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Journal ArticleDOI

Minimal axillary lymph node involvement in breast cancer has different prognostic implications according to the staging procedure.

27 Jun 2009-Breast Cancer Research and Treatment (Springer US)-Vol. 118, Iss: 2, pp 385-394

TL;DR: Treatment recommendations for systemic therapy should not take into account the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s) only for patients undergoing ALND for staging purposes.
Abstract: It is still controversial whether the identification of micrometastases and isolated tumor cells in the axillary lymph nodes of patients with breast cancer has any prognostic value. We evaluated the prognostic role of isolated tumor cells and micrometastases in the axillary lymph nodes in 3,158 consecutive patients pT1-2 pN0-N1mi (with a single involved lymph node) and M0, referred to the Division of Medical Oncology after surgery performed at the European Institute of Oncology from April 1997 to December 2002. Median follow-up was 6.3 years (range 0.1-11 years). Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) were performed in 2,087 and 1,071 patients, respectively. A worse metastasis-free survival was observed for patients with micrometastatic disease compared to node-negative patients, if staged with ALND (log-rank P < .0001; HR: 3.17; 95% CI 1.72-5.83 at multivariate analysis), but not for patients who underwent SLNB (log-rank P = 0.36). The presence of a single micrometastatic lymph node is associated with a higher risk of distant recurrence as compared to node-negative disease only for patients undergoing ALND for staging purposes. Treatment recommendations for systemic therapy should not take into account the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s).
Topics: Sentinel lymph node (74%), Axillary lymph nodes (73%), Axillary Lymph Node Dissection (72%), Sentinel node (63%), Lymph node (59%)

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Minimal axillary lymph node involvement in breast
cancer has dierent prognostic implications according to
the staging procedure
E. Montagna, G. Viale, N. Rotmensz, P. Maisonneuve, V. Galimberti, A.
Luini, M. Intra, P. Veronesi, G. Mazzarol, G. Pruneri, et al.
To cite this version:
E. Montagna, G. Viale, N. Rotmensz, P. Maisonneuve, V. Galimberti, et al.. Minimal axillary
lymph node involvement in breast cancer has dierent prognostic implications according to the stag-
ing procedure. Breast Cancer Research and Treatment, Springer Verlag, 2009, 118 (2), pp.385-394.
�10.1007/s10549-009-0446-6�. �hal-00535376�

