Introduction: In recent years, the efficacy of FNA biopsies has been discussed but it was not investigated why it was less effective than core needle biopsy in the diagnosis of breast cancer. Herein, we tried to identify the reasons for false negative results of FNA biopsies in the diagnosis of breast cancer. Background: c-erbB-2 is a receptor analog of epidermal growth factor and a proto-oncogene. Overexpression of c-erbB-2 occurs in cases where there is an increased potential for aggressive and metastatic disease. In this study, we aimed to retrospectively evaluate FNA false-negative (false(-)) patients during breast mass diagnosis. Patients and Methods: We examined 31 patients admitted to our clinic with breast pain or a palpable breast mass between who underwent FNA for a preoperative diagnosis and were subsequently diagnosed with breast cancer. Patients were divided into two groups in terms of their FNA biopsy results; the false(-) group (n = 20) and the true(+) group (n = 11). The diagnostic accuracy of FNA biopsy in our study increased significantly in cases where c-erbB-2 was negative (p = 0.022). The logistic regression analysis performed for significant c-erbB-2 results provided an odds ratio of 6.222, along with a 95% CI of 1.212–31.937 and a p-value = 0.028. Conclusion: We identified a relationship between the diagnostic accuracy of FNA biopsy and c-erbB-2. It was observed that negative c-erbB-2 increased the accuracy of FNA biopsy.
Breast cancer is an ongoing health problem and its rate of diagnosis is increasing. In addition to genetic mutations, the most powerful diagnostic risk factors for this disease are mammographic density and epithelial atypia [1-4]. Since 2009, all women aged 50–74 years are recommended to undergo breast screening once every 2 years, while those aged 40–49 years are screened on an individual basis depending on various risk factors .
c-erbB-2 (known as HER2/Neu) is a receptor analog of epidermal growth factor and a proto-oncogene. Together with estrogen receptor (ER) and progesterone receptor (PR), c-erbB-2 is a useful biomarker in the pathological classification of breast cancer. Overexpression of c-erbB-2 occurs in cases where there is an increased potential for aggressive and metastatic disease.
Various techniques, such as fine needle aspiration (FNA) biopsy, core needle biopsy, stereotactic core needle biopsy, vacuum-assisted core biopsy, ultrasound or magnetic resonance imaging (MRI)-guided biopsy, and surgical biopsy, can be used for breast masses, but the latter method is a much more invasive procedure.
In this study, we aimed to retrospectively evaluate FNA false-negative (false(-)) patients during breast mass diagnosis, as well as true-positive (true(+)) FNA patients diagnosed with breast cancer, in terms of the overexpression of c-erbB-2, ER, and PR.
We examined a total of 31 patients admitted to our clinic with breast pain or a palpable breast mass between January 2014 and January 2016 who underwent FNA for a preoperative diagnosis and were subsequently diagnosed with breast cancer. May-Grünwald-Giemsa or Papanicolaou dye was used to stain the cytological samples obtained via FNA.
All of the patients diagnosed with breast cancer had undergone a modified radical mastectomy or breast-conserving surgery, but advanced diagnostic methods led to a negative FNA biopsy result and a continuation of the patient’s complaints. In this study, we excluded any inadequate biopsy results and worked under the assumption that benign lesions were benign, and malignant or suspicious lesions were malignant.
|Reseptor Antigen||False(-)n1/n2||True(+)n1/n2||Rho Value||Pa|
Patients were divided into two groups in terms of their FNA biopsy results; the true(+) group (n = 20; average age, 44.63 ± 1.48 years) and the false(-) group (n = 11; average age, 48.85 ± 2.51 years). All patients were female. In the true(+) group, there were 17 cases of invasive ductal carcinoma, one mucinous carcinoma, one ductal carcinoma in situ, and one metaplastic carcinoma. All cases in the false(-) group were invasive ductal carcinoma. We used the SPSS for Windows statistical software package (ver. 18.0; IBM Corp., Armonk, NY, USA), to assess the groups in terms of age. A Kolmogorov-Smirnov test and independent t-test were performed due to the normal distribution of the data. No significant difference was determined between the groups (p = 0.160).
