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ORIGINAL ARTICLE
Predictors of positive axillary lymph nodes in
breast cancer patients with metastatic sentinel
lymph node
Isabel Peixoto Callejoa, José Américo Britoc, José Wheinholtz Bivara, Fernando Jesus Fernandesa, João
Leal Fariaa, María Saudade Andréb, Carlos Santos Costaa, M. Odette Almeidab and J. Meneses e Sousaa
aDepartment
of Surgery. Portuguese Institute of Cancer. Lisbon. Portugal.
of Pathology. Portuguese Institute of Cancer. Lisbon. Portugal.
cDepartment of Mathematics and Statistics. Institute of Health Sciences. Monte de Caparica. Portugal.
bDepartment
Introduction. Breast cancer with metastatic sentinel
lymph nodes (SLN) may have clinico-pathologic
factors associated with the presence of positive nonsentinel axillary nodes (NSLN). The aim of the present study was to determine factors that predict involvement of NSLN in breast cancer patients with
positive SLN.
Material and methods. A prospective database search identified 80 patients who underwent SLN
biopsy for invasive breast cancer between January
1999 and August 2002. Clinico-pathologic data was
analyzed to determine factors that predicted additional positive axillary nodes.
Results. A total of 23 patients had positive SLN and
underwent conventional axillary lymph node dissection. Statistical analysis revealed that lymphovascular invasion (p~0.00000), SLN metastasis >2
mm (p=0.002), and the presence of extra-nodal involvement (p=0.002), were positive predictors of the
metastatic involvement of NSLN.
Conclusions. The likelihood of positive NSLN correlates with pathologic parameters such as the presence of lympho-vascular invasion, size of the SLN
metastasis, and extra-nodal involvement. These data may be helpful with the regard to the decision to
undertake axillary dissection in breast cancer patients with metastatic sentinel lymph nodes.
Key words: sentinel lymph node, clinico-pathologic
predictors, axilla dissection, breast cancer.
Callejo I, Brito J, Bivar JW, Fernandes F, Faria JL, André S,
Costa CS, Almeida MO, e Sousa M. Predictors of positive axillary lymph nodes in breast cancer patients with metastatic
sentinel lymph node. Clin Transl Oncol. 2005;7(1):18-22.
Correspondence: Isabel Callejo.
Clinical Assistant of General Surgery.
Rua Luis Freitas Branco, 5-5º E.
1600-488 Lisboa, Portugal.
E-mail: [email protected]
Received 26 March 2004; Revised 21 June 2004; Accepted 22 July
2004.
18
Factores predictivos de ganglios linfáticos
axilares positivos en los pacientes con
cáncer de mama con ganglio centinela
metastásico
Introducción. El cáncer de mama con ganglio centinela (GC) metastásico podría estar asociado a factores clínico-patológicos relacionados con la presencia de ganglios linfáticos axilares no-centinela
(GLANC) positivos. El objetivo de este trabajo es
determinar los factores que predicen la implicación
de los GLANC en los pacientes con cancer de mama con GC positivos.
Material y métodos. Se procede a análisis retrospectivos de una base de datos que incluyen pacientes
con carcinoma de mama invasivo sometidos a
biopsia del ganglio centinela, correspondiente a
enero de 1999 a agosto de 2002 (n=80). Los factores
clínico-patológicos fueron analizados con el objetivo de determinar los factores predictivos de los ganglios axilares positivos adicionales.
Resultados. En el análisis global de la población, se
verificó que existían 23 pacientes con GC positivos,
que fueron sometidos a disección ganglionar axilar
convencional. El análisis estadístico reveló que la
invasión linfovascular (p~0,00000), la dimensión de
la metástasis mayor de 2 mm (p=0,002) y la presencia de extensión extranodal (p=0,002), correspondieron a factores predictivos positivos de desarrollo
metastásico de los GLANC.
Conclusiones. La probabilidad de la existencia de
GLANC positivos se correlaciona con parámetros
patológicos como la presencia de invasión linfovascular, el tamaño de metástasis de los GC, y la extensión extranodal. Estos datos podrán ser útiles en
lo que concierne a la decisión terapéutica de efectuar la disección ganglionar axilar convencional en
los pacientes con cáncer de mama con GC metastásico.
Palabras clave: ganglio centinela, factores predictivos
clínico-patológicos, disección ganglionar axilar, cáncer de mama.
