Predictors for nonsentinel node involvement in breast cancer patients with micrometastases in the sentinel lymph node.
ABSTRACT Sentinel lymph node (SLN) biopsy in breast cancer allows for a more thorough pathologic assessment with serial sectioning and cytokeratin staining. This has resulted in increased detection of micrometastatic disease (tumor size < 2 mm) in the SLN. Unfortunately, the value of completion axillary dissection after finding micrometastatic disease in the SLN remains poorly defined. Over a 2-year period, a prospective database of 305 patients who underwent SLN biopsy for breast cancer at Baylor University Medical Center was reviewed. Eighty-four (27.5%) of the patients had evidence of metastatic disease in the SLN. Twenty-four of the 41 patients identified as having micrometastatic disease in the SLN underwent completion axillary lymph node dissection. In these patients, all nonsentinel nodes were further studied by serial sectioning and immunohistochemistry. The median age of these 24 patients was 52 years (range, 34-83). Their primary tumor stages were T1a and T1b (n = 5), T1c (n = 15), and T2 (n = 4). A total of 328 nonsentinel lymph nodes were examined, including 225 from patients with infiltrating ductal carcinoma (n = 17) and 103 from patients with infiltrating lobular carcinoma (n = 7). In the patients with infiltrating ductal carcinoma, no additional nodal metastases were identified, while in those with infiltrating lobular carcinoma, additional nodal disease was found in 5 lymph nodes (2 of 12 patients, 17%). Primary tumor characteristics were not predictive of additional nodal disease. These data suggest that patients with micro-metastasis in the SLN from infiltrating lobular carcinoma have a significant risk of harboring additional nodal disease and should undergo completion axillary dissection. However, those with micrometastatic disease from infiltrating ductal carcinoma have a very low incidence of additional metastasis and may not need completion axillary dissection.
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ABSTRACT: BACKGROUND: It has been suggested that selective sentinel node (SN) biopsy alone can be used to manage early breast cancer, but definite evidence to support this notion is lacking. The aim of this study was to investigate whether refraining from completion axillary lymph node dissection (ALND) suffices to produce the same prognostic information and disease control as proceeding with completion ALND in early breast cancer patients showing micrometastasis at SN biopsy. METHODS: This prospective, randomized clinical trial included patients with newly diagnosed early-stage breast cancer (T < 3.5 cm, clinical N0, M0) who underwent surgical excision as primary treatment. All had micrometastatic SN. Patients were randomly assigned to one of the two study arms: complete ALND (control arm) or clinical follow-up (experimental arm). Median follow-up was 5 years, recurrence was assessed, and the primary end point was disease-free survival. RESULTS: From a total sample of 247 patients, 14 withdrew, leaving 112 in the control arm and 121 in the experimental arm. In 15 control subjects (13 %), completion ALND was positive, with a low tumor burden. Four patients experienced disease recurrence: 1 (1 %) of 108 control subjects and 3 (2.5 %) of 119 experimental patients. There were no differences in disease-free survival (p = 0.325) between arms and no cancer-related deaths. CONCLUSIONS: Our results strongly suggest that in early breast cancer patients with SN micrometastasis, selective SN lymphadenectomy suffices to control locoregional and distant disease, with no significant effects on survival.Annals of Surgical Oncology 09/2012; · 4.12 Impact Factor
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ABSTRACT: BACKGROUND: Sentinel lymph node biopsy (SLNB) has become standard of care as a staging procedure in patients with invasive breast cancer. A positive SLNB allows completion axillary lymph node dissection (cALND) to be performed. The axillary recurrence rate (ARR) after cALND in patients with positive SLNB is low. Recently, several studies have reported a similar low ARR when cALND is not performed. This review aims to determine the ARR when cALND is omitted in SLNB-positive patients. METHODS: A literature search was performed in the PubMed database with the search terms "breast cancer," "sentinel lymph node biopsy," "axillary" and "recurrence." Articles with data regarding follow-up of patients with SLNB-positive breast cancer were identified. To be eligible, patients should not have received cALND and ARR should be reported. RESULTS: Thirty articles were analyzed. This resulted in 7,151 patients with SLNB-positive breast cancer in whom a cALND was omitted (median follow-up of 45 months, range 1-142 months). Overall, 41 patients developed an axillary recurrence. 27 studies described 3,468 patients with micrometastases in the SLNB, of whom 10 (0.3 %) developed an axillary recurrence. ARR varied between 0 and 3.7 %. Sixteen studies described 3,268 patients with macrometastases, 24 (0.7 %) axillary recurrences were seen. ARR varied between 0 and 7.1 %. Details regarding type of surgery and adjuvant treatment were lacking in the majority of studies. CONCLUSIONS: ARR appears to be low in SLNB-positive patients even when a cALND is not performed. Withholding cALND may be safe in breast cancer selected patients such as those with isolated tumor cells or micrometastatic disease.Annals of Surgical Oncology 08/2012; · 4.12 Impact Factor
