|Year : 2020 | Volume
| Issue : 1 | Page : 35-40
Expression of human epidermal growth factor receptor 2/neu in breast carcinoma: Experience from a tertiary care center in Tamil Nadu, India
Syed Ahmed Hussain1, S Prakashiny1, Naseem Noorunnisa1, R Revathi Shree1, Senthil N Ganesh2
1 Department of Pathology, Shri Sathya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth University, Kancheepuram, Tamil Nadu, India
2 Primary Health Care, Tiruvannamalai, Tamil Nadu, India
|Date of Submission||27-Mar-2020|
|Date of Decision||28-Apr-2020|
|Date of Acceptance||30-Apr-2020|
|Date of Web Publication||20-Jun-2020|
Dr. S Prakashiny
Department of Pathology, Shri Satya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth University, Ammapettai, Kancheepuram - 603 108, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background and Aim: Women diagnosed with the foremost common cancer are the breast carcinoma. Human epidermal growth factor receptor 2 (HER2)/neu status has become an important part of immunohistochemical evaluation of breast carcinoma. Hence, the main aim of our study was to correlate the HER2/neu expression in breast carcinoma patients with certain clinicopathological parameters to ensure the better prognosis of the disease. Materials and Methods: The present study included 56 breast carcinoma patients. The surgically dissected breast carcinoma specimens were subjected to immunohistochemistry staining and were evaluated for certain clinicopathological prognostic parameters that included tumor size, Nottingham modification of the Scarff Bloom-Richardson (NSBR) grading, necrosis, lymph vascular invasion, fibrosis, stromal reaction, and lymph node metastasis. Statistical analysis by the Chi-square and Student's t-test was performed. Results: Most patients belonged to the postmenopausal age group (62.5%). Only 19 (33.9%) out of 56 patients showed positive for HER2/neu expression with maximum HER2/neu expression noted in the 40–60 years' (44.83%) age group. A greater proportion of cases (66.07%) had tumor size ranging from 2 to 5 cm with a majority of HER2/neu-positive (40.5%) cases among them. Majority of patients (96.24%) were of infiltrating ductal carcinoma. With respect to NSBR grading, 50% patients in Grade 3 showed positive HER2/neu expression (P = 0.048). It was also observed that 17 patients showed positive HER2/neu expression at the varying stages of lymph node metastasis (P = 0.022). Conclusion: The evaluation of HER2/neu expression indicates it to be a stronger prediction of poor prognosis due to its association with prognostic parameters.
Keywords: Breast carcinoma, human epidermal growth factor receptor 2/Neu expression, infiltrating ductal carcinoma, lymph node staging, Nottingham modification of the Scarff Bloom–Richardson tumor grading
|How to cite this article:|
Hussain SA, Prakashiny S, Noorunnisa N, Shree R R, Ganesh SN. Expression of human epidermal growth factor receptor 2/neu in breast carcinoma: Experience from a tertiary care center in Tamil Nadu, India. Arch Med Health Sci 2020;8:35-40
|How to cite this URL:|
Hussain SA, Prakashiny S, Noorunnisa N, Shree R R, Ganesh SN. Expression of human epidermal growth factor receptor 2/neu in breast carcinoma: Experience from a tertiary care center in Tamil Nadu, India. Arch Med Health Sci [serial online] 2020 [cited 2020 Nov 28];8:35-40. Available from: https://www.amhsjournal.org/text.asp?2020/8/1/35/287362
| Introduction|| |
Breast carcinoma is the most common female cancer worldwide, and the global data indicate that the incidence of occurrence is on the rise, with many women being diagnosed in both developed and developing countries. Greater than 50% of cancer cases being diagnosed every year are from the developing countries. By the year 2020, it is estimated that over 10 million people worldwide would die of cancer every year. In 2019 alone, an estimated 268,600 new cases of invasive breast carcinoma were expected of being diagnosed and more than 3.8 million USA women with a history of breast carcinoma were reported to survive the disease. In India, the age-adjusted incidence rate of breast carcinoma is lower than developed countries.,
Breast carcinoma has different prognostic and therapeutic modalities. The progesterone receptor (PR)/estrogen receptor (ER) status and expression of human epidermal growth factor receptor 2 (HER2/neu) are the three most beneficial investigations that influence the response to specific therapeutic agents toward breast cancer. A significant improvement in treatment regimens are vital for the survival of patients. HER2/neu expression is associated with poorer survival as it indicates high-grade tumor, and its status has become an important part of immunohistochemical evaluation of breast carcinoma to predict the response to monoclonal antibody therapy (e.g., herceptin), thereby to achieve favorable response to the treatment and hence survival. HER2/neu has prominent prognostic value than most currently used prognostic factors such as ER and PR status.,
Therefore, the main aim of our study was to determine the proportion of HER2/neu receptor positivity in breast carcinoma patients and to correlate its expression with clinicopathological parameters using the Nottingham modification of the Scarff Bloom–Richardson (NSBR) system of grading breast carcinoma.