Patients were evaluated in terms of c-erbB-2, ER, and PR using either core biopsy or post-surgery specimen results. All samples underwent staining for overexpression of c-erbB-2, ER, and PR. The antigen receptor results were then assessed and graded as negative(-) or positive(+) (with the positive grade further graded as either 1, 2, or 3). A Spearman's rho test was then performed for the categorical values (Table 1) and logistic regression analysis was performed on significant c-erbB-2 values (Table 2).
The diagnostic accuracy of FNA biopsy in our study increased significantly in cases where c-erbB-2 was negative (p = 0.022). However, there was no similar increase when ER and PR were taken into consideration (pER = 0.48, pPR = 0.195).
The logistic regression analysis performed for significant c-erbB-2 results provided an odds ratio of 6.222, along with a 95% confidence interval of 1.212–31.937 and a p-value = 0.028.
|Reseptor Antigen||Exp(B) 95% CI(Lower-Upper)||Pb|
Mammography is performed using two standard views: craniocaudal and mediolateral-oblique. Results from screenings are reported by a radiologist using the Breast Imaging-Reporting and Data System (BIRADS) developed by the American College of Radiology (ACR) and are used to direct clinicians toward the most appropriate treatment. For example, a BIRADS score of 4 or above suggests a preoperative pathological diagnosis that might indicate the need for surgery.
The c-erbB-2 (HER2/neu) proto-oncogene is located on chromosome 17 and encodes a 185 kDa transmembrane phosphoglycoprotein with tyrosine kinase activity . The proto-oncogene is encountered in solid tumors, particularly breast tumors, and allows the proliferation, survival, and differentiation of normal cells by various signaling pathways.
FNA biopsy provides some advantages over core biopsy. For example, the incidence of hematoma and pneumothorax is very low. However, core biopsy is a robust and reliable diagnostic method [7, 8]. In addition, stereotactic and ultrasound biopsies can also be used in non-palpable breast masses.
In a study of invasive ductal carcinoma of no special type, the sensitivity of FNA biopsy was found to be 83.7%, compared with 95.3% for core biopsy; this difference was not significant (p = 0.2). However, the sensitivity in invasive lobular carcinoma was found to be 61.5%, versus 92.9% for core biopsy; this difference was statistically significant (p < 0.001) .
Several studies have shown that overexpression of c-erbB-2 causes a low response to tamoxifen and a decrease in survival. On the other hand, negative expression of c-erbB-2, ER, and PR indicates a poor prognosis and is usually seen in patients over 50 years old . A positive expression of c-erbB-2 is directly correlated with the histological grade [11-13]. Thus, a better prognosis is found in patients with a negative c-erbB-2 status and a positive ER/PR status.
There are several guidelines concerning the use of FNA biopsies. Various problems can occur during the procedure, including failure to enter the mass during aspiration, failure to apply enough suction – thus leaving the piston needle behind while exiting the tissue – and attempting to spray material while moving back and forth without aspirating air (causing cells to adhere to the walls of the injector). These issues can affect the quality of the cells used for analysis and, thus, the interpretation of the results. However, even taking into account such problems, malignant lesions may still appear to be benign because of the particular characteristics of the tumor (e.g., those with a greater amount of connective tissue, such as scirrhous carcinoma, and tumors that contain large necrotized areas) . The presence of necrosis indicates that a tumor is growing rapidly despite inadequate neovascularization. In a previous study, microvascular density was shown to increase in cases of c-erbB-2 overexpression . c-erbB-2 is positive in fast-growing and aggressive tumors, but false(-) results may be obtained depending on the placement of the necrotized areas. Scirrhous carcinoma, one of the three subtypes of invasive ductal carcinoma, has small compartments of cancer cells separated from each other and is accompanied by significant fibrosis. A previous study of this disease suggested a 44.8% rate of positivity of c-erbB-2 . In our study, all of our false(-) patients had invasive ductal carcinoma.
