Keywords: Neoplasias mamárias - Biópsia com agulha fina - Terapia neoadjuvante - Linfonodo sentinela.
Descritores: Neoplasias mamárias - Biópsia com agulha fina - Terapia neoadjuvante - Linfonodo sentinela.
INTRODUCTION
Breast cancer is the most common cancer among women. Approximately 2 million women
each year are diagnosed with breast cancer and it is responsible for approximately
15% of female cancer deaths in the world.[
[1 ]
]
When cancer is diagnosed in the early stages, it is considered as good prognosis,
having greater chances of cure. Although it is much studied, there is still no universal
consensus for screening, diagnosis, treatment, and follow-up on breast cancer. The
prognosis is defined by several factors such as age, staging and tumor characteristics.[
[2 ]
[3 ]
[4 ]
]
Axillary involvement is one of the main prognostic factors in breast cancer. For decades,
axillary dissection (AD) has been the method of choice for assessing and treating
axillary metastases, as well as making decisions in relation to systemic therapy.[
[5 ]
[6 ]
[7 ]
] Sentinel lymph node biopsy (SLNB) was consolidated as a method of choice for the
study of these metastases in patients with clinically negative axilla, with low local
recurrence rate, without altering survival, resulting in less morbidity.[
[6 ]
[8 ]
[9 ]
[10 ]
]
In 40-65% of the cases in which SLNB has positive findings for malignancy, the sentinel
lymph node is the only one involved, therefore, AD is not necessarily indicated and
its role in this scenario remains uncertain.[
[11 ]
[12 ]
[13 ]
[14 ]
] Studies have demonstrated the benefit of AD omission in selected patients, even SLNB
with evidence of metastasis.[
[11 ]
[12 ]
[13 ]
[14 ]
]
Axilla ultrasound (A-US) alone has moderate sensitivity and specificity in identifying
lymph nodes with metastatic involvement, when combined with fine needle aspiration
cytology (US-FNAC), this becomes a more accurate method.[
[5 ]
[6 ]
[15 ]
[16 ]
[17 ]
[18 ]
]
Histopathological assessment after neoadjuvant systemic therapy (performed before
surgery), allows to know the response of a determined tumor in this therapy. A complete
pathological response (absence of residual disease in the histopathology examination
of the surgical specimen) is related to a lower chance of relapse and has better prognosis.[
[19 ]
[20 ]
] Evidence points that the US-FNAC when performed before the neoadjuvant therapy, can
be helpful in identifying lymph nodes with a higher degree of involvement, facilitating
the option to perform or not the axillary dissection after neoadjuvant therapy, but
its role is not completely defined yet.[
[10 ]
[21 ]
[22 ]
[23 ]
[24 ]
]
This present study aims to assess the accuracy of US-FNAC to detect axillary involvement
in breast cancer and to compare with other methods of axilla assessment, as AP and
A-US alone.
METHODS
This is a retrospective study of accuracy, which used the information collected from
the medical records of patients with breast cancer treated at the breast cancer service
at the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), in Recife, Brazil,
from June 2013 to December 2017.
The following inclusion criteria were considered: to have invasive breast carcinoma
diagnostic, to have axillary histopathological result registered in the medical records
and have been treated at IMIP. As exclusion criteria were considered: metastatic disease
and tumors with skin or chest wall involvement.
Patients were selected through registries books in which were admitted with suspected
or confirmed diagnosis of breast cancer at the breast cancer department at the institution.
A consecutive and convenience sample was used. First, we planned to analyze all the
patients with breast cancer in the study period, however, we were not able to find
all these medical records. Of 1,091, 491 medical records were found.
All the selected patients underwent the A-US. The lymph nodes were defined suspicious
when one of the following characteristics was observed: cortical thickness >2mm, eccentric
cortical thickening, loss of fatty hilum and round shape. US-FNAC of suspected lymph
nodes was performed by one of the breast radiologists from our service, with at least,
2 years of experience.
For the FNA, a 22-gauge needle was inserted into the cortex of the ALN using a manual
aspiration. Collected material was analyzed by a breast pathologist. Cytology was
considered positive when neoplastic cells were identified.