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ABSTRACT: To evaluate the long-term disease-free and overall survival of patients with sentinel lymph node (SLN) micrometastases, in whom a completion axillary lymph node dissection (ALND) was systematically omitted. The use of step sectioning and immunohistochemistry for SLN analysis results in a more accurate histopathologic examination and a higher detection rate of micrometastases. However, the clinical relevance and therapeutic implications of SLN micrometastases remain a matter of debate. In this prospective study, 236 SLN biopsies were performed in 234 consecutive early-stage breast cancer patients (T1, T2 ≤ 3 cm, cN0 M0) between 1998 and 2002. The SLN were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry. None of the patients with negative SLN or SLN micrometastases (International Union Against Cancer classification, >0.2 to ≤ 2 mm) underwent a completion ALND or radiation to the axilla. Long-term overall and disease-free survivals were compared between patients with negative SLN and those with SLN micrometastases by log rank tests. The SLN was negative in 55% of patients (123 of 224). SLN micrometastases were detected in 27 patients (27 of 224, 12%). After a median followup of 77 months (range, 24-106 months), neither locoregional recurrences nor distant metastases occurred in any of the 27 patients with SLN micrometastases. There were no statistically significant differences for overall (P = 0.656), locoregional (P = 0.174), and axillary and distant disease-free survival (P = 0.15) between patients with negative SLN and SLN micrometastases. This analysis of unselected patients provides evidence that a completion level I and II ALND may be safely omitted in early-stage breast cancer patients with SLN micrometastases.Indian journal of surgical oncology. 01/2010; 1(1):59-67.
BUMC PROCEEDINGS 2003;16:3–6
Sentinel lymph node (SLN) biopsy in breast cancer allows for a more thor-
ough pathologic assessment with serial sectioning and cytokeratin stain-
ing. This has resulted in increased detection of micrometastatic disease
(tumor size <2 mm) in the SLN. Unfortunately, the value of completion
axillary dissection after finding micrometastatic disease in the SLN re-
mains poorly defined. Over a 2-year period, a prospective database of
305 patients who underwent SLN biopsy for breast cancer at Baylor
University Medical Center was reviewed. Eighty-four (27.5%) of the
patients had evidence of metastatic disease in the SLN. Twenty-four of
the 41 patients identified as having micrometastatic disease in the SLN
underwent completion axillary lymph node dissection. In these patients,
all nonsentinel nodes were further studied by serial sectioning and im-
munohistochemistry. The median age of these 24 patients was 52 years
(range, 34–83). Their primary tumor stages were T1a and T1b (n = 5), T1c
metastases increases, patient survival decreases (1–3). The num-
ber of lymph nodes containing tumor also determines the need
for and type of adjuvant therapy. As breast cancer surgery be-
comes more conservative, the best method of obtaining this in-
formation is evolving. Traditionally, an axillary dissection
comprising level I and II lymph nodes was done to provide stag-
ing and prognostic information (4). With the advent of senti-
nel lymph node (SLN) biopsy, this same information can be
obtained by removal of only a few nodes, thus avoiding much of
the morbidity associated with a standard axillary dissection.
SLN biopsy findings have been shown to be a very sensitive
predictor of regional metastasis, with accuracies of 90% to 100%
(5–15). Recent reports suggest that the SLN is often the only
node containing metastatic disease (6, 7, 10, 11, 16–18). Thus,
removing additional lymph nodes may not provide additional
useful information. It may be valuable to identify the subset of
patients in whom tumor cells are confined only to the sentinel
node. Some studies have suggested that small primary tumors
with micrometastases (tumor size <2 mm) in the SLN harbor a
very low incidence of nonsentinel lymph node (non-SLN) me-
tastasis (3, 19). Turner et al suggested that the size of the primary
tumor and peritumoral lymphovascular invasion correlate with
non-SLN metastasis (20). Unfortunately, most prior studies have
not included extensive pathologic evaluation of the non-SLNs.