CLINICAL TRIAL
Minimal axillary lymph node involvement in breast cancer
has different prognostic implications according to the staging
procedure
E. Montagna Æ G. Viale Æ N. Rotmensz Æ P. Maisonneuve Æ V. Galimberti Æ
A. Luini Æ M. Intra Æ P. Veronesi Æ G. Mazzarol Æ G. Pruneri Æ G. Renne Æ
R. Torrisi Æ A. Cardillo Æ G. Cancello Æ A. Goldhirsch Æ M. Colleoni
Received: 8 June 2009 / Accepted: 10 June 2009 / Published online: 27 June 2009
Ó Springer Science+Business Media, LLC. 2009
Abstract It is still controversial whether the identifica-
tion of micrometastases and isolated tumor cells in the
axillary lymph nodes of patients with breast cancer has any
prognostic value. We evaluated the prognostic role of
isolated tumor cells and micrometastases in the axillary
lymph nodes in 3,158 consecutive patients pT1-2 pN0-
N1mi (with a single involved lymph node) and M0,
referred to the Division of Medical Oncology after surgery
performed at the European Institute of Oncology from
April 1997 to December 2002. Median follow-up was
6.3 years (range 0.1–11 years). Sentinel lymph node
biopsy (SLNB) and axillary lymph node dissection
(ALND) were performed in 2,087 and 1,071 patients,
respectively. A worse metastasis-free survival was
observed for patients with micrometastatic disease com-
pared to node-negative patients, if staged with ALND
(log-rank P \ .0001; HR: 3.17; 95% CI 1.72–5.83 at
multivariate analysis), but not for patients who underwent
SLNB (log-rank P = 0.36). The presence of a single
micrometastatic lymph node is associated with a higher
risk of distant recurrence as compared to node-negative
disease only for patients undergoing ALND for staging
purposes. Treatment recommendations for systemic ther-
apy should not take into account the presence of a single
micrometastatic lymph node identified during complete
serial sectioning of sentinel node(s).
Keywords Micrometastasis Lymph node
Breast cancer
Introduction
The prognostic implications of minimal lymph node (MLN)
involvement (i.e., isolated tumor cells and micrometastases)
for patients with operable breast cancer have long been
debated [14]. However, the repeated observation that even
the minimal involvement of a single axillary lymph node
correlates with a significantly worse outcome in comparison
with uninvolved lymph nodes has influenced the clinical
practice to the point that patients with minimal axillary node
involvement are offered similar treatment choices than
patients with nodal macrometastases.
The introduction and the generalized adoption of senti-
nel lymph node biopsy (SLNB) into the clinical practice
have magnified this problem, because the more accurate
histopathologic scrutiny and the molecular assays per-
formed on the sentinel lymph nodes have increased the
E. Montagna (&) R. Torrisi A. Cardillo G. Cancello
A. Goldhirsch M. Colleoni
Research Unit in Medical Senology, Department of Medicine,
European Institute of Oncology, Via Ripamonti 435,
20141 Milan, Italy
e-mail: emilia.montagna@ieo.it
G. Viale G. Mazzarol G. Pruneri G. Renne
Division of Pathology, European Institute of Oncology,
Via Ripamonti 435, 20141 Milan, Italy
N. Rotmensz
Unit of Quality Control, European Institute of Oncology,
Via Ripamonti 435, 20141 Milan, Italy
P. Maisonneuve
Division of Epidemiology and Biostatistics, European Institute
of Oncology, Via Ripamonti 435, 20141 Milan, Italy
V. Galimberti A. Luini M. Intra P. Veronesi
Division of Senology, European Institute of Oncology,
Via Ripamonti 435, 20141 Milan, Italy
G. Viale P. Veronesi G. Mazzarol G. Pruneri G. Renne
University of Milan School of Medicine, Milan, Italy
123
Breast Cancer Res Treat (2009) 118:385–394
DOI 10.1007/s10549-009-0446-6