To identify sentinel lymph nodes, the radioisotopes method was used (38% of the procedures)
or blue dye (62% of the procedures), according to availability of the service. The
radioisotope (technetium-99m phytate) was injected before surgery, about 2 hours,
and the blue dye was applied at the time of the surgery, 10 minutes before axillary
incision. ALNs identified by a gamma probe or axillary lymph nodes containing blue
dye were regarded as sentinel nodes and removed. Axillary dissection was performed
on patients who underwent neoadjuvant chemotherapy; one and two Berg's levels were
assessed.
The variables analyzed were sociodemographic data, tumor characteristics and diagnostic
tests: AP, A-US and the US-FNAC. The histopathology examination (of SLNB and/or AD)
was considered as gold standard for this study. The information was collected from
the medical records and entered in an Excel ™ database. The data were reviewed, corrected and submitted to cleaning and consistency
tests, before the statistical analysis.
Stata 12.1 was used for data analysis. Records with insufficient data were excluded
from the analysis. Frequency tables were created for the categorical variables. For
the methods of axilla assessment (AP, A-US and US-FNAC): sensitivity, specificity,
accuracy, positive predictive value (PPV) and negative predictive value (NPV) were
calculated as 95% confidence interval. The kappa coefficient was calculated to assess the agreement between the methods, considering
the Landis and Koch (1977)[
[25 ]
] criteria to classify the strength of association: slight (0-0.20); fair (0.21-0.40);
moderate (0.41-0.60); substantial (0.61-0.80); almost perfect (0.81-1).
RESULTS
After reviewing 491 medical records of women suspected or diagnosed with breast cancer,
were excluded: 9 cases with histopathological result prior to the selected period
of the study, 65 patients had no sufficient information on their medical files for
analysis, 25 cases were diagnosed with benign disease, 24 cases of ductal in situ
carcinoma, 5 cases of primary tumor in other areas with metastasis in the breast,
24 cases of tumor with skin and/or chest wall involvement, 40 cases due to metastatic
disease, 12 performed treatment outside IMIP, and 83 tumors with no residual disease
after neoadjuvant chemotherapy without previous axillary histopathology. Thus, 204
women's medical records were analyzed, 2 of them had bilateral tumor, totaling the
analysis of 206 tumors as shown in[Figure 1 ].
Figure 1 Patients' flowchart.
Patients and tumor characteristics in the overall study population are in[Table 1 ].
Table 1
Patients and tumors characteristics in women with breast cancer assisted at the breast
cancer service at IMIP, Recife, Brazil, 2013-2017.
Variablesw
N=206
%
Age (years) - Mean (SD[* ] ) = 56
(±12.5)
Live in Recife and adjacent cities
167
81.6
Marital status
In relationship
94
46.6
Not in relationship
106
51.5
No information
6
2.9
Tumor size at axilla palpation (AP)
<2cm
41
19.9
2.1-5cm
123
59.7
>5cm
42
20.4
Tumor size on the ultrasound (US)
<2cm
76
37.0
2.1-5cm
116
56.0
>5cm
12
6.0
No information
2
1.0
Histological type
Invasive ductal carcinoma (IDC)
170
82.5
Invasive lobular carcinoma (ILC)
11
5.4
Others
25
12.1
Nuclear tumor grade
I
35
17.0
II
114
55.0
III
43
21.0
No information
14
7.0
Immunohistochemistry[** ]
Estrogen receptor
153
74.3
Progesterone receptor
132
64.1
HER-2 overexpression
45
21.8
Triple negative
32
15.5
Clinical staging
I
29
14.1
II
144
69.9
III[*** ]
33
16.0
* Standard deviation;
** The same tumor may have more than one immunohistochemical classification;
*** Predominated in women under 40-years-old.
The women's mean age was 56 (SD=12.5) years old and the majority (81.6%) were from
Recife and adjacent cities.
