|Year : 2010 | Volume
| Issue : 1 | Page : 1-6
|Immunohistochemical study of p16 INK4A and survivin expressions in cervical squamous neoplasm
Geok Chin Tan1, Sydee Norlatiffah1, N Akmal Sharifah1, Ghazali Razmin2, M Sidik Shiran3, A Zailani Hatta4, H Oon Paul-Ng4
1 Department of Pathology and Obstetrics, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
2 Department of Pathology, Hospital Kuala Lumpur, Malaysia
3 Department of Pathology, Universiti Putra Malaysia, Kuala Lumpur, Malaysia
4 Department of Gynaecology, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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|Date of Web Publication||19-Jan-2010|
| Abstract|| |
Introduction:Cervical cancer is the second most common cancer affecting Malaysian women. Despite the implementation of pap smear screening, many women are still diagnosed only in the advanced stage of cervical cancer. This could partly be due to failure of detection of its precursor lesions; hence the need to search for novel biomarkers to assist in the screening and diagnosis of cervical neoplasia. This study aims to determine the expression of p16INK4A and survivin as possible predictive biomarkers in cervical squamous neoplasm. Material and Methods: This is a retrospective study on 201 cases of cervical neoplasm comprising of 129 cervical intraepithelial neoplasia (CIN) and 72 squamous cell carcinoma (SCC). All samples were evaluated by two independent observers using p16INK4A and survivin monoclonal antibodies. The p16 INK4A expression was graded as negative, focal and diffuse positivity. The intensity for survivin expression was graded as weak, moderate and intense. Results: It is seen that p16 INK4A expression in CIN 1, CIN 2 and CIN 3 were 25.4%, 42.9% and 95.9% respectively. Majority of SCC (98.6%) showed p16 INK4A expression. Survivin expressions in CIN 1, CIN 2, CIN 3 and SCC were 56.7%, 33.4%, 87.5% and 98.6%. There was a linear relationship between increasing grade of CIN and p16 INK4A expressions. Conclusion: Our study showed that p16 INK4A expressions correlate well with the increasing grade of CIN. Although survivin does not correlate well to the increasing grade of CIN, it could be useful in differentiating CIN 3 from SCC.
Keywords: Cervix, cervical cancer, immunohistochemistry, p16, survivin
|How to cite this article:|
Tan GC, Norlatiffah S, Sharifah N A, Razmin G, Shiran M S, Hatta A Z, Paul-Ng H O. Immunohistochemical study of p16 INK4A and survivin expressions in cervical squamous neoplasm. Indian J Pathol Microbiol 2010;53:1-6
|How to cite this URL:|
Tan GC, Norlatiffah S, Sharifah N A, Razmin G, Shiran M S, Hatta A Z, Paul-Ng H O. Immunohistochemical study of p16 INK4A and survivin expressions in cervical squamous neoplasm. Indian J Pathol Microbiol [serial online] 2010 [cited 2020 Jan 24];53:1-6. Available from: http://www.ijpmonline.org/text.asp?2010/53/1/1/59173
| Introduction|| |
Cervical cancer is the second most frequent cancer among women in Malaysia with an incidence of 16.5 per 100 000 Malaysian population.  Prevention of cervical carcinoma requires early detection and eradication of it's precursor lesion, cervical intraepithelial neoplasia (CIN), which consists of low grade (CIN 1) and high grade (CIN 2 and CIN 3) lesions. The current method of using cytological smear in screening for precursor lesion of cervical carcinoma has significantly reduced the mortality and morbidity of cervical carcinoma.  However, cytological screening alone is insufficient to detect these precancerous states due to its high false-negative rate.  Hence, there is a need for more objective diagnostic parameters to accurately diagnose CIN.  Histological cervical assessment plays an important role in identification of CIN and squamous cell carcinoma (SCC).  but there could be intraobserver and interobserver diagnostic variability. To further improve early detection of high grade lesion of CIN, many immunohistochemical markers have been used to identify and distinguish the different grade of CIN. ,,,,,,
There are approximately 40 Human Papilloma Virus (HPV) types that can infect the genital tract through sexual contact.  The integration of HPV gene in the human genome results in transformed gene E6 and E7. , The E6 protein stimulates p53 protein degradation through a selective ubiquitin-dependent proteolytic pathway or inactivates it by forming a complex thus preventing cell cycle arrest or apoptosis. 