prevalence of patients diagnosed with MLN involvement
[57]. Whether this minimal involvement detected by the
very extensive evaluation of the SLN has the same clinical
implications of the corresponding disease detected at the
routine histopathologic examination of axillary lymph node
dissection (ALND) remains to be unveiled. The aim of this
retrospective study is to evaluate, in a large series of
patients who were homogeneously diagnosed and treated in
a single Institution, the prognostic role of MLN involve-
ment according to the methodology used for the axilla
staging (i.e., SNLB vs. complete axillary dissection).
Patients and methods
We prospectively collected data on 8,200 consecutive
breast cancer patients surgically treated and referred for
interdisciplinary evaluation between April 1997 and
December 2002 at the European Institute of Oncology in
Milan. All patients with pT1-pT2 pN0-pN1mi (with a
single positive lymph node) breast cancer were eligible for
the study.
Data on the patient’s medical history, concurrent dis-
eases, type of surgery, histopathologic features and results
of staging procedures were compiled. The study was
notified to the Institutional Review Board.
All patients had the pathologic assessment performed on
the primary tumor, including the evaluation of the primary
tumor size, grade and histologic type, occurrence of
peritumoral vascular invasion, extent of intraductal com-
ponent, and lymph nodes status, after complete ALND or
an SLNB [8]. Tumor grade was evaluated according to
Elston and Ellis [9], and peritumoral vascular invasion
(PVI) was assessed according to Rosen and Oberman [10].
Immunostaining experiments for the localization of ER
and PgR, HER2 protein and Ki-67 antigen were performed
on consecutive tissue sections from the primary tumor, as
previously reported [111].
Only nuclear reactivity was taken into account for ER,
PgR and Ki-67 antigen, whereas only an intense and
complete membrane staining in [10% of the tumor cells
qualified for HER2 over-expression (3?). The results were
recorded as the percentage of immunoreactive cells over at
least 2,000 neoplastic cells. The value of 20% for Ki-67
labeling index (LI) was used as a cut-off in distinguishing
tumors with low (\20%) and high (C20%) proliferative
fraction [11]. Steroid hormone receptors status was clas-
sified as negative (lack of any ER and PgR immunoreac-
tivity, or\1% immunoreactive tumor cells) or positive (ER
and/or PgR C 1% of the cells).
The nodal status was determined according to the
revised tumor-node-metastasis (TNM) staging system for
breast cancer, as presented in the sixth edition of the
American Joint Committee on Cancer Staging Manual
[12]. In particular, if no regional lymph node metastasis
was detected, the tumor was classified as pN0. In case of
only isolated tumor cells, defined as a single tumor cell or
small clusters of cells not more than 0.2 mm in the greatest
dimension detected by immunohistochemistry or hema-
toxylin and eosin stains, the tumor was classified as pN0i?.
In case of micrometastases (larger than 0.2 mm but none
larger than 2 mm in greatest dimension), the tumor was
classified as pN1mi. If nodal metastases larger than 2 mm
were diagnosed, the tumor was classified as pN1a.
Examination of SLN
Lymph nodes were bisected along their major axis if they
measured [5 mm and were frozen. Fifteen adjacent pairs
of 4–5 lm thick, frozen sections in each half lymph node
(total 60 sections) were cut at 50 lm intervals. Additional
pairs of sections were cut at 100 lm intervals in any
residual tissue until the lymph node was sampled com-
pletely. One section from each adjacent pair was stained
with hematoxylin and eosin (H&E).
Examination of axillary non-SLN
The non-SLNs were tagged by Berg level. They were
isolated carefully from surrounding tissue, bisected if they
measured [5 mm and processed routinely. Three to six
H&E stained sections per lymph node cut at 250–500 lm
intervals were examined.
Treatment received
All patients received adequate local treatment (breast-
conserving surgery or total mastectomy) with SLNB or
complete ALND. In general, patients with primary breast
cancer were assigned to SLNB in case of cytologically or
histologically verified breast carcinoma 3 cm or less in size
(measured clinically and/or by imaging techniques) and
clinically uninvolved axillary lymph nodes. The SLN was
identified and isolated using a gamma probe as a guide, as
previously published [13]. SLNB was followed by axillary
dissection if the sentinel node contained metastasis or
MLN involvement. Only 58 patients with MLN involve-
ment in SLN, included in a randomized trial, did not
receive axillary dissection.
Breast irradiation was proposed to all the patients who
received breast-conserving surgery, excluding few elderly
patients for whom radiation was considered inappropri-
ate [14]. Systemic adjuvant therapy was recommended
386 Breast Cancer Res Treat (2009) 118:385–394
123

