| Abstract|| |
Background: Human epidermal growth factor receptor 2 (HER2)/neuprotooncogene (neu) is a proven molecular prognostic marker in breast, ovarian, gastric, and ovarian cancers. In head-and-neck cancers, varied expression is documented and therefore its prognostic role is debatable. Aim of the Study: To find the rate of overexpression of HER2/neu in head-and-neck cancers and to understand its prognostic role by evaluating its association with nodal stage and overall stage of the patient. Methodology: A total of 70 surgically resected cases of head-and-neck cancers were evaluated for expression of HER2/neu by immunohistochemistry. Scoring was done according to the American Society of Clinical Oncologists/College of American Pathologistsguidelines for Her2/neu testing in breast cancer. Results: Of the 70 cases studied, 57 were of oral cavity and 13 were laryngeal squamous cell cancers and 14 (20%) were Her2/neu positive. On correlating the expression of HER2/neu in T1/T2 (41 cases) versus T3/T4 (27 cases), the P value was found to be 0.8273 which was statistically insignificant. Furthermore, no statistically significant difference in expression of HER2/neu was found in between node negative and node positive cases (49 vs. 19 cases, respectively), with P = 0.512. Conclusion: In the current settings, HER2/neu is not found to be a prognostic marker in head-and-neck cancers. Standard immunohistochemistry staining protocols need to be established like in breast cancers to aid uniform reporting and further evaluate the role of this important protooncogene in head-and-neck cancers.
Keywords: Head and neck, human epidermal growth factor receptor 2/neu, prognosis, squamous cell cancer, targeted therapy
|How to cite this article:|
Vats S, Ganesh M S, Agarwal A. Human epidermal growth factor receptor 2 neu expression in head and neck squamous cell cancers and its clinicopathological correlation: Results from an Indian cancer center. Indian J Pathol Microbiol 2018;61:313-8
|How to cite this URL:|
Vats S, Ganesh M S, Agarwal A. Human epidermal growth factor receptor 2 neu expression in head and neck squamous cell cancers and its clinicopathological correlation: Results from an Indian cancer center. Indian J Pathol Microbiol [serial online] 2018 [cited 2018 Aug 22];61:313-8. Available from: http://www.ijpmonline.org/text.asp?2018/61/3/313/236599
| Introduction|| |
Squamous cell carcinoma (SCC) of the head and neck is a malignant epithelial disease arising from the mucosa of the upper aerodigestive tract (oral cavity, larynx, oropharynx, and hypopharynx). The disease is characterized by local tumor aggressiveness, early recurrence, and high frequency of second primary tumors.
Although performance status, tumor-node-metasis (TNM) staging, and pathologic grading of differentiation remain the most important factors in predicting prognosis of head-and-neck SCC (HNSCC), several clinical studies have demonstrated a prognostic role for molecular indicators in tumor progression.
An attempt to find more significant information to predict the biological behavior of this neoplasm and to look at the possible relationship between the tumoral progression and the products of genes which regulate cell proliferation and differentiation, such as protooncogenes, anti-oncogenes, and apoptosis regulating genes, has been reported recently.
Many studies have focused on the roles of p53, cyclin D1, p16 proteins, matrix metalloproteinases, and angiogenic factors (VEGF, CD34, CD105) and have suggested that these new molecular markers may be independent significant predictors of survival. Furthermore, the use of targeted agents against molecular markers belonging to the epidermal growth factor receptor (EGFR) family has recently become integrated into the treatment protocols of many malignancies such as breast cancer and clinical studies with these agents are currently under way in patients with HNSCC.
Similarly, human epidermal growth factor receptor (HER2)/neu (cerbB2) oncoprotein expression in HNSCC has been investigated, although reports on its clinical relevance have led to conflicting results.,
The HER2/neu is amplified and overexpressed in approximately 30% of human breast cancers and in several other tumors, including ovarian, gastric, and colorectal cancers. The prognostic relevance of HER2/neu in these tumors has been documented.