In relation to the tumor size, 123 (59.7%) tumors found were between 2.1 and 5cm,
in AP and 116 (56.0%) were between 2.1 and 5cm in the A-US. The prevalent histological
type was invasive ductal carcinoma (IDC) in 170 (82.5%) cases. Regarding to the tumor
nuclear grade, grade II tumors prevailed in 114 (55.0%) cases. Most of the tumors
presented positive hormone receptor: estrogen receptor (ER) in 153 (74.3%) and progesterone
receptor (PR) in 132 (64.1%) tumors. Thirty-two (15.5%) tumors were triple negative
and 45 (21.8%) had HER-2 overexpression (this category included patients with pure
HER-2 positive and those with HER-2 positive is associated to positive hormone receptor).
The clinical stage (CS) II was the most prevalent (69.9%) for all age groups.
The AP was truly positive, in other words, capable of detecting lymph node involvement
in 34.0% of the cases and truly negative in 36.0%, similar values were obtained for
A-US (36.4% and 31.5%, respectively). The lowest incidence of false negative was in
the USFNAC (16.5%). Axillary involvement was identified in 82 (39.8%) cases, while
in the ultrasound, 96 (46.6%) were identified. The US-FNAC was performed in 79 cases
(which were positive according to the ultrasound), and 51 (64.5%) were identified
as true positive and 13 (16.5%) were false negative ([Table 2 ]).
Table 2
Comparative results of AP, A-US and US-FNAC with a gold standard (histopathology)
in the diagnosis of axillary involvement due to breast cancer in women assisted at
the breast cancer service at IMIP, Recife, Brazil, 2013-2017.
Exam
True (+) N (%)
True (-) N (%)
False (+) N (%)
False (-) N (%)
AP
(n=206)
70
(34.0%)
74
(36.0%)
12
(5.8%)
50
(24.3%)
A-US (n=206)
75
(36.4%)
65
(31.5%)
21
(10.2%)
45
(21.8%)
US FNAC (n=79)
51
(64.5%)
15
(19.0%)
0 (0.0%)
13
(16.5%)
AP = Axillary palpation; A-US = Axillary ultrasound; US-FNAC = Ultrasound-guided fine
needle aspiration cytology.
When analyzing the comparative results of AP, A-US and the US-FNAC of the axilla with
gold standard (histopathology), it was observed that AP presented the lowest sensitivity
(58.3%, 95%CI=49-67.3), however, with an accuracy of 69.9% (95%CI=63.176.1), it was
better than the A-US, whose accuracy was 68% (95%CI=61.1-74.3). The US-FNAC showed
high specificity (100%, 95%CI=81.9-100%), of PPV at 100% (95%CI=94.3-100%), but with
low NPV (53.6%, 95%CI=33.9-72.5). The best NPV was AP (59.7%, 95%CI=50.5-68.4), followed
by A-US (59.1%, 95%CI=49.3-68.4). The US-FNAC accuracy was 83.5% (95%CI=73.5-91.0)
([Table 3 ]).
Table 3
Sensitivity, specificity, accuracy and predictive values of the AP, A-US and US-FNAC
with a gold standard (histopathology) in the diagnosis of axillary involvement in
breast cancer in women assisted at the breast cancer service at IMIP, Recife, Brazil,
2013-2017.
Exam
Sensitivity % (95%CI)
Specificity % (95%CI)
Accuracy % (95%CI)
PPV
% (95%CI)
NPV
% (95%CI)
AP
(n=206)
58.3 (49.0-67.3)
86.0 (76.9-92.6)
69.9 (63.1-76.1)
85.4 (75.9-92.2)
59.7 (50.5-68.4)
A-US
(n=206)
62.5 (53.2-71.2)
75.6 (65.1-84.2)
68.0 (61.1-74.3)
78.1 (68.5-85.9)
59.1 (49.3-68.4)
US-FNAC (n=79)
79.7 (67.8-88.7)
100.0 (81.9-100.0)
83.5 (73.5-91.0)
100.0 (94.3-100.0)
53.6 (33.9-72.5)
AP = Axillary palpation; A-US = Axillary ultrasound; US-FNAC = Ultrasound-guided fine
needle aspiration cytology; PPV = Positive predictive value; NPV = Negative predictive
value.