according to recent St. Gallen Consensus Conferences
Guidelines [15, 16]. For patients with lower risk (e.g. pN0)
and endocrine responsive disease, adjuvant endocrine
therapy alone according to menopausal status was pre-
scribed (tamoxifen or aromatase inhibitor) for 5 years in
postmenopausal patients, or tamoxifen for 5 years plus
gonadotropin releasing hormone analogs for at least
2 years in premenopausal [15]. In patients with features of
incomplete endocrine responsiveness, chemotherapy was
added to the endocrine treatment program (e.g. classical
CMF oral cyclophosphamide, methotrexate and fluoroura-
cil) for a duration of 3–6 courses or AC, adriamycin and
cyclophosphamide, for 4 courses [17, 18]. For patients with
non-endocrine responsive disease, 6 months of chemo-
therapy was considered as the first option (e.g. AC for 4
cycles) followed by classical CMF for 3 courses or clas-
sical CMF for 6 courses [18].
Statistical analysis
The Fisher’s exact test and the Mantel-Haenszel X
2
test for
trend were used to assess the association between cate-
gorical and ordinal variables, respectively. The primary
end points were disease-free survival (DFS) and overall
survival (OS). DFS was defined as the length of time from
the date of surgery to any relapse (including ipsilateral
breast recurrence), the appearance of a second primary
cancer (including contralateral breast cancer), or death,
whichever occurred first. OS was defined as the time from
surgery until the date of death (from any cause) or the date
of last follow-up. Secondary end points were locoregional
relapse free survival, metastasis-free survival (MFS) and
contralateral breast cancer-free survival.
We estimated the cumulative incidence of locoregional
relapse (defined as confined to the ipsilateral breast, chest
wall including mastectomy scars, ipsilateral axillary,
supraclavicular and internal mammary lymph nodes) and
contralateral breast cancer. Plots of the survival according
to nodal status and dimension of the micrometastasis were
drawn using the Kaplan-Meier method. The log-rank test
was used to assess the survival difference between strata.
Cox proportional hazards regression was used to assess the
independent prognostic significance of various clinical and
histopathologic characteristics of the tumor on survival.
Factors included in multiple regression analyses were age,
tumor size, size of micrometastasis, tumor grade, Ki67,
multifocality/multicentricity, ER/PgR status, presence of
PVI, HER2 over-expression and type of surgery. In mul-
tivariate analysis, only variables that retained statistical
significance were included in the final model. All analyses
were performed with the SAS software (SAS Institute,
Cary, NC). All tests were two sided.
Results
A total of 3,158 patients were available for the analysis.
SLNB and ALND were performed in 2,087 and 1,071
patients, respectively. Patients’ characteristics are shown in
Table 1. In the ALND group, 87% of patients were staged
pN0, 4% pN0i?, and 9% pN1mi. In the SLNB group the
lymph node status was as follows: 84% pN0, 4% pN0i?
and 12% pN1mi.
When compared with the SLNB group, the patients in
the ALND group more often had tumor size larger than
2 cm (39 vs. 15% P \ .0001), multifocal/multicentric
breast cancer (22 vs. 7% P \ .0001), Ki-67 C 20%
(54 vs. 41% P \ .0001), higher tumor grade (40 vs. 24
P \.0001), PVI (20 vs. 14% P \ .0001) and HER2 over-
expression (21 vs. 13% P \ .0001).
Treatment
Breast-conserving surgery was the type of surgery more
frequently performed in the SLNB group compared with
the ALND group (97 vs. 68% P \ .0001). Adjuvant
radiotherapy was performed in a higher proportion of
patients in the cohort of SLNB compared with ALND
dissection (95 vs. 67% P \ .0001).
Treatment modality according to nodal status and
endocrine responsiveness are shown in Table 2. Overall,
6.5% of patients were not candidates to adjuvant treatment.
A higher percentage of patients with MLN involvement
who underwent ALND received anthracycline-containing
chemotherapy compared with patients staged with SLNB
(41 vs. 21% P \ .0001). Patients with MLN involvement
staged with ALND were less likely to receive endocrine
therapy alone compared with patients staged with SLNB
(27 vs. 48% P \ .0001).
Events
The median follow-up was 6.3 years (range 0.1–11 years).
The Kaplan-Meier curves for DFS and OS according to
type of axillary staging (SLNB or ALND) are displayed in
Fig. 1. DFS and OS were significantly better for patients in
the SLNB group: 5-DFS was 85% (95% CI: 82.5–87.0%)
in the ALND group compared to 90% (95% CI: 88.5–91.2)
in the SLNB group. Overall survival at 5 years was 95%
(95% CI: 93.5–96.2%) for patients with ALND and 97%
(95% CI: 96.3–97.8%) for patients undergoing SLNB.
Figure 2 displays the DFS and OS curves according to
the presence and size of MLN involvement. In SLNB or
ALND groups, there was no difference in outcome between
Breast Cancer Res Treat (2009) 118:385–394 387
123