In HNSCC, most studies of the HER2/neu, involving detection of the p185 protein by immunohistochemical techniques, have reported an overexpression rates between 0% and 47%.,,,, However, there is doubt over the prognostic significance of this oncogene in these tumors, and thus its utility as a target of new therapy is still unclear.,,,
Aims of the study
This study aims to detect the presence of HER2/neu overexpression in HNSCCs and to determine its association with the T stage of the tumor, the nodal status, and the TNM stage.
| Methodology|| |
In a cross-sectional study of 70 cases of HNSCC diagnosed and treated between August 2011 and April 2013 were included in this study. All patients were informed about the research and agreed to participate on the study by signing a free and informed consent form.
All the patients who were surgically treated of head-and-neck squamous cell cancers.
- Improperly fixed specimens (delayed, over, or underfixed specimens)
- Specimens from all female patients with known history of treatment of breast carcinoma.
The specimens were routinely fixed in 10% neutral buffered formalin (NBF). Dimensions of the biopsy specimen were noted; the lesion was identified and relevant tissue submitted for processing in labeled capsules. The tissue was embedded in paraffin wax and 3–4 μm thick sections were taken and subsequently stained with hematoxylin and eosin stain. The microscopic features were assessed and diagnosis was rendered accordingly.
Immunohistochemical determination of the human epidermal growth factor receptor 2/neuoncoprotein
All the sections from the tumor were subjected to immunohistochemical (IHC) staining. The Rabbit Anti-Human c-erb-2 Oncoprotein Antibody was used to demonstrate the HER2/neu expression. IHC was done using peroxidase-antiperoxidase method.
Staining procedure 
NBF-fixed paraffin-embedded tissue sections of 3–4 μm were taken on poly-L-lysine-coated slides. The slides were fixed in an incubator at 600°C for 20 min. Deparaffinization was done. Hydration was done in running tap water then changed to distilled water for 5 min. Antigen retrieval was done with citrate buffer (pH 6.0–6.8) using microwave oven at 950°C for 2 cycles 10 min each. Slides were brought to room temperature and washed with distilled water. Slides were then treated with endogenous peroxidase block for 10 min. Further, slides were washed in wash buffer (phosphate), 3 times for 3 min. Treated with power block for 10 min, the solution was allowed to drain. Primary antibody was applied for an hour then washed with wash buffer, 3 times for 3 min. Super enhancer was added, for 20 min. Secondary antibody was applied for 30 min and then washed with wash buffer, 3 times for 3 min. Diaminebenzidine chromogen was applied for 5 min and then it was washed with distilled water to stop chromogen reaction. Counter staining was done with Mayers Hematoxylin for 2 min and then finally washed with tap water.
HER2/neu is a membrane stain. Staining pattern was compared with control slides. Positive controls were sections of a breast carcinoma previously found to be positive for Her2/neu (with score 3+). Negative controls were duplicate sections of the same sample in which the primary antibody had been excluded and replaced with PBS.
Representative fields were selected in each immunohistochemistry stained section. Ten fields were chosen for each section. We counted the total number and intensity of staining of positive cells for all ten examined fields per case was calculated. Hence. the mean number and intensity of staining of Her2/neu-positive cells per field was calculated. IHC was scored according to the American Society of Clinical Oncologists/College of American Pathologists (ASCO/CAP) guidelines for Her2/neu testing in breast cancer, as described by Lebeau et al 2001:
- 3+: Complete and intense membrane staining of >10% tumor cells
- 2+: Complete but moderate staining of >10% cells
- 1+: Weak and incomplete staining in >10% cells
- 0: No membrane staining or staining in <10% cells
Score 0 was considered negative and Score 1, 2, and 3 were positive.
The Chi-square test was used for analysis of contingency tables, with P < 0.05 as the criterion of statistical significance. Her2/neu overexpression was correlated with various variables (stage of tumor and TNM status).
| Results|| |
Out of 70 cases, 41 were male and 27 were female. Male-to-female ratio was 1.6:1. Majority of the patients (41) were >50 years of age. The age range observed was between 22 and 80 years.
Twenty-five patients were smokers, 53 were tobacco chewers, while 18 patients had both habits.