The results of concordance analysis with the kappa coefficient had shown moderate agreement (0.60; 95%CI=0.42-0.78) between US-FNAC
and histopathology. The kappa coefficient of the AP and histopathology was also moderate (0.42; 95%CI=0.300.53)
and between A-US and histopathology was fair (0.37; 95%CI=0.24-0.49) ([Table 4 ]).
Table 4
Level of agreement between AP, A-US and US-FNAC, with the gold standard (histopathology)
in the diagnosis of breast cancer in women assisted at the breast cancer service at
IMIP, Recife, Brazil, 2013-2017.
Exams
Kappa value (95%CI)
Strength of association*
AP vs. HTP
0.42 (0.30-0.53)
Moderate
A-US vs. HTP
0.37 (0.24-0.49)
Fair
US-FNAC vs. HTP
0.60 (0.42-0.78)
Moderate
DISCUSSION
To design a profile of the studied patients, it was possible to perceive that the
most came from the State capital of Pernambuco and adjacent neighboring cities, an
expected fact, since these patients have better access to the health service, when
compared to those residing in the countryside. The mean age was over 50-years-old,
a similar data also found in other studies and it was compatible with the age group
risk known worldwide.[
[1 ]
[26 ]
[27 ]
]
The most prevalent histological subtype of the tumors assessed was the IDC, followed
by the ILC, a similar result is described in the literature.[
[17 ]
[27 ]
[28 ]
[29 ]
] The prevalence of tumors with HER-2 overexpression found in this study did not differ
from what has been described on this category, about 20% of the tumors.[
[27 ]
[28 ]
[29 ]
]
Staging and therapeutic planning are of a paramount importance in patients with breast
cancer, since the identification of axillary lymph node involvement can change the
options of offering clinical or surgical treatment.[
[30 ]
[31 ]
]
The AP is the oldest method used to assess axillary lymph node involvement in breast
cancer. In this present study, AP had an accuracy of approximately 70%, with sensitivity
of approximately 60% and specificity of 86%, values comparable to those described
in the literature, although previous studies have shown a lower sensitivity for AP
between 3040%.[
[30 ]
[32 ]
] This difference could be related to the professionals' experience who have performed
AP.[
[30 ]
[32 ]
] The necessity for clinical experience is the main factor limiting the physical axilla
examination, reported as the most difficult to differ enlarged lymph nodes from the
reactive inflammatory or metastatic involvement.[
[30 ]
[33 ]
[34 ]
]
In the present study, the A-US presented accuracy of 68.0% and sensitivity of around
60%, similar results found for AP, however, with a sensitivity discreetly higher than
the values described in the literature, which are around 50%.[
[30 ]
[35 ]
]
The US-FNAC is a cost effective and fast performance method and has been used in several
services with the objective of defining the axillary involvement of the patient with
breast cancer. So, this procedure could avoid the necessity of a surgical procedure,
such as SLNB, and the delay of a possible systemic treatment, due to surgical complications.[
[19 ]
[36 ]
[37 ]
]
When the US-FNAC was performed, the diagnosis was improved by an accuracy of around
84%, compared to the values already described in the literature.[
[34 ]
[38 ]
]
Dihge et al. (2016)[
[15 ]
] in a hospital-based study in Sweden, from 2009 to 2012, 473 women found a sensitivity
of 23% and specificity of 95% of the A-US, however, when associated to the US-FNAC,
presented improvement on the diagnostic sensitivity, reaching a sensitivity of 73%.
This result was close to what was found in the present study, which was 79.7%. Both
studies had PPV of 100%, a value which was already described in other studies.[
[15 ]
[33 ]
[34 ]
]
The US-FNAC significantly improves the PPV, although, its use is limited, as, in order
to perform the test, it is necessary that the suspected lymph node be visualized in
the ultrasound and accessible for the puncture, which often reduces the number of
patients undergoing this procedure. Of the 473 women who performed the ultrasound
on the axilla from Dihge et al. (2016)[
[15 ]
] study, 55 presented lymph nodes with suspicious characteristics and only 45 underwent
the US- FNAC. In this present study, of the 206 patients submitted to the A-US, only
96 had lymph nodes with suspicious characteristics, of which 79 were submitted to
the US-FNAC. Despite a high PPV, the high numbers of false negatives (n=13, 16.5%)
make the negative examination incapable of excluding the axillary lymph node metastasis.[
[11 ]
[22 ]
[39 ]
]
The SLNB has a false-negative rate of around 10-12%, a value that makes it a safe
procedure to exclude axillary metastases in breast cancer, considered as gold standard
in patients with clinically negative axilla.[
[11 ]
[22 ]
[23 ]
[39 ]
] Currently, even lower sentinel node false negative rates of around 8% are expected.[
[39 ]
[40 ]
]
This present study showed, by kappa , moderate agreement between the results of the US-FNAC and the histopathology, associated
to a high PPV.