Clin Transl Oncol. 2005;7(1):18-22
34
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PEIXOTO CALLEJO I, BRITO JA, WHEINHOLTZ BIVAR J, ET AL. PREDICTORS OF POSITIVE AXILLARY LYMPH NODES IN BREAST
CANCER PATIENTS WITH METASTATIC SENTINEL LYMPH NODE
INTRODUCTION
Over the past decade, sentinel lymph node (SLN)
biopsy has emerged as an important tool to assess the
axillary node status in patients with breast cancer. Several studies have demonstrated that the status of the
SLN accurately reflects the status of the entire nodal
basin1,2, and thus, some centers routinely perform SLN
dissection for breast cancer, offering patients the option of no further axillary surgery if the SLN is negative. Axillary lymph node dissection (ALND) is performed if the SLN contains tumor or if there are clinically
suspicious of non-sentinel axillary nodes (NSLNs) palpable at the time of surgery. However, the need for
routine completion axillary dissection in these patients
has been questioned3-5.
ALND has remained the standard of practice of invasive carcinoma in breast cancer patients. Some authors believed6-10 that ALND provides excellent locoregional control. Therefore, potential for improved
overall survival. Furthermore, a recent meta-analysis11 of randomized trials, involving axillary lymph
node dissection, concluded that there is a 5.4% survival benefit associated with prophylatic axillary dissection for clinically node-negative patients. However,
there is substantial evidence that axillary dissection
is important only for staging purposes, resulting no
survival benefit associated with ALND12. Despite years of controversy, the therapeutic value of axillary
dissection is still unclear. Moreover, the role of further axillary dissection in patients with a positive SLN
is also under debate. Nevertheless, axillary nodal involvement remains the most significant predictor of
outcome in breast cancer13.
This analysis was performed to assess clinicopathologic features in cases of SLN-positive breast cancers
that might help to predict involvement of NSLNs.
METHODS
We reviewed the prospective database at the Portuguese Institute of Cancer, Lisbon, which includes patients who have undergone intraoperative lymphatic
mapping and SLN biopsy for invasive breast cancer.
Between January 1999 and August 2002, 80 patients
with breast carcinoma had intraoperative lymphatic
mapping with SLN biopsy and subsequent ALND.
Within this group, we identified 23 patients who had
a positive SLN by either hematoxylin and eosin
(H&E) staining or immunohistochemistry (IHC) for
cytokeratin.
Technique of intraoperative lymphatic mapping
and sentinel lymph node biopsy
Intraoperative lymphatic mapping was performed with
injections of blue dye in combination with techne35
tium-labeled sulfur colloid. Patients received filtered
technetium-99m (99mTc) sulfur colloid, which was
injected into the breast parenchyma surrounding the
tumor on day of surgery (1.0 mCi). Before the procedure on the breast (excision or mastectomy), with
the patient under general anesthesia, 1-2 ml of 1%
patent blue-V was injected subdermally, and the breast was massaged for 5 minutes. Prior to the skin incision, a handheld gamma detection probe (NeoProbe 2000, US Surgical) was used to scan the axilla
transcutaneously and identify the most radioactive
area. Through an axillary incision over this ‘hot
spot’, SLNs were identified as those with blue dye
uptake, radiotracer uptake (>2 times background
count), or both.
Pathologic evaluation of sentinel lymph nodes
The SLN was bivalved (along the longitudinal axis),
and processed. If no metastases were found in routine H&E section, the lymph node was submitted to 5
serial sectioning, analyzing 4 levels with 250 micro
intervals. Each level was further submitted to another 5 serial sectioning, evaluated by routine H&E
staining (one level), and cytokeratin by IHC (two levels), keeping two levels reserved for further examination.
The maximum dimension of the metastasis and the
presence or absence of extranodal extension in each
SLN was evaluated. Micrometastases will be defined
as having a maximum diameter between 0.2 mm and
2 mm. Macrometastases will be defined as having a
minimum diameter equal or greater than 2 mm.
NSLNs from the ALND specimen were analyzed by
H&E staining only, one level for each node. Each primary tumor was evaluated for pT, histologic type
(OMS), histological grade (according to Elston and
Ellis criteria), estrogen receptor (ER) status, and presence of lymphovascular invasion. For hormonal receptor status, greater than 10% staining of cells by
IHC was considered positive.
Statistical methods
Descriptive statistics were used to assess the frequency distribution among the study population.
χ2 test was used to analyze the association between
the presence of positive NSLNs and the following
characteristics: age, pT, histologic type, ER status,
histological grade, lymphovascular invasion in the
primary tumor, number of SLNs removed, number of
histologically positive SLNs, size of the largest SLN
metastasis and extranodal extension. P values of less
than or equal to 0.05 were considered to be statistically significant.