The purpose of this study was to correlate the size of nodal me-
tastasis and tumor histology as predictors of involvement of non-
Predictors for nonsentinel node involvement in
breast cancer patients with micrometastases in the
sentinel lymph node
ARCHANA GANARAJ, MD, JOSEPH A. KUHN, MD, RONALD C. JONES, MD, MICHAEL D. GRANT, MD,
VALERIE R. ANDREWS, MD, SALLY M. KNOX, MD, GEORGES J. NETTO, MD, BASEL ALTRABULSI, MD,
SHERYL A. LIVINGSTON, RN, MSN, AND TODD M. MCCARTY, MD
From the Departments of Surgery (Ganaraj, Kuhn, Jones, Grant, Andrews, Knox,
Livingston, McCarty) and Pathology (Netto, Altrabulsi), Baylor University Medi-
cal Center, Dallas, Texas.
Corresponding author: Todd M. McCarty, MD, 3409 Worth Street, Suite 420, Dal-
las, Texas 75246.
(n = 15), and T2 (n = 4). A total of 328 nonsentinel lymph nodes were
examined, including 225 from patients with infiltrating ductal carcinoma
(n = 17) and 103 from patients with infiltrating lobular carcinoma (n =
7). In the patients with infiltrating ductal carcinoma, no additional nodal
metastases were identified, while in those with infiltrating lobular car-
cinoma, additional nodal disease was found in 5 lymph nodes (2 of 12
patients, 17%). Primary tumor characteristics were not predictive of
additional nodal disease. These data suggest that patients with micro-
metastasis in the SLN from infiltrating lobular carcinoma have a signifi-
cant risk of harboring additional nodal disease and should undergo
completion axillary dissection. However, those with micrometastatic dis-
ease from infiltrating ductal carcinoma have a very low incidence of
additional metastasis and may not need completion axillary dissection.
egional lymph node metastasis has long been considered
the most important predictor of survival in patients with
invasive breast cancer. As the number of lymph node
SLNs based on serial sectioning and immunohistochemistry of
PATIENTS AND METHODS
Between October 1997 and December 1999, 305 patients
who were enrolled in an institutional review board–approved
prospective study underwent SLN biopsy at Baylor University
Medical Center in Dallas, Texas. The SLN was identified by
preoperative injection of unfiltered technetium 99 sulfur colloid
(99 Tc; CIS, Bedford, Mass) and intraoperative injection of blue
dye. A total of 1 mCi of 99 Tc in an 8-cc volume was injected
around the tumor the morning of surgery in the nuclear medi-
cine department. Preoperative lymphoscintigraphy was done in
all patients, and a hand-held gamma probe (C-trak; Carewise
Medical, Palo Alto, Calif) was used intraoperatively to identify
the hot nodes. Approximately 5 minutes before incision, 3 to 5
cc of isosulfan blue dye (Lymphazurin; USSC, Norwalk, Conn)
was injected peritumorally. Nodes were considered sentinel if
they were hot, blue, or both hot and blue. The nodes were then
sent for pathological review.
SLNs suggestive of disease were evaluated by frozen section.
Tissue sections were fixed in 10% formalin and embedded in
paraffin. All SLNs were serially sectioned along their long axis
BAYLOR UNIVERSITY MEDICAL CENTER PROCEEDINGS
VOLUME 16, NUMBER 1
at 1- to 2-mm intervals. Three sections were taken from each
node, at the 30-, 60-, and 90-µ levels, and were stained with rou-
tine hematoxylin and eosin. An additional section of each SLN
was taken for immunohistochemical studies, which were per-
formed on a Ventana Basic DAB 320 Automated Immunostainer
(Tucson, Ariz) using the standard avidin-biotin-peroxidase tech-
nique. Pancytokeratin primary antibody (AE1–AE3, dilution 1/
2000; Boehringer Mannheim, Indianapolis, Ind) was used for
these studies. All patients with positive results on the SLN bi-
opsy were advised to undergo completion axillary dissection.