The HPV E7 protein inactivates retinoblastoma tumor suppressor protein (pRB) by hyperphosphorylation of pRB and subsequently results in the release of transcription factor E2F from pRB-E2F complex.  E2F transcriptor is able to induce cyclin E which results in overexpressed cyclin-dependent kinase 2 which in turn stimulates pRB phosphorylation creating a positive feedback loop and hyperproliferation of HPV affected cell. ,
Accumulation of E2F also leads to induction of p16 INK4A activity,  a CDK inhibitor. The p16 INK4A expression belongs to the family of cell cycle regulators called cyclin-dependent kinase inhibitors (CDKI), which bind to cyclin-CDK complexes and cause cell cycle arrest in the G1 phase. It exerts its anti-proliferative effects by binding to and inhibiting the actions of CDK 4 and 6. However, when pRB is inactivated at the nucleic acid or protein level, such cells are released from the growth-inhibitory stimuli of the CDK inhibitor of p16 INK4A and continue to proliferate even in the presence of high levels of p16 INK4A .  This concept leads to the development of biomarkers to identify the association of HPV infection and development of CIN, invasive cervical carcinoma. Studies have shown that there is an increased immunoexpression of p16 INK4A in neoplastic cervical epithelial cells and a positive correlation with HPV infection and degree of cervical neoplasia. , Studies have shown a linear relationship between p16 INK4A expression and the grade of dysplasia. ,,,
Apoptosis is important because it removes unwanted or potentially dangerous damage cells throughout life. Survivin is an inhibitor of apoptosis which exerts its effect by binding to the caspases (cystein-containing aspartate-specific protease) in particular, caspase 3 and caspase 7, resulting in their direct suppression.  As a result, cell death does not occur and the transformed cell continues to grow. Further, cells which lack apoptotic activity with subsequently increased survivin expression have a tendency to be resistant towards anticancer therapy. This study aimed to determine p16 INK4A and survivin as possible biomarkers in cervical squamous neoplasm.
| Methodology|| |
This is a retrospective study of p16 ink4a and survivin expressions on cases with CIN and SCC using immunohistochemical method. The paraffin embedded samples were obtained from the archives of the Department of Pathology in two tertiary hospitals for a period of four years from January 2003 to December 2007. This study was approved by the Ethics and Clinical Research Committee of the faculty of Medicine of our university. The total number of cases studied was 201, comprising of 60 CIN 1, 21 CIN 2, 48 CIN 3 and 72 SCC. Ten normal cervical tissue sections were included as control. Information on histological report, age and race of patients was retrieved from the intergrated laboratory management system (ILMS).
Types of Specimen
The types of specimen include tissue biopsy, cervical cone biopsy, large loop excision of the transformation zone (LLETZ) specimen and total abdominal hysterectomy and bilateral salphingo-oophorectomy (TAHBSO) specimen. One representative slide was selected from each case if more than one block was retrieved from the department archive.
Paraffin blocks were sectioned at four micrometer in thickness, mounted on sialinized slides and placed in the oven for 10 minutes. Sections were then deparaffinized by passage through xylene and subsequently rehydrated in graded alcohol of decreasing concentration i.e. 100, 80 and 70% at three minutes interval per change. They were then rinsed in running water. Antigen retrieval, in which the sections were placed in the target retrieval solution (0.01M citrate buffer, pH 7.6), was performed using a pressure cooker method followed by cooling at room temperature for 20 minutes. They were washed with running water and then rinsed with tris-buffer saline (TBS). Sections were incubated for 30 minutes at room temperature with mouse monoclonal anti- p16 INK4A antibody (1:100 dilution, from NeoMarkers, Fremont, CA) or rabbit polyclonal anti- survivin antibody (1:100 dilution, from NeoMarkers, Fremont, CA).
After washing thoroughly with TBS, the detection kit 'chemmate envision' was added on the slides and incubated for 30 minutes at room temperature, followed by rinsing with TBS. A drop of diamino benzidene (DAB) was then spread over the sections for seven minutesand then it was rinsed in water. The sections were counter-stained with haematoxylin for 30-45 seconds before rinsing with running water for three minutes and dehydrated in increasing alcohol concentration and mounted.
The positive control in the assay was as recommended by the manufacturer i.e. rectal carcinoma tissue for p16 INK4a and normal pancreatic tissue (alpha cell) for survivin. The negative control was processed similarly by omitting the primary antibody. The status of p16 INK4a and survivin expressions were evaluated by the two independent observers.