patients with pN0 or MLN involvement (ITC, microme-
tastasis 0.2–1 mm or micrometastases 1–2 mm).
Figure 3 shows breast cancer-free survival curves
according to the presence and size of MLN involvement. A
worse MFS was observed for patients with micrometastatic
disease as compared to that of patients with pN0 or with
pNi? only when staged with ALND (log-rank P \ .001).
For patients who had SLNB, however, the presence and
size of MLN involvement did not affect MFS.
Multivariate analysis
The independent association between biological variables
and the risk of relapse and death in the overall population
was analyzed. The results, obtained using Cox proportional
hazards regression analysis, are displayed in Table 3. At the
multivariate analysis, no association was found between
axillary staging methodology and DFS, MFS or OS. The
axillary staging procedure was not associated with the
outcome also when the analysis was restricted to patients
with negative lymph node involvement.
Size of tumor greater than 2 cm was significantly
associated with poorer DFS (HR 1.58; 95% CI: 1.29–1.94),
MFS (HR 2.68; 95% CI: 1.88–3.82) and OS (HR 1.69; 95%
CI:1.21–2.36). Younger (\35 years) and older ([70 years)
ages were significantly associated with increased risk of
any event (HR 1.69; 95% CI: 1.19–2.41 and HR 1.81; 95%
CI: 1.28–2.55, respectively, for DFS) and worse OS (HR
1.89; 95% CI: 1.10–3.26 and HR 2.88; 95% CI: 1.73–4.81,
respectively). High tumor grade was associated with poorer
MFS (HR 2.84; 95% CI: 1.25–6.47) and OS (HR 2.64; 95%
CI: 1.29–5.39). High Ki67 (C20%) was associated with
Table 1 Baseline features according to SLNB and ALND
Characteristics All patients SLNB ALND P-value
All patients 3,158 2,087 1,071
Age group
\35 144 71 (3.4) 73 (6.8)
35–49 1,085 663 (31.8) 422 (39.4)
50–59 1,005 714 (34.2) 291 (27.2)
60–69 710 489 (23.4) 221 (20.6)
70? 214 150 (7.1) 64 (6.0) \.0001
Tumor size (cm)
\0.5 198 156 (7.6) 42 (4.0)
0.5–1 649 520 (25.2) 129 (12.1)
1–2 1,555 1,082 (52.4) 473 (44.5)
2–5 721 308 (14.9) 419 (39.4) \.0001
Unknown 29 21 8
Pt
pT1 2,430 1,776 (85.1) 652 (60.9)
pT2 730 311 (14.9) 419 (39.1) \.0001
Size micrometastasis (mm)
None 2,697 1,762 (84.4) 935 (87.3)
\0.2 132 88 (4.2) 44 (4.1)
0.2–1 230 169 (8.1) 61 (5.7)
1–2 99 68 (3.3) 31 (2.9) 0.03
Tumor Grade
G1 742 555 (27.7) 187 (18.5)
G2 1,396 973 (48.5) 423 (41.9)
G3 878 478 (23.8) 400 (39.6) \.0001
Unknown 142 81 61
Proliferative fraction (Ki67)
\20% 1,701 1,222 (59.4) 479 (45.8)
C20% 1,402 836 (40.6) 566 (54.2) \.0001
Unknown 55 29 26
Multifocality/multicentricity
Monofocal/
monocentric
2,766 1,932 (92.6) 834 (77.9)
Mulifocal/
multicentric
392 155 (7.4) 237 (22.1) \.0001
ER/PgR status
ER-/PgR- 489 260 (12.5) 229 (21.6)
ER-/PgR? 23 9 (0.4) 14 (1.3)
ER?/PgR- 414 271 (13.1) 143 (13.5)
ER?/PgR? 2,206 1,533 (74.0) 673 (63.6) \.0001
Unknown 26 14 12
HER2
0/?/?? 1,832 1,509 (87.1) 323 (78.6)
??? 312 224 (12.9) 88 (21.4) \.0001
Unknown 1,014 354 660
PVI
Absent 2,581 1,758 (86.2) 823 (80.2)
Present 485 282 (13.8) 203 (19.8) \.0001
Unknown 92 47 45
Table 1 continued
Characteristics All patients SLNB ALND P-value
Type of surgery
Breast
conserving
2,753 2,020 (96.8) 733 (68.4)
Mastectomy 405 67 (3.2) 338 (31.6) \.0001
HT
No 649 359 (17.9) 290 (28.4)
Yes 2,381 1,649 (82.1) 732 (71.6) \.0001
CT
No 2,015 1,510 (72.5) 505 (47.2)
Yes 1,140 574 (27.5) 566 (52.8) \.0001
Radiotherapy
No 464 109 (5.2) 355 (33.2)
Yes 2,694 1,977 (94.8) 716 (66.8) \.0001
SLNB sentinel lymph node biopsy, ALND axillary lymph node dis-
section, ER estrogen receptor, PgR progesterone receptor, CT che-
motherapy, HT hormone therapy, PVI peritumoral vascular invasion
388 Breast Cancer Res Treat (2009) 118:385–394
123