Clin Transl Oncol. 2005;7(1):18-22
19
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PEIXOTO CALLEJO I, BRITO JA, WHEINHOLTZ BIVAR J, ET AL. PREDICTORS OF POSITIVE AXILLARY LYMPH NODES IN BREAST
CANCER PATIENTS WITH METASTATIC SENTINEL LYMPH NODE
RESULTS
TABLE 1. Patient and tumor characteristics
Demographic and primary tumor data
Total number of patients:
Age (median, range):
Type of operation, nº. of patients
Lumpectomy:
Mastectomy:
Size of primary tumor, median (range), cm:
Histologic type, nº. of patients
Ductal:
Lobular:
Other:
Nº. SLN removed, median (range):
Nº. positive SLN, median (range):
Ratio of SLN metastase
(macrometastase/micrometastase):
Nº. patients with additional positive NSLN:
Nº. NSLN recovered in completion lymph
node dissection specimens, median (range):
Nº. positive NSLN, median (range):
We evaluated the records of 80 consecutive patients
who underwent SLN biopsy for breast cancer. Of these patients, 23 had a positive SLN. Thus, our study
group consisted of 23 patients with positive SLNs
who underwent ALND (table 1).
The median patient age was 56 years (range, 42-74 years). The predominant primary tumor histologic type
was invasive ductal carcinoma (19 patients; 82.6%).
The median tumor size was 2.2 cm (range, 1.0-4.0
cm), and the majority of tumors were grade 2 (table
2). Ninety-one percent of tumors were estrogen receptor positive. Lymphovascular invasion was identified
in 39% of tumors.
23
56 (42-74)
17
6
2.2 (1.0-4.0)
19
2
2
1.3 (1-3)
1.3 (1-3)
1:0.6
9
16 (7-29)
2 (1-11)
Characteristics of sentinel lymph nodes and
non-sentinel axilary nodes
SLN: sentinel lymph nodes; NSLN: non-sentinel axillary nodes.
The median number of SLNs identified was 1.3 (range, 1-3; standard deviation, 0.6). The median number
of SLNs found to be positive was 1.3 (range, 1-3) (table 1). The ratio of macrometastases/micrometastases of the SLN was 1:0.6. Micrometastases were identified on 9 cases (39%), and 14 SLNs (61%) were
grossly involved with tumor. Extranodal extension
was present in 21.7% of positive lymph nodes.
The median number of lymph nodes harvested with
ALND was 16 (range, 7-29), and the median number
of positive NSLNs was 2 (range, 1-11). Nine (39%) of
the 23 patients in our series were found to have positive NSLNs by standard H&E examination.
SLN. In this study, 9 (39%) of 23 patients with a positive SLN who underwent ALND were found to have
residual disease in the axilla. In the other 61% of the
patients in this series, the SLN was the only node involved with tumor. This rate is similar to that found
at other high-volume breast centers2,14–16.
The results of the current study demonstrated that
the presence of lymphovascular invasion, largest SLN
metastasis greater than 2 mm, and extranodal disease
were independent prognostic factors that predicted
additional disease in NSLNs.
Other published series17-23 have focused attention on
the sentinel lymph node and factors associated with
it, as well as patient and tumor factors, in terms of
predicting additional positive lymph nodes.
In our series, lymphovascular invasion was the strongest predictor of NSLN involvement (p = 0.0000). All
the tumors with lymphovascular invasion had positive
NSLNs. Conversely, those without lymphovascular invasion did not have additional positive nodes. Other
groups17,18,23 also demonstrated that peritumoral lymphovascular invasion was significantly associated with
positive NSLNs.
In the current study, the size of the SLN metastasis
was associated strongly with NSLN metastasis (p =
0.002). Of 14 patients with SLN macrometastases (>
2.0 mm), 9 (64%) had NSLN metastases. This fact
was also demonstrated by other groups17-21,23. In the
series of Turner et al17 and Abdessalam et al18, 63%
and 47% of patients with SLN metastasis larger than 2
mm were found to have positive NSLNs respectively.
Consistent with other two studies17,18, we found that
extranodal tissue invasion represents a positive predictor of NSLN involvement and clinical outcome. In
the current study, extranodal disease was observed in
22% of patients with SLN metastasis and was correlated strongly with NSLN metastasis (p = 0.002).