| Materials and Methods|| |
The histopathological study was conducted on 56 mastectomy specimens of breast carcinoma selected by the convenient sampling method at a tertiary care center during January 2012–September 2017 after obtaining the clearance from the ethical committee. The consent from patients involved in the study was acquired before their surgery.
The study included patients with malignant breast carcinoma while those with benign lesions were excluded. Samples for the study were taken from the representative areas of carcinoma. The specimens received by the pathology department were initially subjected for adequate fixation using 10% neutral-buffered formalin, followed by routine processing involving dehydration, clearing, impregnation, and paraffin embedding. About ten 3–4 μ thick-paraffin sections from the representative areas of carcinoma were routinely stained with hematoxylin and eosin (H and E) and were examined under the microscope (×10, ×40).
Each specimen was assessed for clinicopathological prognostic parameters such as tumor size, histological grade, presence of necrosis, lymphovascular invasion, involvement of surgical margins, fibrosis, stromal reaction, involvement of the skin in the form of nipple and areola/pagetoid spread, metastases in the axillary lymph nodes, clinical staging, and lymph node staging of tumors. With respect to lymph node staging, breast carcinoma cases with no lymph nodes were classified as Stage N0, 1–3 lymph nodes with metastases as Stage N1, 4–9 as Stage N2, and >10 as Stage N3. The NSBR grading system was used for the tumor grading [Table 1]. Tumors with combined NSBR scores of 3–5 are classified as Grade 1; scores of 6 and 7 as Grade 2; and scores of 8 and 9 as Grade 3.
|Table 1: Tumor grading using Nottingham modification of the Scarff Bloom - Richardson system|
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All the 56 cases were subjected to immunohistochemistry (IHC) study for HER2/neu from the representative areas of the carcinoma with sections approximately 2–3 μ thick as per the instructions given by the polymer-based IHC kit of DAKO. The HER2/neu protein overexpression was assessed under the microscope (×10, ×40). A score of 0 was given when no or membrane staining was observed in <10% of tumor cells, score of 1+ when a faint membrane staining was detected in >10% of tumor cells, score of 2+ for moderate membrane staining in >10% of tumor cells, and score of 3+ for strong complete membrane staining in >30% of tumor cells. The original standardized immunohistochemical testing algorithm recommended by the Modified 2013 American Society of Clinical Oncology/College of American Pathologists Guidelines on HER2 testing in breast cancer was used for the evaluation of HER2/neu expression.
The statistical analysis was performed using R version 386 3.6.0 and SPSS 2.0 software (IBM company, Armonk, New York, United States of America) involving the Chi-square test and Student's t-test. The association of HER2/neu expression with the clinicopathological prognostic parameters and NSBR was evaluated. The values were represented as mean ± standard deviation. P≤ 0.05 was considered as statistically significant.
| Results|| |
In our study, the age of patients with breast carcinoma ranged from 27 to 74 years, and majority of the patients (51.79%) were in the age group of 40–60 years with 25% under <40 years and 23.21% >60 years of age, with a mean age being 49.5 ± 12.71 years.