Interpretation of p16 ink4a Reactivity
The p16 ink4a reactivity was graded by determining the percentage of p16 ink4a mmunoreactive cells i.e. brown nuclear and cytoplasmic reactivity. 
The staining reactivity was graded as follows:
0: negative - 0% to 5% immunoreactive cells
Interpretation of Survivin Reactivity
- focal/ scattered positivity - greater than five per cent to less than 50% immunoreactive cells
- diffuse positivity - greater than 50% of immunoreactive reactive cells
The survivin expression was scored into four categories based on the staining intensity.
0: negative - no stained cells
1: weak - scattered or diffuse, weakly stained cells
2: moderate - scattered or diffuse, moderately stained cells
3: intense - all cells stained strongly and diffusely throughout the lesion
SPSS (statistical package for social science), Version 12 was used in statistical analysis. The percentage of cases with p16 INK4A and survivin expressions for CIN and SCC were evaluated using chi-square of Fisher exact test as appropriate. Any p value les than 0.05 was considered statistically significant.
| Result|| |
Range of Samples
There were a total of 201 cervical squamous neoplastic lesions, comprising of 129 cases of CIN (60 CIN 1 (29.8%), 21 CIN 2 (10.4%) and 48 CIN 3 (23.9%)) and 72 (39.8%) cases of SCC.
The ethnic distribution in this study consisted of 101 (47.9%) cases of Malays, 73 (34.6%) cases of Chinese, 34 (16.1%) cases of Indian and 3 (1.4%) cases of others. The average age of patients with cervical neoplasm was 47 years. The youngest patient was 21 and the oldest patient was 83. Patient with SCC (mean 52.5 years) was older compared to CIN 1 (mean 43.6), CIN 2 (mean 43.7) and CIN 3 (mean 47.6 years).The study included four patients with high grade CIN and three with SCC between 20-29 years old.
The p16 INK4A Expression
All normal cervical tissues showed negative staining for p16 INK4A . In addition, normal area adjacent to CIN lesion did not express p16 INK4A . The p16 INK4A expression increased with the increasing grade of CIN and also in SCC. Majority of the CIN 1 cases were p16 INK4A negative (74.6%). The p16 INK4A expression in CIN 2 was 42.9% and CIN 3 was 95.9%. Most of the SCC (98.6%) showed p16 INK4A expression except for one which was negative. We also noticed p16 INK4A staining confined to the lower 1/3 of epithelium in CIN 1. In CIN 2, p16 INK4A staining was confined to the lower 2/3 of the epithelium, and in CIN 3, the dysplastic epithelium showed full thickness p16 INK4A staining [Figure 1]. Diffuse and intense p16 INK4A staining was observed in SCC. The difference of p16 INK4A expression in CIN 3 and SCC was not statistically significant (p value is equal to 0.56)
All normal cervical tissue showed weak staining for survivin with mild nuclear staining confined to the lower half of the mucosa. The survivin expression in various grades of CIN was (CIN 1 (56.7%), CIN 2 (33.4%), CIN 3 (87.5%) and SCC (98.6%)). In CIN and SCC, survivin staining showed both nuclear as well as cytoplasmic positivity [Figure 2]. The difference of survivin expression in CIN 3 and SCC was statistically significant (p value is equal to 0.016).
Relationship of CIN grade and SCC in combined p16 INK4A and survivin expressions
The percentages of p16 INK4A and survivin expressions in combination, in increasing grade of CIN and SCC, were 0% in normal, 41.7% in CIN 1, 38.2% in CIN 2, 91.7% in CIN3 and 98.6 % in SCC [Table 1]. The difference in CIN 3 and SCC evaluated by combined p16 INK4A and survivin expression was not statistically significant (p value is equal to 0.0583) [Table 2].
| Discussion|| |
Increasing number of women are being diagnosed with equivocal cytological abnormalities in cervical smear samples, namely, atypical squamous cells. Follow-up of these cases could be positive for squamous intraepithelial lesion, reactive changes associated with inflammation or presence of squamous metaplastic cells. It reflects the possibility of failure to identify some of the cancer precursor lesions.