It is possible that diagnostic accuracy may be reduced because false(-) results can be caused by excess connective tissue or tumors that contain large areas of necrosis in c-erbB-2 positive patients.
In our research, we were unable to find any data on the diagnostic accuracy of FNA biopsy in cases of c-erbB-2 overexpression. When we evaluated our data, we identified a relationship between the diagnostic accuracy of FNA biopsy and c-erbB-2. It was observed that negative c-erbB-2 increased the accuracy of FNA biopsy. Even if a FNA biopsy returns a negative result, patients should be kept under surveillance and, if possible, advanced diagnostic methods should still be applied.
All the above mentioned authors have contributed to this article from data collection to final drafting work. All authors also declare to have read and approved the final manuscript.
- Fabian C, Kimler B, Zalles C, Klemp J, Kamel S, Zeiger S, et al. Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J Natl Cancer Inst. 2000;92:1217-27 pubmed
- Dupont W, Page D. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146-51 pubmed
- Hartmann L, Sellers T, Frost M, Lingle W, Degnim A, Ghosh K, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353:229-37 pubmed
- Boyd N, Guo H, Martin L, Sun L, Stone J, Fishell E, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356:227-36 pubmed
- Ariga R, Zarif A, Korasick J, Reddy V, Siziopikou K, Gattuso P. Correlation of her-2/neu gene amplification with other prognostic and predictive factors in female breast carcinoma. Breast J. 2005;11:278-80 pubmed
- Dowlatshahi K, Jokich P, Schmidt R, Bibbo M, Dawson P. Cytologic diagnosis of occult breast lesions using stereotaxic needle aspiration. A preliminary report. Arch Surg. 1987;122:1343-6 pubmed
- Evans W, Cade S. Needle localization and fine-needle aspiration biopsy of nonpalpable breast lesions with use of standard and stereotactic equipment. Radiology. 1989;173:53-6 pubmed
- Ohashi R, Matsubara M, Watarai Y, Yanagihara K, Yamashita K, Tsuchiya S, et al. Diagnostic value of fine needle aspiration and core needle biopsy in special types of breast cancer. Breast Cancer. 2015;: pubmed
- Ambroise M, Ghosh M, Mallikarjuna V, Kurian A. Immunohistochemical profile of breast cancer patients at a tertiary care hospital in South India. Asian Pac J Cancer Prev. 2011;12:625-9 pubmed
- Ohta M, Konno H, Tanaka T, Baba M, Kamiya K, Syouji T, et al. The significance of circulating vascular endothelial growth factor (VEGF) protein in gastric cancer. Cancer Lett. 2003;192:215-25 pubmed
- Lönn U, Lonn S, Friberg S, Nilsson B, Silfversward C, Stenkvist B. Prognostic value of amplification of c-erb-B2 in bladder carcinoma. Clin Cancer Res. 1995;1:1189-94 pubmed
- Vollmer R, Humphrey P, Swanson P, Wick M, Hudson M. Invasion of the bladder by transitional cell carcinoma: its relation to histologic grade and expression of p53, MIB-1, c-erb B-2, epidermal growth factor receptor, and bcl-2. Cancer. 1998;82:715-23 pubmed
- Sagin BH, Kiroglu, Y., Bakir, S. Meme Ince Igne Aspirasyon Biyopsisinde Sitolojik Kriterler. Turk patoloji dergisi. 1995;11(1):16-9.
- Vameşu S. Angiogenesis and co-expressed of ER and c-erbB-2 (HER2/neu) protein in primary breast cancer patients: an analysis of 158 needle core biopsies. Rom J Morphol Embryol. 2008;49:469-78 pubmed
- Nagae Y, Kameyama K, Yokoyama M, Naito Z, Yamada N, Maeda S, et al. Expression of E-cadherin catenin and C-erbB-2 gene products in invasive ductal-type breast carcinomas. J Nippon Med Sch. 2002;69:165-71 pubmed