Citations
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Journal ArticleDOI
Oreste Gentilini1, Umberto Veronesi1Institutions (1)
TL;DR: A new trial was designed comparing SLNB vs observation when axillary ultra-sound is negative in patients with small breast cancer candidates to breast conserving surgery.
Abstract: Sentinel lymph node biopsy (SLNB) is the standard approach for axillary staging in patients with early breast cancer. Recent data showed no outcome difference in patients with positive sentinel node between axillary dissection vs no further axillary surgery, raising doubts on the role of SLNB itself. Therefore, a new trial was designed comparing SLNB vs observation when axillary ultra-sound is negative in patients with small breast cancer candidates to breast conserving surgery.

302 citations


Journal ArticleDOI
Gábor Cserni1Institutions (1)
TL;DR: It is uncertain whether the advantage of OSNA of detecting practically all metastases due to complete sampling of lymph node tissue is clinically more important than the exclusion of metastases greater than micrometastasis that can be reliably done by intraoperative microscopy followed by permanent section histology.
Abstract: One-step nucleic acid amplification (OSNA) is a novel method introduced for the lymph node staging of breast cancer and has been tested in multiple series. The present review summarises current literature and concerns related to the new method. The results of this automated molecular assay based on the quantification of cytokeratin 19 mRNA show a 96% concordance rate with detailed histopathology complemented with immunohistochemistry when alternative slices of the same lymph node are used for the two tests. The low false-negative rate makes OSNA suitable for the intraoperative evaluation of sentinel lymph nodes. The false-positive rate also seems very low. Most discordant cases are explainable by low volume metastases (micrometastases), which may be missing from the material submitted for one test, but not from the different part used for the other test. It is tempting to change the gold standard for comparisons between the methods, and if this is done, histology seems to come out as a weaker test for the identification of metastases. OSNA detects more low volume nodal involvement, but it is uncertain whether these require further axillary treatment, and this will be a subject for future investigations. Therefore, it is also uncertain whether the advantage of OSNA of detecting practically all metastases due to complete sampling of lymph node tissue is clinically more important than the exclusion of metastases greater than micrometastasis that can be reliably done by intraoperative microscopy followed by permanent section histology.

100 citations


Additional excerpts

  • ...Although there are increasing amounts of data suggesting that micrometastases are of prognostic importance,(47) 48 there has also been a proposal suggesting that micrometastases detected in SLN do not have the same bearing on prognosis as micrometastases from older series.(49) If this proved true and was confirmed by others, it seems that micrometastases should not be looked for in SLN samples, and the general recommendation of identifying possibly all macrometastases(36) 50 would be further supported....

    [...]


Journal ArticleDOI
TL;DR: The high five-year survival and low cumulative incidence of axillary recurrence in this cohort provide justification for the increasingly common practice of foregoing axillary dissection in women with minimal SN involvement, and suggest in particular that AD can safely be avoided in Women with small, low-grade tumors.
Abstract: There is considerable interest in foregoing axillary dissection (AD) when the sentinel node (SN) is positive in early breast cancer, particularly when involvement is minimal (micrometastases or isolated tumor cells). To address this issue we analyzed outcomes in patients with a single micrometastatic SN who did not receive AD. We selected 377 consecutive patients treated at the European Institute of Oncology between 1999 and 2007 for invasive breast cancer. Classical and competing risks survival analyses were performed to estimate prognostic factors for axillary recurrence, first events and overall survival. Median age was 53 years (range 26–80); median follow-up was 5 years (range 1–9). Most (91.8%) patients received conservative surgery; 209 (55.4%) had only one SN (range 1–8). Five-year overall survival was 97.3%. There were 10 local events, 2 simultaneous local and axillary events, 6 axillary recurrences and 12 distant events. The cumulative incidence of axillary recurrence was 1.6% (95% CI 0.7–3.3). By multivariable analysis, tumor size and grade were significantly associated with axillary recurrence. The high five-year survival and low cumulative incidence of axillary recurrence in this cohort provide justification for the increasingly common practice of foregoing AD in women with minimal SN involvement, and suggest in particular that AD can safely be avoided in women with small, low-grade tumors. Nevertheless, a subset of patients might be at high risk of developing overt axillary disease and efforts should be made to identify such patients by ancillary analyses of the results of ongoing or recently published clinical trials.

