IHC.49Micrometastasis in ASLN,
detected solely by IHC, appears to be more frequent in
patients with LIC.49In patients with LIC, micrometas-
tases correspond to isolated cells,49and isolated cells
are detectable only with IHC. In our experience, the
detection micrometastases with IHC was more fre-
quent in patients who had LIC compared with patients
who had DIC; however, that result did not reach sta-
tistical significance. It is not our practice to make a
distinction between micrometastases and isolated
cells. In our institution, these two situations are con-
sidered indications for performing complete axillary
lymphadenectomy, but not for adjuvant chemother-
apy. In fact, it is controversial whether axillary lymph-
adenectomy should be performed even in a patient
with an involved sentinel lymph node.50Hansen et al.,
in a study of 683 patients, found that patients who had
ASLN detected solely by IHC had the same overall
survival rate as patients who had negative ASLN sta-
On the basis of preoperative diagnosis and accurate
evaluation of tumor size, ASLN detection appears to
be a feasible and accurate method for axillary staging
of early breast LIC. This finding must be confirmed
through a larger series. The management of immuno-
histochemically detected micrometastases remains a
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