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Title of article
Comparison of immunohistochemical markers in core needle biopsy and excisional biopsy in
breast carcinoma
Title of article
Comparison of immunohistochemical markers in core needle biopsy and excisional biopsy in
breast carcinoma
Abstract
Introduction: Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor
receptor 2 (HER2) immunohistochemistry are important markers in the management of patient with
breast carcinoma. In this study, we determine the concordance rate of ER, PR and HER2
immunohistochemistry markers between core needle biopsy (CNB) and excisional biopsy (EB) of
breast carcinoma in patients of UKMMC from January 2002 until December 2012.
Methods: A total of 93 female patients with CNB and subsequent EB were included in this
retrospective descriptive study. Immunohistochemistry (IHC) is used to determine ER, PR and HER2.
ER and PR was graded using Allred score (0 to 8) while HER2 was scored from 0 to 3+. The markers
between these two biopsies were compared to determine the concordance rate.
Results: In ER and PR, 93 samples were compared. ER was concordant in 80 cases (86.0%) and 13
cases (14.0%) was discordant. PR was concordant in 82 cases (88.2%) and discordant in 11 cases
(11.8%). In HER2, 87 samples were compared and 62 cases (71.3%) were concordant while 25 cases
(28.7%) were discordant.
Conclusion: Concordance between CNB and EB was high for ER and PR. However, concordance rate
for HER2 immunohistochemistry was less consistent. Overall, immunohistochemical analyses of CNB
reflect the tumour marker status of the excised specimen.
Key words:
breast carcinoma, core needle biopsy, estrogen receptor, progesterone receptor, HER2
Introduction
Breast cancer is the most commonly diagnosed cancer in Malaysia 1. According to the National
Institute for Health and Clinical Excellence (NICE) guidelines as stated in the Clinical Practice
Guidelines of Management of Breast Cancer Second Edition 2010, the diagnosis of breast cancer is
made by triple assessment consisting of clinical examination and history, mammography and/or
ultrasonography imaging, and core biopsy and/or fine needle aspiration cytology 2.
Core needle biopsy (CNB) is widely used in routine preoperative practice as part of the triple
assessment in patients with suspected breast carcinoma. The accuracy of the CNB for the diagnosis of
breast carcinoma has been extensively studied and good concordance rate has been reported between
CNB and excisional biopsy (EB) for diagnosis of breast carcinoma (91%–100%) with a specificity rate
ranging from 96% to 100% 3.
In addition to the histopathological diagnosis, there is a growing demand for prognostic information
and in particular the determination of estrogen receptor (ER), progesterone receptor (PR) and HER2 for
treatment planning. In situations where neoadjuvant therapy is used, such information is often needed
for selection of therapy and maybe the only tissue available for consideration of postsurgical care, for
example in cases achieving a pathological complete response with treatment 4.
The status of ER, PR and HER2 is critical in the management of patients with invasive breast
carcinoma. ER is a powerful predictive factor for response to endocrine treatment and long-term
outcome. The use of endocrine therapy for patients with a positive HRs status in breast cancer has been
shown to have a dramatic impact on improving disease free survival and overall survival. Similarly,
HER2 overexpression has been associated with worse prognosis in patients with newly diagnosed
breast carcinoma, is a determinant of response to trastuzumab and a possible marker of resistance to
certain endocrine and chemotherapy treatments 4.
Immunohistochemical markers such as oestrogen receptor (ER), progesterone receptor (PR) and HER2
performed on tumor samples from core needle biopsies has been used as biologic markers in breast
cancers for predicting response to specific therapeutic agents. However, a challenge arises as studying
these hormonal receptor markers on core needle biopsies containing small tissue samples may not
accurately reflect the overall biologic profile of the heterogenous tumor. Thus, hormonal receptor (HR)
markers on core needle biopsies may lead to false negative or positive results. When “false negative”
HR test results are found, these deprive women of the proven benefits of endocrine therapies and may
lead to choosing unwarranted chemotherapy treatments with significant financial costs and toxicities 5 .
The main purpose of this study is to compare the hormonal status of ER, PR and HER2 performed on
core needle biopsies with the immunohistochemical results in the subsequent mastectomy/wide local
excision, lumpectomy for patients diagnosed with breast cancer. More specifically, this study will
determine the level of concordance between hormonal status identified on CNB and mastectomy/wide
local excision, lumpectomy performed in one of the local teaching hospitals in Malaysia.
Objective
The purpose of this study is to compare the ER, PR and HER2 immunohistochemistry findings in CNB
and subsequent EB for patients diagnosed with breast cancer to determine the concordance &
discordance rate between CNB and EB.
Patients and Methods
Our data was collected from our records of patient diagnosed with breast carcinoma presenting to
Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from January 2002 until December 2012.
A total of 107 female patients with CNB and subsequent EB were included in this retrospective
descriptive study. Patients who had local recurrent or non-primary carcinoma were totally excluded
from this study. None of the patients had received neoadjuvant radio or chemotherapy or hormonal
treatment between CNB and the final excised specimens.
Immunohistochemistry (IHC) is used to determine ER, PR and HER2. ER and PR were graded using
Allred score from 0 to 8 and scores of more than 2 were considered positive. HER2 was scored from 0
to 3+. Scoring of 2+ and 3+ were taken as positive while 0 and 1+ were considered negative. The final
results between CNB and EB were compared to determine the concordance and discordance rate.
By using SPSS version 19, the results were compared by considering CNB as test assessment and EB
as the gold standard.