All non-SLNs obtained from the axillary dissection were
recut at the 30-, 60-, and 90-µ levels and stained with hematoxy-
lin and eosin. An additional section was obtained for immuno-
Of the 305 patients who underwent SLN biopsy, 84 (28%)
had positive findings for metastatic disease in the SLN. These
patients ranged in age from 32 to 83 years, with a median age of
53 years. Tumor pathology included infiltrating ductal carcinoma
in 67 patients and infiltrating lobular carcinoma in 17 patients.
As tumor size increased, so did the percentage of SLNs that were
positive for disease (Table 1). One half of all patients with dis-
ease in the SLN had a T1c tumor. Micrometastases were identi-
fied in the SLNs of 41 patients (49%).
Of the 17 patients with infiltrating lobular carcinoma in the
SLN, 5 had macrometastasis and 12 had micrometastasis. Four
of the 5 patients with macrometastasis had completion axillary
dissection, and 3 (75%) of these patients had positive findings
in node(s) other than the SLN by hematoxylin-eosin staining.
Of the 12 patients with infiltrating lobular carcinoma who had
micrometastatic disease, only 7 agreed to undergo completion
axillary dissection, and 2 (29%) of these patients were found to
have additional positive node(s) on hematoxylin-eosin staining
In the group of 67 patients with infiltrating ductal carcinoma,
38 had macrometastasis and 29 had micrometastasis. Most of the
patients with macrometastasis (35/38) underwent completion
axillary dissection, and 11 (31%) of these patients were found
to have other positive nodes. Of the 29 patients with micro-
metastatic disease, 17 underwent completion axillary dissection.
None of these patients were found to have additional nodal dis-
ease (Table 2), a significant difference from patients with macro-
metastasis in the SLN (P = 0.025).
The 24 patients with micrometastatic disease who underwent
completion axillary dissection were further evaluated. These
patients ranged in age from 34 to 83 years, with a median age of
52 years. Five of these patients had a primary tumor size ≤1 cm,
12 had a primary tumor between 1 and 2 cm, and 7 had a pri-
mary tumor >2 cm. Eleven (46%) of these patients had lympho-
vascular invasion. Three patients had grade 1 tumors, 11 had
grade 2 tumors, 6 had grade 3 tumors, and in 4 patients the grade
was unknown. The tumors were negative for estrogen receptor
in 4 patients and for progesterone receptor in 5 patients.
Fifty of the 84 patients with metastatic disease underwent
frozen section analysis. This analysis successfully identified me-
tastasis in the sentinel node only about half of the time. All pa-
tients whose sentinel node was positive on frozen section analysis
had an immediate axillary dissection. In all, 63% of the positive
nodes were found by hematoxylin-eosin staining alone; 30%, by
frozen section and hematoxylin-eosin staining; and 8%, by cyto-
keratin staining alone.
Table 1. Sentinel lymph nodes positive for disease according to
stage of primary tumor
Tumor stagenNo. positive SLN%
142 42 30
48 22 46
Table 2. Patients with sentinel and axillary lymph nodes positive for disease among 305 breast cancer patients evaluated with
sentinel lymph node biopsy
Infiltrating ductal carcinoma
Infiltrating lobular carcinoma
Number of patients
Number who underwent completion axillary dissection
Number with additional nodes positive on hematoxylin-eosin
11 (31%)0 3 (75%) 2 (29%)
*Macrometastases are defined as >2 mm; micrometastases, as <2 mm.
Table 3. Cytokeratin staining of axillary lymph nodes in 24 patients
with sentinel lymph node micrometastases who underwent
completion axillary lymph node dissection
Infiltrating breast carcinoma
Cytokeratin staining of all axillary nodes
Total number of nodes studied
Median number of nodes per patient
Additional nodes positive by cytokeratin
Number of patients with additional
All of the lymph nodes obtained through completion axil-
lary dissections of patients with micrometastatic disease were
serially sectioned and stained by immunohistochemical tech-
niques in a blinded fashion. A total of 328 non-SLNs were ex-
amined, including 225 from the 17 patients with infiltrating
ductal carcinoma and 103 from the 7 patients with infiltrating
lobular carcinoma. Among the 103 lymph nodes associated with
infiltrating lobular carcinoma, 5 nodes from 2 patients were posi-
tive for disease by cytokeratin staining. Of the 225 nodes asso-
ciated with infiltrating ductal carcinoma, no additional nodal
metastases were seen, even with immunohistochemical stains (P
= 0.117) (Table 3).