The youngest patient in this study was 21 and the oldest was 83 years old. The age of patients may reflect the selection of cases for cervical screening in Malaysia where all women who are, or have been sexually active, between the ages of 20 and 65 years, are recommended to undergo Pap smear More Details test. There were four patients with high grade CIN and three with SCC in the age group between 20-29 years. A national study in 2004, involving 18,805 people, found that the median age they had sex for the first time was 23 years old; 38.2% had sex before the age of 20  . This finding suggests that younger women should have cervical screening to obtain maximum benefit from the cervical screening program.
In this study, most of the CIN 1 cases were p16 INK4a negative (73.3%). The high percentage of negativity of p16 INK4a in CIN 1 may be due to latent or subclinical HPV infection with low viral load that may be insufficient for p16 INK4A expression. Ishikawa et al.  found that overexpression of p16 INK4A in CIN 1 was more common in cases with HPV 16 and HPV 52 infection. The other possible reason for lower expression of p16 INK4a in low grade lesions may be because a certain percentage is thought to be caused by low risk HPV types. Previous studies indicated that viral oncoprotein of low-risk HPV such as HPV-6 have no effect on p16 INK4A because the affinity of HPV-6 E7 protein for cellular pRb is ten-fold lower than that of HPV-16 E7 for pRb. 
Studies show that the rate of regression, persistent and progression to CIN 3 and SCC are CIN 1 (60%, 30%, 10%, 1%), CIN 2 (40%, 40%, 20%, 5%) and CIN 3 (33% regressed, greater than 12% progressed to SCC), respectively.  To predict the outcome of CIN lesion, p16 INK4A could be the suitable marker because it reflects the types of HPV infection. A population based five-year follow-up study of HPV infection in Sweden found that 92% of HPV infection disappeared spontaneously without treatment. However, when the HPV type 16 persisted, the possibility of inducing cancer markedly increased.  Other studies also suggested that persistent infection by specific viral type, especially HPV 16 and 18 has the greatest tendency to result in CIN 2 or 3. ,
Our study shows that nearly all (98.6%) SCC lesion show p16 INK4A over-expression, this further emphasizes the important causal relationship between HPV and cervical cancer. However, a few patients with cervical cancer had p16 INK4A negativity. Nieh et al. showed that a proportion of their cervical cancer cases had neither HPV infection nor p16 INK4A expression. The possible explanation for the absence of p16 INK4A expression in these high grade lesions could be methylation of the p16 INK4A promoter resulting in silencing of the p16 INK4A gene.  Our findings were similar to those of of Branca et al.  and Ozgul et al.  which also found that p16 INK4A expression was directly related to the increasing grade of CIN.
Our study showed that all normal cervical squamous epithelial cells expressed weak survivin staining, however, the intensity increased with increasing grade of the CIN. The presence of survivin staining in normal epithelium was also seen in studies of other human malignant neoplasm and normal tissue. ,,, Branca et al.  study result was similar to our study; normal squamous epithelium was in the negative-weak category. The authors also described that survivin staining of normal squamous epithelium was only demonstrated in the cells of parabasal layer. In contrast, CIN and SCC showed both nuclear as well as cytoplasmic survivin staining. Frost et al. suggest that the shift in intracellular distribution of survivin could be due to nuclear translocation mechanism or a result of artifactual disruption caused by HPV infection which leads to survivin expression in the nucleus and cytoplasm.
Branca et al.  discuss the value of survivin as independent predictor of high-risk HPV where 84.6% of high risk HPV type shows moderate and intense survivin expression. They found that survivin overexpression was a specific marker of CIN as it was consistently negative in biopsy without CIN. This is in accordance to our study where survivin expression was either absent or weakly expressed in normal cervical tissue and consistently moderately to intensely express in CIN. However, in contrast to their study where survivin expression was directly related to the grade of CIN, our study shows no such correlation. The expression was found to be even higher in CIN 1 compared to CIN 2.
| Conclusion|| |
We suggest the use of p16 INK4A as an adjunct in differentiating the various grade of CIN as our study shows that p16 INK4A expressions correlate well with the increasing grade of CIN. Although survivin does not correlate well to the increasing grade of CIN, it could be useful in differentiating CIN 3 from SCC. Hence, these data support the use of p16 INK4A and survivin immunohistochemistry in determining the various grades in CIN as well as between CIN 3 and SCC, especially in diagnostically difficult situations.
| Acknowledgment|| |
This study was funded by the Faculty of Medicine, Universiti Kebangsaan Malaysia. We would like to thank Mohd. Harisfazal, B. Mohamed Basri for expert help in immunohistochemical staining.
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Geok Chin Tan
Department of Pathology, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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