As far as the site of primary is concerned, oral cavity was the most common site with 50% cases had buccal mucosa primary, 15.7% tongue, 7.1% retromolar trigone, 5.7% alveolus, and 2.8% lip. A total of 13 patients (18.5%) were laryngeal squamous cell cancers. fifty-five cases (78.5%) were well differentiated, 11 cases (15.7%) were moderately differentiated, while 2 cases each (2.85%) were poorly differentiated and verrucous carcinomas.
17, 24, 14, and 13 patients were T1, T2, T3, and T4 stages, respectively., 19% cases were stage 1,22% stage 2,25% stage 3 and 34% were Stage 4 resectable cases.
Her2/neu protein is located in the cell membrane and membrane staining was considered positive. Of the 70 cases, 14 (20%) were Her2/neu positive. The site-wise distribution of Her2/neu positivity in percentage is shown in [Table 1]. Out of these 14 cases, 5 showed both cytoplasmic and membrane staining. In the adjacent epithelium, usually showing various degrees of epithelial dysplasia, faint and diffuse cytoplasmic reaction was seen in the prickle cell layer of two positive cases [Figure 1].
|Table 1: Location of head and neck squamous cell carcinomas and percentage of human epidermal growth factor receptor 2/neu positive cases|
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|Figure 1: (a) Squamous cell carcinoma depicting cytoplasmic staining (negative membrane staining; Her2/neu, ×400); (b) Squamous cell carcinoma, membrane staining (Her2/neu, ×400); (c) Squamous cell carcinoma depicting membrane and cytoplasmic staining (Her2/neu, ×100); (d) Dysplastic epithelium depicting staining in the prickle cell layer in a case of positive membrane staining (Her2/neu, ×100)|
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P value was 0.8273 and 0.5120 for the correlation between Her2/neu with T-stage (T1 and T2 vs. T3 and T4) and nodal status (node negative vs. node positive). respectively. This value is considered to be statistically insignificant. Hence, the present study indicates no correlation between the Her2/neu status with the T stage or the nodal status of the patients [Table 2].
|Table 2: Co-relation between tumour size and nodal stage and human epidermal growth factor receptor 2/neu expression|
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P value for correlation between Her2/neu status and stage of tumor (Stage 1 and 2 vs. Stage 3 and 4) was 0.6643 which is statistically insignificant. The study indicates no correlation between Her2/neu status and stage of the tumor [Table 3].
|Table 3: Co-relation between stage of tumor and human epidermal growth factor receptor 2/neu status|
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| Discussion|| |
On comparison of the demographic variables following observations were noted.
The number of males outnumbered the females. This observation is consistent with that in the literature. This marked gender difference may be due to higher susceptibility for smoking and alcohol consumption in males.
Tobacco smoking and alcohol consumption have been regarded as major risk factors while betel nut chewing as a common risk factor in the development of HNSCCs by Yan et al. In the present study also, it was observed that 75% patients were betel nut chewers and 36% were smokers while 26% revealed habit of both tobacco smoking and betel nut chewing.
A difference has been noted in the most common site of occurrence of SCCs in the head-and-neck region, depending on geographic area of occurrence. Larynx was observed to be the most common site of occurrence of HNSCC by Cavalot et al. and M Guery et al. (1998, France) found oral cavity to be the most common site while tongue was the most common site in the studies by Xia et al. In India, oral cavity is the most common site of primary tumor as per the NCRP data. Gingivobuccal cancer is called “Indian oral cancer” because of the custom of placing tobacco in the sulcus leading to chronic exposure.
Maximum number of patients in the study had SCC in the buccal mucosa (50%), followed by larynx (18.57%), tongue (15.7%), RMT (7.1%), alveolus (5.7%), and lips (2.85%).
By TNM stage, 19% of patients had Stage I disease, 22% had Stage II, 25% had Stage III, and 34% had Stage IV. At the moment of diagnosis, 19 patients were lymph node positive (28%). As mentioned in literature, HNSCC has been known to progress into late stages before coming to clinical diagnosis.
According to grade, most of the tumors were well differentiated (78.5%), 15.7% were moderately differentiated while poorly differentiated and verrucous SCC were 2.85% each.