Thus, the inclusion of the US-FNAC as a routine for breast cancer staging helps identify
patients who are candidates for neoadjuvant therapies, without the necessity of a
surgical procedure, and offers the possibility of a conservative treatment in the
axilla, according to the response to this therapy.[
[19 ]
[23 ]
[36 ]
[40 ]
[41 ]
[42 ]
]
When indicated, neoadjuvant therapy has the advantage in permitting the physician
to assess the tumor response in vivo
[
[15 ]
[19 ]
[23 ]
] and enables early treatment for micro-metastases, besides, decreasing the risk of
delaying systemic treatment due to surgical complications. It also allows time to
program and individualize the best procedure with or without immediate breast reconstruction
for each patient.[
[5 ]
[15 ]
[23 ]
[43 ]
]
For the analysis of specificity, sensitivity, accuracy, PPV and NPV, patients who
underwent neoadjuvant chemotherapy and who obtained axillary histopathology after
chemotherapy without any evidence of residual disease were excluded, because in these
cases, the axilla could be negative due to a good response to systemic therapy, causing
a bias both in identifying false positives and identifying true negatives through
the US-FNAC.
The role of the sentinel lymph node when negative is already well established in the
literature and it is known that in these cases there is no benefit of the axillary
dissection.[
[43 ]
] However, much is still discussed about the role of axillary dissection when the sentinel
lymph node is positive. The Giuliano et al. (2010)[
[12 ]
] study, which demonstrated that there was no additional benefit with the axillary
dissection for selected patients undergoing conservative surgery and up to two compromised
sentinel lymph nodes, have changed the conducts throughout the world. Thus, identifying
patients as candidates for conservative axilla surgery, even with positive sentinel
lymph node, is still a challenge.[
[5 ]
[44 ]
]
The Boughey et al. (2013)[
[23 ]
] study demonstrated the possibility of performing the sentinel lymph node biopsy after
neoadjuvant chemotherapy, safely, when well indicated and using the appropriate technique.[
[23 ]
]
Among the limitations of this study, it is mentioned that the fact was performed with
the data collected from the medical records, which may not contain all the information
properly registered, limiting the sample. Another limitation of this study is that,
of the 160 patients who underwent neoadjuvant chemotherapy, 83 did not present axillary
residual disease. Of these patients, 67 had positive US-FNAC for neoplasia before
the neoadjuvant chemotherapy, of these, 23 showed no evidence of axillary disease
after systemic therapy. This result may mean that these 23 patients responded well
to chemotherapy and could become candidates for less morbidity surgery if the SLNB
was performed after the neoadjuvant therapy.[
[23 ]
[45 ]
]
Much has been evolved in relation to breast cancer. Treatments that were once considered
gold standard, but with an important morbidity, which were replaced by less aggressive
techniques and with fewer side effects for the patients. In this scenario, it is possible
that the US-FNAC is an important ally in the diagnosis of axillary involvement in
breast cancer without the necessity of a surgical procedure, thus allowing the option
of an early systemic treatment with a possibility of reducing axillary tumor burden.[
[36 ]
] In properly selected patients, the use of US-FNAC may result in a less aggressive
axillary surgical treatment.
Identifying patients with axillary involvement without a surgical procedure is of
a great value to better define the therapeutic plan.
CONCLUSION
The good accuracy associated to the high specificity and the PPV of the US-FNAC suggests
this to be a promising examination in the diagnosis of axillary involvement in breast
cancer and an ally to better define therapeutic conducts.
Bibliographical Record