Tumor particulars of patients
In addition to the lump in the breast, twenty patients experienced pain and nine experienced ulceration of skin over the breast region. Only two patients presented nipple discharge. None of the patients had a family history of breast cancer. Upon clinical examination, the tumor was based in the upper outer quadrant in 41 (73%) patients. In 5 (9%) patients, the tumor was central in location and in 10 (18%), the tumor was based in multiple quadrants. Regarding the clinical staging of tumor, 3 (05.35%) patients were in Stage I, 17 (30.35%) in Stage 2A, 21 (37.50%) in Stage 2B, 12 (21.42%) in Stage 3A, none in Stage 3B, and 3 (05.35%) in Stage 4. The tumor size in 3 (5.36%) of the patients was <2 cm, in 37 (66.07%) of them, the size ranged between 2 and 5 cm and in 16 (28.57%) patients, it was >6 cm.
A gross photograph of carcinoma breast showing the presence of carcinoma in more than one quadrant that is multicentricity along with the areas of hemorrhage was depicted in [Figure 1]a. The size of the tumor was 9 cm × 8 cm × 7 cm, gritty in nature. The carcinoma showed an infiltrating pattern of growth. The nipple and areola were slightly retracted, and the skin showed “peau d'orange” changes. Another gross photograph of carcinoma breast depicted in [Figure 1]b revealed the tumor which was firm hard mass. The cut surface showed irregular gray-white solid tumor. The size of the tumor was 6 cm × 6 cm × 5 cm, which was in the left quadrant and right quadrant. Nipple and areola were normal, and no changes were noted in the appearance of the skin. The microscopic view in [Figure 1]c depicted an infiltrating ductal carcinoma (IDC) showing adenoid cystic pattern (H and E, ×10). The tumor cells exhibited a dual population of cells-luminal epithelial cells, with variable glandular differentiation and basaloid cells in a trabecular pattern. [Figure 1]d depicts mucinous carcinoma of the breast (H and E, ×40) depicting hypocellularity with a round-to-polygonal tumor cells seen floating in the sea of mucin throughout. There was abundant mucin noted. Round-to-polygonal tumor cells were present in the upper and central portion of the image. [Figure 1]e (H and E, ×40) depicted an IDC with clear-cell pattern, showing nests and lobules of neoplastic cells composed of pleomorphic cells with abundant clear cytoplasm a small dark hyperchromatic nuclei. [Figure 1]f (H and E, ×40) depicts an IDC with a small-cell variant, showing tumor cells of round-to-oval shape with scant cytoplasm and hyperchromatic nuclei.
|Figure 1: Photograph of carcinoma breast showing (a) infiltrating growth pattern, (b) irregular grey-white solid tumour, H and E staining of (c) infiltrating ductal carcinoma-adenoid cystic pattern (×10), (d) mucinous carcinoma-hypocellularity with abundant mucin (×40), (e) infiltrating ductal carcinoma-clear cell pattern (×40) and (f) infiltrating ductal carcinoma-small cell variant (×40)|
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Histological examination of tumors
Important microscopic features such as deep-resected margins and skin, fibrosis, necrosis, lymphovascular invasion, pagetoid spread, stromal reaction, and in situ component were studied [Table 2]. Out of the 56 breast carcinoma patients, 54 were diagnosed with IDC and 2 with mucinous carcinoma. Fibrosis and necrosis were observed in 52 and 22 patients, respectively. Lymphovascular invasion was observed in 16 patients, and the pagetoid spread of tumors was seen only in three patients. Stromal reaction and in situ component were observed in 51 and 26 patients, respectively.
|Table 2: Distribution of carcinoma breast according to microscopic features of the tumor|
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Out of the 56 breast cancer patients in the study, 13 had Grade 1, 27 had Grade 2, and 16 had Grade 3 tumor as per the NSBR system. Tumor in lymph nodes was not observed in 22 patients. Whereas 19 patients exhibited Stage N1, 9 exhibited Stage N2, and 6 exhibited Stage N3 with respect to lymph node tumor [Table 3].