73 citations


Cites background from "Minimal axillary lymph node involve..."

  • ...It is noteworthy that a recent comparative retrospective study from our Institute found that presence of a single micrometastatic SN was not associated with increased risk of distant recurrence compared to node-negative disease [28]....

    [...]


Journal ArticleDOI
M Salhab1, Neill Patani1, Kefah Mokbel1Institutions (1)
TL;DR: Therapeutic recommendations regarding patients with SLN MM should be taken in the context of multidisciplinary team setting and in selected cases of SLNMM, complete ALND may be safely omitted.
Abstract: Introduction The advent of sentinel lymph node biopsy (SLNB) and advances in histopathological and molecular analysis techniques have been associated with an increase in micrometastasis (MM) detection rate. However, the clinical significance of sentinel lymph node micrometastasis (SLN MM) continues to be a subject of much debate. In this article we review the literature concerning SLN MM, with particular emphasis on the prognostic significance of SLN MM. The controversies regarding histopathological assessment, clinical relevance and management implications are also discussed. Methods Literature review facilitated by Medline and PubMed databases. Cross referencing of the obtained articles was used to identify other relevant studies. Results Published studies have reported divergent and rather conflicting results regarding the clinical significance and implications of axillary lymph node (ALN) MM in general and SLN MM in particular. Some earlier studies demonstrated no associations, however most recent studies have found SLN MM to be an indicator of poorer prognosis and to be associated with non-SLN involvement. The use of adjuvant chemotherapy and/or hormonal manipulation therapy is associated with an improved survival in patients with SLN MM. Complete ALND may be safely omitted provided that adjuvant systemic therapy recommendations are equal to patients with node-positive disease. However, optimal management of SLN MM is yet to conclude. Furthermore, the identification of MM remains largely dependant on the analytical technique employed and the use of immunohistochemistry (IHC) increases the detection rate of SLN MM. Discrepancies in the histopathological interpretation of TNM classification of SLN tumour burden do exist. Published studies were non-randomized and have significant limitations including a small sample size, limited follow-up period, and lack of standardization and reproducibility of pathological examination of the SLN. Conclusion Patients with SLN MM have a poorer prognosis than those who are SLN negative. Therapeutic recommendations regarding patients with SLN MM should be taken in the context of multidisciplinary team setting and in selected cases of SLN MM, complete ALND may be safely omitted. A better reproducibility of pathological interpretation of the TNM classification is required so that future therapeutic guidelines can be applied without confusion.

45 citations


Journal ArticleDOI
Bernd Gerber1, Kristin Heintze1, Johannes Stubert1, Max Dieterich1  +3 moreInstitutions (1)
TL;DR: increasing data support the thesis that remaining axillary metastases neither increase the axillary recurrence rate nor decrease overall survival, and 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.
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.

35 citations


Additional excerpts

  • ...Montagna [98] Prospective cohort 1997–2002 3,158 6....

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References
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Journal ArticleDOI
C. W. Elston1, Ian O. Ellis1Institutions (1)
TL;DR: The results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained.
Abstract: Morphological assessment of the degree of differentiation has been shown in numerous studies to provide useful prognostic information in breast cancer, but until recently histological grading has not been accepted as a routine procedure, mainly because of perceived problems with reproducibility and consistency. In the Nottingham/Tenovus Primary Breast Cancer Study the most commonly used method, described by Bloom & Richardson, has been modified in order to make the criteria more objective. The revised technique involves semiquantitative evaluation of three morphological features--the percentage of tubule formation, the degree of nuclear pleomorphism and an accurate mitotic count using a defined field area. A numerical scoring system is used and the overall grade is derived from a summation of individual scores for the three variables: three grades of differentiation are used. Since 1973, over 2200 patients with primary operable breast cancer have been entered into a study of multiple prognostic factors. Histological grade, assessed in 1831 patients, shows a very strong correlation with prognosis; patients with grade I tumours have a significantly better survival than those with grade II and III tumours (P less than 0.0001). These results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained. Histological grade forms part of the multifactorial Nottingham prognostic index, together with tumour size and lymph node stage, which is used to stratify individual patients for appropriate therapy.