There is a wide variation in the HER2 overexpression in HNSCCs. Reported rates of HER2/neu expression in HNSCCs vary from 2% to 59% [Table 4].,
|Table 4: Literature review of expression of human epidermal growth factor receptor 2/neu in head and neck squamous cell cancers|
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Hence, for clinical trial and treatment, it is very important to develop a standard HER2/neu detection test to recruit eligible patients for Trastuzumab treatment.
Xia et al. in their study of Her2/neu expression in HNSCCs considered those tumor cells that were immunostaining with red granules in the cytoplasm and cellular membrane as positive and those cells without any immunostaining as negative. The final scoring of immunoreactivity was based on the percentage and the intensity of HER2/neu expression. On the other hand, Lebeau et al., Khan et al., Cavalot et al., Seifi et al., and Bernardes et al. (2010) used the ASCO/CAP guidelines for Her2/neu testing in breast cancer. While Bernardes et al. categorized the data as negative or positive expression, Cavalot et al. considered a cutoff point for positivity between 1 + and 2+. This lack of standardization in scoring causes a drastic variation between the results by various methods. This observation reaffirms the importance of standardization of scoring as a prerequisite for selecting patients for targeted therapy.
It is possible that the discrepancies in the results may be attributable to the initial lack of standardization of the assay methods. In fact, a careful review of these studies shows a wide variation in the methods used, such as the use of different antibodies that recognize different epitopes of the protein, the lack of uniformity when HER-2/neu assays are performed in different laboratories, and the different interpretation of the IHC assays. In particular, the significance of cytoplasmic staining is the most widely debated question.
Xia et al. used immunohistochemistry in 80 patients with HNSCC and considered cytoplasmic and membrane staining for Her2/neu as positive. They reported Her2/neu to be the most significant factor in predicting disease outcome, while Angiero et al. and Khan et al. could not demonstrate Her2/neu as a prognostic factor or treatment indicator in patients with HNSCC.
Controversial results in different studies might be due to:
- Using different IHC methods (direct, indirect)
- Using different type of antibody (clone cerbB2, CB11, ICR 1b, polyclonal DAKO, and monoclonal zymed)
- No specific criteria for positive staining for Her2/neu protein (membrane and/or cytoplasmic)
- Different techniques (immunosorbent assay, radioimmunoassay, IHC)
- Different locations of lesions and sex of patients with HNSCC.
The staining pattern and intensity considered as positive may account for discrepancies in the percentage of Her2 positive cases reported in various studies. In our study, membrane staining was associated with cytoplasmic staining in 5 of 14 positive cases [Figure 1]c, while in one case pure cytoplasmic staining was observed [Figure 1]a. Obviously, till the biological basis and prognostic signifance of cytoplasmic staining in HNSCC has not been settled, discrimination among results of various studies will prevail.
Angiero et al. in their study on 40 patients of tongue SCC used IHC with two types of antibody and fluorescence in situ hybridization (FISH) with Her2/neu. Using Hercept test kit, they found only 1 positive case and with CB11 monoclonal antibody 10 cases came out to be Her-2/neu positive but FISH did not approve these IHC results.
In our series, 14 out of 70 tumors showed Her2/neu immuneexpression, that is, 20%.
Maximum percentage of positive cases were observed in the region of tongue (27.3%) followed by alveolus (25%), buccal mucosa (22.9%), and larynx (15.4%). None of the tumors occurring in lip or RMT were Her2/neu positive.
There was no significant association between Her-2/neu positivity and stage, grade or lymph node status of the patient. Similar results have been reported in the study by Khan et al. However, Cavalot et al. and Xia et al. reported a correlation between Her2/neu expression and nodal status. Cavalot et al. concluded by their study that Her2/neu expression and lymph nodal status are independent predictors of DFS in HNSCC patients.
Out of the six recurrent SCCs, two turned out to be Her2/neu positive. However, Khan et al. in their study reported no significant association between Her-2/neu positivity and local, regional, or distant recurrence. Interestingly, the study by Guerry et al. revealed an unexpected significant association between Her2/neu overexpression and decreased risk of distant metastases in patients with pharyngeal tumors.