|Table 3: Nottingham modification of the Scarff Bloom - Richardson grading and Lymph node staging of breast carcinoma patients|
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[Figure 2]a depicts the IDC cells showing no immunostaining for HER2/neu (DAB, ×10). On histological examination, the tumor cells were noted to be in diffuse sheaths and of varying sizes with pleomorphic nuclei and prominent nucleoli. The score for the immunohistochemical staining HER2/neu was zero in this case. [Figure 2]b depicts a faint, incomplete membranous HER2/neu immunostaining (score of 1+) in IDC cells (DAB, ×40), where 95% of the tumor cells showed incomplete membranous staining. [Figure 2]c depicts a strong, complete membranous immunostaining (score of 3+) in IDC cells (DAB, ×40). About 96% of the tumor cells showed strong complete membranous staining with HER2/neu antibody.
|Figure 2: Immunohistochemical staining in infiltrating ductal carcinoma cells showing (a) no immunostaining (DAB, ×10), (b) faint, incomplete (DAB, ×40) and (c) strong, complete membranous immunostaining (DAB, ×40) with human epidermal growth factor receptor 2/neu antibody|
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In our study, a total of 19 patients exhibited a score of 3+ indicating a strong continuous membranous staining, and only 8 patients exhibited a score of 1+ indicating faint membranous staining corresponding to HER2/neu expression.
Association of human epidermal growth factor receptor 2/neu expression with varying parameters
The expression of HER2/neu in all the breast carcinoma was assessed which revealed 19 out of 56 patients testing positive for the same. Maximum HER2/neu positivity was noted in the age group of 40–60 (44.83%) years, but the association of HER2/neu with age was insignificant (P = 0.122). In our study, 21 (37.5%) patients were in the premenopausal and 35 (62.5%) in the postmenopausal age group. Maximum HER2/neu positivity (40%) was seen in the postmenopausal age group, but the association of HER2/neu with menopausal status was statistically insignificant (P = 0.215). The association of HER2/neu with tumor size was statistically insignificant (P = 0.555). The association of HER2/neu expression with the histologic subtype of the tumor in the study revealed 19 out of 54 patients being positive for HER2/neu expression in IDC with the association being insignificant (P = 0.432). The association of HER2/neu expression with varying histologic features of tumor was statistically insignificant (P > 0.05) [Table 4].
|Table 4: Association of human epidermal growth factor receptor 2/Neu expression with demographic and tumor features|
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Statistically significant association of HER2/neu expression with the histological grading as per NSBR (P = 0.048), clinical staging of tumor (P = 0.029), and lymph node staging (P = 0.022) was observed [Table 5].
|Table 5: Association of human epidermal growth factor receptor 2/Neu expression with clinicopathological characteristics|
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| Discussion|| |
Breast carcinoma patients present with high mortality and morbidity which makes it the most diagnosed cancer in women, and hence, one of the leading reasons of cancer-related deaths in women. Patients with the HER2/neu-positive expression typically represent a cancer type with special biological behavior and clinical features with aggressive tumor progress and poor survival.
With the aim of our study being to establish the association of HER2/neu expression in breast cancer patients with varying clinicopathological parameters, 56 patients diagnosed with breast carcinoma were involved with a greater proportion belonging to the age group of 40–60 years with the mean age of 49.5 years and more common in the postmenopausal age group (62.5%). Similar observations were noted in an earlier study. A greater proportion of cases (66.07%) had tumor size ranging from 2 to 5 cm, followed by 28.5% cases of tumor size >5 cm. Earlier studies revealed similar findings with higher percentage (75%) of tumors ranging between 2 and 5 cm. Majority of the patients (96.24%) exhibited IDC, comparable to that observed in earlier reports.,, A higher percentage of patients exhibited the patterns of fibrosis (92.85%) and stromal reaction (91.07%) patterns.