Results
A total sample of 93 samples was included in this study. Out of 93 samples, 76 patients were diagnosed
with infiltrating ductal carcinoma both in the CNB and EB (81% respectively).
PR was scored as positive in 65 (70%) of the CNB and negative in 28 (30%). In the EB, PR was
positive in 62 (67%) of the cases and negative in 31 (33%) (Table I). There was concordance between
the PR in CNB and EB in 82 cases (88.2%), with discordance only in 11 cases (11.8%).
Table I: Concordance rate between CNB and EB for ER, PR and HER2 results
HORMONAL MARKERS
ER
PR
HER
NUMBER OF SAMPLES
93
93
87
CONCORDANCE (%)
80 (86%)
82 (88.2%)
62 (71.3%)
For ER, in the CNB has 53% scored as positive compared to 48% in the excision specimen. The
concordance rate for ER was 86%. Only 12 samples were discordant (14%). There were 8 samples
which showed ER positivity on CNB but negative on EB. 4 of the total samples are false negative
result.
From the 93 samples, only 87 samples are available for assess for HER2. 49 (56.3%) patients were
HER2 positive in the core needle biopsy and 38 (43.7%) were negative. In the EB, 39 samples were
HER2 positive (44.8%) and 48 samples were negative (55.2%). 26 samples are discordant and give the
discordant rate of 28.7% out of which 18 samples were false positive.
Rate for sensitivity, specificity, negative predictive value and positive predictive value using the EB as
reference for each marker are summarised in table II.
Table II: Sensitivity, specificity, positive and negative predictive value for CNB compared with EB
RATE
Sensitivity
Specificity
Positive predictive value
Negative predictive value
ER (%)
91.111
83.333
83.673
90.909
PR (%)
93.548
77.419
89.231
85.714
HER2 (%)
79.487
62.5
63.265
78.947
Table III: Concordance between CNB and EB for ER, PR and HER2 results
CNB
ER
Positive
Negative
Total
Excisional Biopsy
Positive
Negative
41
8
4
40
45
48
Total
49
44
93
PR
Positive
58
7
65
Negative
Total
4
62
24
31
28
93
Positive
Negative
Total
31
8
39
18
30
48
49
38
87
HER2
Discussion
In routine preoperative practice in UKMMC, CNB is often used as part of a triple assessment in
patients with suspected breast carcinoma. The expression of these markers will guide the clinician in
the therapeutic management of the patient. Previous studies concluded that immunohistochemical
results from CNB tend to be less reliable than those analysed on excised specimens as CNB represent
limited sample of tissue with possible tumour heterogeneity.
CNB and EB samples from patients assessed in this study was not subjected to any mode of
preoperative treatment, as treatment have been known to alter the tumour biologic marker such as ER,
PR and HER2 6. However, the tumour marker alterations seen in treated specimens may not be
consistent with HER2. More recently, HER2 status has shown to remain unchanged when
preneoadjuvant and post neoadjuvant specimens are compared 7.
ER findings on CNB correlated well with that on EB (86% of cases) with a sensitivity of 91.1% and
specificity of 83.3%, and in agreement with findings from other studies 8-11. Similarly, there was also
good concordance rate of PR between CNB and EB (88.2%) with a sensitivity and specificity of 93.5%
and 77.4% respectively. Between ER and PR markers, a positive PR marker is more likely on a CNB
rather than on EB. Discordance for ER was 14% and in keeping with a previous study 12. False
negativity for ER was seen in 4 cases, indicating that all ER negative results on CNB should be further
confirmed with EB. False positivity for ER was observed in 8 cases, suggesting sampling error within
the tumour periphery and that tumour cells in the centre are more likely to be ER negative as indicated
by Connor et al 12. Furthermore, the type and duration of fixation in the final excised specimen may
have influenced marker positivity 12.
On the contrary, the concordance rate between CNB and EB for HER2 was lower than that seen for ER
and PR (71.3%, Table I) with a much lower sensitivity and specificity rates (Table II). This finding is in
keeping with other studies 9,11,13. The less consistent concordance rate for HER2 is possibly due to
limited number of samples analysed in this study as well as intratumour heterogeneity. Given the
limitation of tumour diversity, the concordance rates appear to be dependent on the number of cores
analysed in that the more cores are analysed, the more concordant are the tumour markers between EB
and CNB 13.
Although findings of this study are in keeping with those of previous, several limitations that may have
potentially result in discordant cases were noted. Some of the various factors that may have contributed
to the discordant cases have been discussed in the preceding sections. In addition, technical preparation
of immunohistochemistry and retrospective nature of this study may have also influenced the findings
of this study. Breast cancers with HER2 2+ on immunohistochemistry are considered equivocal and are
therefore retested using fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization
(CISH) for confirmation. However, in this study, FISH/CISH status of HER 2+ cases were not directly
accessible due to time constraint and so were considered as positive for ease of analysis. The
assumption of HER2 2+ cases as truly positive may have caused selection bias in this study and
possibly the high discordant rates seen in HER2.
Conclusion
In conclusion, ER and PR immunohistochemistry performed on CNB produce results which accurately
reflect those assessed on EB. The concordance rate for HER2 was less consistent, suggesting
intratumoural heterogeneity among contributing factors. Concurrent analysis of HER2 with FISH/CISH
on breast cancers is required for HER2 2+ cases given the high discordant rates between EB and CNB.
Acknowledgement
We acknowledge staff and doctors of Department of Pathology UKM for supporting this research.
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