Correlation between Her2/neu overexpression, clinicopathologic variables, and overall survival
cerbB2 (Her2/neu) overexpression and amplification has been correlated with shorter survival in breast cancer (Paik et al). The prognostic value of Her2/neu has not been extensively studied in HNSCCs.
The studies that included patients with HNSCCs of different sites and stages , found no correlation between Her2/neu overexpression and survival. Guerry et al. in their study on pharyngeal SCCs also reported similar results. Ulanovski et al. in their study on tongue SCCs found no correlation between Her2/neu overexpression and survival. However, Xia et al. suggested a strong correlation between Her2/neu overexpression and shorter disease survival in OSCCs. Cavalot et al. also suggested that Her2/neu expression is an independent risk factor in the prognosis of HNSCC. The discrepancies in these results suggest that location of the carcinoma might be an important factor in terms of prognosis.
Her2/neu and conventional treatment
The conventional routine treatment for HNSCCs is surgery with adjuvant therapy with radiotherapy or chemotherapy (RT/CT). Literature reveals that de novo or acquired chemoresistance and radioresistance comprises a significant problem in management of HNSCCs.
In the present study, one out of the two patients who had received neoadjuvant chemotherapy, turned out to be Her2/neu positive. Of the three patients who had received preoperative radiation therapy, two turned out to be Her2/neu positive. Also, four patients had received both chemoradiotherapy and one of them turned out to be Her-2/neu positive. These findings suggest that Her-2/neu might play a role in imparting chemoradio resistance to HNSCCs.
Akimoto et al. were the first to provide evidence that EGFR expression may have an effect on radiation sensitivity, a result that has been validated clinically. EGFR overexpression in head-and-neck cancer cell lines was found to have greater radioresistance compared with cell lines that had relatively lower levels of EGFR expression. It was also found that following radiation, EGFR becomes upregulated within the tumor, leading to increased activation of its downstream signaling pathways. Her2/neu belongs to EGFR family and is known to activate PI3k signaling pathway and the downstreaming activated factors are suggested to be part of cellular response to radiation therapy. The work by Akimoto et al. culminated in the landmark 2006 publication of the randomized trial by Bonner and colleagues that showed an overall and progression-free survival advantage with the addition of cetuximab to standard radiation therapy.
Emerging data suggest that cancer stem cells (CSCs) may be responsible for the acquired resistance to CT/RT in HNSCCs. CSCs is a subpopulation of cells that can self renew and generate differentiated cells that form the bulk of the tumor.
The current HNSCC treatment regimens selectively kill the differentiated cancer cells producing tumor regression, but do not eliminate the CSCs. Hence, understanding the molecular pathways of HNSCC will help to define targets for designing novel therapeutic strategies.
| Conclusion|| |
The conventional treatment by surgery with adjuvant chemotherapy and RT has failed to improve survival in HNSCC patients beyond a certain limit and the same treatment is being given for the last three decades. Extensive research is been carried worldwide to certain biological markers which can serve as therapeutic targets and hence aid in improving patient survival. The present study aptly views and indicates the role of Her-2/neu as a molecular predictive marker in HNSCCs. To the best of my knowledge, there is no published Indian study on the role of Her2/neu in HNSCCs. The role of Her2/neu in HNSCCs has been studied extensively but consistent results are not available. A different scoring system is required for assessing Her2/neu positivity in HNSCCs. Lack of a well-defined scoring system has led to variation in results from different studies. Hence, the evaluation of Her2/neu as a routine diagnostic work-up and its utility needs to be studied further. Future research may be warranted if a subset of population shows significant overexpression of Her2 to evaluate the role of trastuzumab.
Limitations of the present study
The criteria for scoring of Her2/neu immunoexpression are not well defined in literature and hence the results of the study might differ from various other studies. HER2/neu overexpression of the tumor immunohistochemically was not further confirmed by FISH. Follow-up study was not done to correlate HER2/neu positivity with overall survival.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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M S Ganesh
Department of Surgical Oncology, Vydehi Institute of Oncology, 82, EPIP Area, Whitefield, Mallya Hospital, Vittal Mallya Road, Bengaluru - 560 066, Karnataka
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4]