The NSBR grading system revealed a greater proportion of the patients (48.21%) were of Grade 2, followed by 28.57% of Grade 3. A majority (39.28%) of patients were of Stage N0, followed by 33.92% in Stage N1, 16.07% in Stage N2 and 10.71% in Stage N3. In contrast to this, earlier studies found that majority of the tumors belonging to N1 Stage (41.1%) followed by N2 (34.2%) and N3 (24.7%). Similar observations were recorded in earlier studies.,
Overall, only 19 (33.9%) out 56 patients showed positive HER2/neu expression with earlier studies conducted reporting a similar trend.,, Maximum positivity with respect to HER2/neu expression was noted in the age group of 40–60 years (44.83%) but insignificant (P = 0.1219). Some studies revealed an increasing pattern of HER2/neu expression with age; however, few studies have revealed that younger age groups also showed greater expression,, thereby lacking statistical significance. Postmenopausal patients showed more HER2/neu positivity (40%)than premenopausal patients (23.81%). HER2/neu association with menopause was insignificant (P = 0.2154) with similar studies earlier reported.,
All the 19 positive cases expressing HER2/neu had IDC. Tumor size is one of the important prognosis predictor of breast cancer. In this study, majority of HER2/neu-positive (40.5%) cases had tumor size ranging from 2 to 5 cm. Owing to the small sample size in our study, the association of HER2/neu with tumor size was insignificant (P = 0.4518). Similar number of cases expressing HER2/neu with tumor size ranging 2–5 cm have been reported earlier. Associating the NSBR grading with HER2/neu expression, majority of patients, i.e., 8 (50%) out of 16 belonged to Grade 3 followed by 10 (37.03%) out of 27 patients belonging to Grade 2. A pattern of increase in the expression of HER2/neu in higher grade tumor was observed in comparison to similar studies., In our study, the association of HER2/neu with NSBR grading was found to be statistically significant (P = 0.048). With respect to clinical staging of tumors, majority of 12 (57.14%) out of 21 HER2/neu-positive cases was noted in Stage 2B. Significant association of HER2/neu with clinical stage was noted (P = 0.029). However, few studies reported of no such significance. In our study, it was observed that out of the 34 patients who showed positive lymph node staging, 17 (50%) of them showed positive HER2/neu expression at varying stages of lymph node metastasis with P= 0.022. Similar studies were earlier reported.,, In our study HER2/neu expression was observed in 19 cases (33.92%) with a score of 3+ but IHC indicates a very weak association which indicates that fluorescence in situ hybridization (FISH) is a standard and a more reliable technique for HER2/neu gene amplification studies, particularly in IHC equivocal cases.
The first ever monoclonal antibody approved for the treatment of breast carcinoma was trastuzumab that directly targets HER/neu. Although during treatment, patients tend to develop drug resistance and a combination of drugs is preferred for further course of action. In such cases, blocking the nonreceptor tyrosine kinase cellular-SRC or PI3K/AKT/mTOR intracellular signal pathway could overcome the resistance, specifically with trastuzumab. Drugs such as neratinib or enviroximes have been in use for such cases. Till date, the emergence of many new drugs provides a new view for combined treatment strategies against HER2/neu.
One of the limitations of our study was the smaller sample size considered, which could be one of the reasons for the observed statistical insignificance of HER2/neu expression with the demographic and tumor features. The ER and PR receptor status were not considered for our study since HER/neu has a stronger prognostic value to predict the response for monoclonal antibody therapy.
Future recommendations would be to conduct the study with larger sample size, associating HER2/neu expression with various clinicopathological parameters along with investigating HER2/neu amplification. In cases of equivocal breast cancer, performing FISH analysis could confirm the receptor status. Additional evidence regarding ER and PR receptor status or certain cell-signaling pathways could become a stronger evidence for the disease prognosis and thereby assisting the physician in deciding the further course of treatment.
| Conclusions|| |
The findings of our study present a stronger evidence in evaluating the HER2/neu expression as an independent prognostic factor in case of metastatic breast carcinoma, indicated by the association between HER2/neu expression and clinical stage, NSBR grading and lymph node staging being significant. Further evidence was provided by the association of HER2/neu expression with prognostic parameters such as tumor size and histological type of which could aid in deciding the future course of treatment.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]