5,229 citations


"Minimal axillary lymph node involve..." refers methods in this paper

  • ...Tumor grade was evaluated according to Elston and Ellis [9], and peritumoral vascular invasion (PVI) was assessed according to Rosen and Oberman [10]....

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Journal ArticleDOI
C. W. Elston1, Ian O. Ellis1, Sarah E Pinder1Institutions (1)

2,186 citations


Journal ArticleDOI
TL;DR: Patients without clinical involvement of the axilla should undergo sentinel-node biopsy routinely, and may be spared complete axillary dissection when the sentinel node is disease-free, and thereby provide important information about the status of axillary nodes.
Abstract: Summary Background Axillary lymph-node dissection is an important staging procedure in the surgical treatment of breast cancer. However, early diagnosis has led to increasing numbers of dissections in which axillary nodes are free of disease. This raises questions about the need for the procedure. We carried out a study to assess, first, whether a single axillary lymph node (sentinel node) initially receives malignant cells from a breast carcinoma and, second, whether a clear sentinel node reliably forecasts a disease-free axilla. Methods In a consecutive series of 163 women with operable breast carcinoma, we injected microcolloidal particles of human serum albumin labelled with technetium-99m. This tracer was injected subdermally, close to the tumour site, on the day before surgery, and scintigraphic images of the axilla and breast were taken 10 min, 30 min, and 3 h later. A mark was placed on the skin over the site of the radioactive node (sentinel node). During breast surgery, a hand-held γ-ray detector probe was used to locate the sentinel node, and make possible its separate removal via a small axillary incision. Complete axillary lymphadenectomy was then done. The sentinel node was tagged separately from other nodes. Permanent sections of all removed nodes were prepared for pathological examination. Findings From the sentinel node, we could accurately predict axillary lymph-node status in 156 (97·5%) of the 160 patients in whom a sentinel node was identified, and in all cases (45 patients) with tumours less than 1·5 cm in diameter. In 32 (38%) of the 85 cases with metastatic axillary nodes, the only positive node was the sentinel node. Interpretation In the large majority of patients with breast cancer, lymphoscintigraphy and γ-probe-guided surgery can be used to locate the sentinel node in the axilla, and thereby provide important information about the status of axillary nodes. Patients without clinical involvement of the axilla should undergo sentinel-node biopsy routinely, and may be spared complete axillary dissection when the sentinel node is disease-free.

1,827 citations


"Minimal axillary lymph node involve..." refers background in this paper

  • ...All patients had the pathologic assessment performed on the primary tumor, including the evaluation of the primary tumor size, grade and histologic type, occurrence of peritumoral vascular invasion, extent of intraductal component, and lymph nodes status, after complete ALND or an SLNB [8]....

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Journal ArticleDOI
TL;DR: Sentinel-node biopsy is a safe and accurate method of screening the axillary nodes for metastasis in women with a small breast cancer.
Abstract: Background Although numerous studies have shown that the status of the sentinel node is an accurate predictor of the status of the axillary nodes in breast cancer, the efficacy and safety of sentinel-node biopsy require validation. Methods From March 1998 to December 1999, we randomly assigned 516 patients with primary breast cancer in whom the tumor was less than or equal to 2 cm in diameter either to sentinel-node biopsy and total axillary dissection (the axillary-dissection group) or to sentinel-node biopsy followed by axillary dissection only if the sentinel node contained metastases (the sentinel-node group). Results The number of sentinel nodes found was the same in the two groups. A sentinel node was positive in 83 of the 257 patients in the axillary-dissection group (32.3 percent), and in 92 of the 259 patients in the sentinel-node group (35.5 percent). In the axillary-dissection group, the overall accuracy of the sentinel-node status was 96.9 percent, the sensitivity 91.2 percent, and the specifi...

1,808 citations


"Minimal axillary lymph node involve..." refers methods in this paper

  • ...The SLN was identified and isolated using a gamma probe as a guide, as previously published [13]....

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