Univariate analysis
Table 2 summarizes the results of the statistical analyses to determine the relationship between pathologic
variables and positive NSLNs. The presence of lymphovascular invasion, extranodal extension, and macrometastases remains significant. So, the cases (n =
5) with lymphovascular invasion, extranodal extension, and a sentinel lymph node metastasis >2 mm,
were all found to have additional positive nodes. Conversely, those without lymphovascular invasion, without extranodal extension, and a sentinel lymph node
metastasis <2 mm (9 patients), did not have additional
positive nodes.
DISCUSSION
Over the past decade, sentinel lymphadenectomy has
emerged as a minimally invasive alternative to routine ALND for identifying axillary metastases from an
invasive breast carcinoma. The role of axillary dissection continues to evolve as investigators have
questioned its benefit, even in the setting of a positive
20
Clin Transl Oncol. 2005;7(1):18-22
36
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PEIXOTO CALLEJO I, BRITO JA, WHEINHOLTZ BIVAR J, ET AL. PREDICTORS OF POSITIVE AXILLARY LYMPH NODES IN BREAST
CANCER PATIENTS WITH METASTATIC SENTINEL LYMPH NODE
TABLE 2. Correlation between clinicopathological features and positive NSLN
Variable
Patient characteristics
Age
≤ 50 years
> 50 years
Primary tumor characteristics
Histologic type
Ductal
Lobular
Other
Histological grade
1
2
3
Primary tumor size
≤2 cm
>2 cm
Stage T
T1b
T1c
T2
Hormone receptor status
Positive
Negative
Lymphovascular invasion
Yes
No
SLN characteristics
Nº. SLN removed
1
2
≥3
Nº. Positive SLN
1
2
≥3
Size of Largest SLN metastasis
≤2 mm
>2 mm
Extranodal extension
Yes
No
N
Patients with Positive NSLN N (%)
Univariate χ2 (DF)
P Value
6
17
2 (33.3%)
7 (41.2%)
0.115 (1)
0.735
3.11 (2)
0.211
19
2
2
9 (47.4%)
0
0
4.527 (2)
0.104
5
15
3
0
8 (53.3%)
1 (33.3%)
2.1 (1)
0.147
12
11
3 (25%)
6 (54.5%)
2.39 (2)
0.303
1
11
11
0
3 (27.3%)
6 (54.5%)
0.108 (1)
0.742
21
2
8 (38.1%)
1 (50%)
23.0 (1)
0.0000
9
14
9 (100%)
0
2.27 (2)
0.321
16
6
1
5 (31.2%)
3 (50%)
1 (100%)
4.69 (2)
0.096
18
4
1
5 (27.7%)
3 (75%)
1 (100%)
9.505 (1)
0.002
9
14
0
9 (64.3%)
9.938 (1)
0.002
5
18
5 (100%)
4 (22.2)
NSLN:non-sentinel axillary nodes; SLN: sentinel lymph nodes.
Although many series17,18-23 reported that tumor size
was a predictor of additional positive nodes, our data
did not confirm this. But our sample is too small to
infirm a significant difference in prognostic value of
tumor size. The single patient included in our study
with T1b tumor did not had further lymph node involvement, whereas T1c, and T2 tumors were associated with positive NSLNs in 27%, and 54.5% of cases, respectively.
Axillary treatment decisions are complex and require
individualized scrutiny of all available data. We should
expect a clearer understanding in the near future of
micrometastases or isolated tumor cells in regional
lymph nodes24-26. Some studies27 suggest that micrometastases have no adverse prognostic implication,
whereas others28,29 question the clinical significance of
37
tumor deposits detected by immunohistochemistry.
Further studies are needed to determine the significance of micrometastases30,31.
One prospective randomized trial currently in progress address the controversy for further axillary dissection in patients with positive SLNs (American College of Surgeons Oncology Group Z0011), in whom
patients with positive SLNs by H&E will be randomized to either ALND or observation. This study will
help to evaluate the therapeutic impact of axillary node dissection in sentinel node positive patients.
In summary, SLN was the only positive axillary node
in 61% of our patients. The present study has demonstrated that the finding of such high-risk variables as lymphovascular invasion, metastasis greater
than 2 mm within the SLN, or extranodal extension
Clin Transl Oncol. 2005;7(1):18-22
21
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PEIXOTO CALLEJO I, BRITO JA, WHEINHOLTZ BIVAR J, ET AL. PREDICTORS OF POSITIVE AXILLARY LYMPH NODES IN BREAST
CANCER PATIENTS WITH METASTATIC SENTINEL LYMPH NODE
increases the possibility of having additional positive
nodes. The Z0011 trial will help determine whether
axillary node dissection has any impact on survival
in this group of pathologically node-positive patients.
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