The 17 patients with micrometastases who refused axillary
dissection have now been followed for a mean of 30 months, and
there have been no axillary recurrences.
The best predictor of survival among patients with breast
cancer has long been considered to be axillary lymph node sta-
tus. As breast cancers are being detected and treated at very early
stages, the incidence of axillary nodal involvement has decreased.
Previously, an axillary dissection comprising level I and II nodes
was done to provide staging and prognostic information (4).
However, most researchers point to the NSABP B04 trial, which
showed no survival benefit when comparing mastectomy with
axillary dissection, mastectomy alone, or mastectomy plus radia-
tion for clinically negative axilla (21). Axillary node dissection
can be associated with a wide range of complications, including
paresthesia due to intercostobrachial nerve injury, wound infec-
tion, seroma, drain complications, and lymphedema (22), which
develops in 15% to 20% of patients after breast cancer treatment
(23). SLN biopsy can provide the prognostic information that
is needed while avoiding the morbidity of an axillary dissection
in patients with a low risk of axillary metastasis.
With an SLN biopsy, only a few nodes are biopsied, and the
examination of these nodes can be more thorough than that with
axillary dissection. Serial sectioning and immunohistochemical
staining can identify small deposits of tumor. Retrospective and
prospective studies have shown that these intensive pathologic
studies in patients with clinically negative nodes can detect oc-
cult metastatic disease in as many as 33% of patients with breast
cancer (24). This study found that approximately 14% of the
total group of patients who underwent axillary dissection for
breast cancer had micrometastasis, which was largely detected
by serial sectioning and immunohistochemical staining. Trojani
et al (25) found a higher incidence of micrometastasis in patients
with lobular carcinoma, which correlates well with the results
of this study.
The significance of these micrometastases has remained con-
troversial. Earlier investigations showed micrometastases to have
no significance in survival (26, 27). More recent studies, how-
ever, suggest that micrometastases can have a negative impact
on disease-free and overall survival (25, 28–32). However, in all
of these prior studies on micrometastases, a completion axillary
dissection had been done. Therefore, these micrometastatic de-
posits had been removed.
When the SLN is positive for disease, the current standard
management includes completion axillary dissection based on
the belief that axillary dissection may have therapeutic benefit
in a patient with known metastasis. Protocol Z0011 of the Ameri-
can College of Surgeons Oncology Group (ACOSOG) random-
izes patients with SLN positive for metastatic disease to either
completion axillary dissection plus adjuvant therapy or adjuvant
therapy alone. The rationale for the ethical randomization into
this study is based on several concepts. It is possible that after
accurate staging with SLN biopsy, no residual tumor is left in the
remainder of the axilla. Guiliano et al (6, 9) have shown that in
approximately 70% of cases in which the SLN is positive, it is
the only involved node. However, it is also possible that some
women with SLN metastases will have micro- or macrometastases
in non-SLNs that will progress and develop into regional recur-
rences that may or may not be associated with a decrease in overall
survival. On the other hand, metastases in the non-SLNs may be
destroyed or inhibited by the adjuvant systemic chemotherapy
that is given to most women with involved lymph nodes. Oppos-
ing tangential fields of radiation therapy may also ablate some
Historically, the need for systemic adjuvant chemotherapy
or hormonal therapy has been based upon the presence or ab-
sence of axillary metastasis. Over the past few years, this focus
has changed. The characteristics of the primary tumor, includ-
ing size and biologic characteristics, determine the need for these
systemic agents. This means that many women with negative
axilla receive adjuvant chemotherapy. Since dissection quite
possibly won’t change therapy recommendations, the continued
need for immediate axillary dissection comes into question.
In this study, a thorough evaluation of the non-SLNs in pa-
tients with micrometastases showed that the incidence of addi-
tional metastasis was markedly lower in the invasive ductal group
compared with the infiltrating lobular group. The results of the
prospective ACOSOG protocol may give further guidance for
the management of patients with micrometastases. These data
suggest that patients with micrometastasis in the SLN from in-
filtrating lobular carcinoma have a significant risk of harboring
additional nodal disease and should undergo completion axillary
dissection. However, those with micrometastatic disease from
infiltrating ductal carcinoma have a very low incidence of addi-
tional metastasis and may not need completion axillary dissec-
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