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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 4  |  Page : 661-665
Expression of Ki67 and P53 in primary squamous cell carcinoma of the larynx


1 Department of Pathology, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Otolaryngology, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

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Date of Web Publication27-Oct-2010
 

   Abstract 

We studied a series of untreated laryngeal carcinomas in an attempt to determine the relationship between Ki67 and p53 expression and clinicopathological findings. The relationship between expression of these markers in non-tumoral tissue was also evaluated in order to investigate the possible role of immunohistochemistry as a diagnostic aid in evaluating laryngeal biopsies. Materials and Methods: Samples from 54 patients with laryngeal squamous cell carcinoma (SCC) were analyzed retrospectively. The uninvolved vocal cord was evaluated as a non-tumoral sample. Paraffin sections of tumors were immunohistochemically stained for p53 and Ki67 expression. Results: Overall, p53 expression was found in 35 (64.8%) of the patients. There was a significant correlation among tumoral p53 expression and tumor location, tumor stage and lymph node involvement. Most grade I tumors had a Ki67 labeling index <50% and a labeling index ≥50 was found mainly in high-grade tumors. Tumoral Ki67 expression correlated significantly with tumor grade and mitotic count. There was no correlation between Ki67 labeling index and tumor region. In non-tumoral tissue, 95% of high-grade pre-neoplastic lesions revealed a high expression of Ki67. Non-tumoral p53 expression did not correlate with histological findings. Conclusion: p53 and Ki67 expression in tumoral tissue may be a prognostic marker in patients with laryngeal SCC. Evaluation of the proliferative index in biopsy samples of dysplastic laryngeal mucosa is potentially useful for predicting the progression toward carcinoma.

Keywords: Ki-67, larynx, p53, squamous cell carcinoma

How to cite this article:
Ashraf MJ, Maghbul M, Azarpira N, Khademi B. Expression of Ki67 and P53 in primary squamous cell carcinoma of the larynx. Indian J Pathol Microbiol 2010;53:661-5

How to cite this URL:
Ashraf MJ, Maghbul M, Azarpira N, Khademi B. Expression of Ki67 and P53 in primary squamous cell carcinoma of the larynx. Indian J Pathol Microbiol [serial online] 2010 [cited 2019 Dec 7];53:661-5. Available from: http://www.ijpmonline.org/text.asp?2010/53/4/661/72019



   Introduction Top


Laryngeal squamous cell carcinoma (SCC), the most common malignant neoplasm of the upper airway in adults, accounts for about 1.5% of all cancers. [1] Although many factors have been evaluated as potential prognostic indicators, including clinical stage, site and size of the tumor, histologic grade, depth of invasion and host reaction, none have proven to be reliable or to have any real clinical value. [2],[3],[4] The exact molecular mechanisms of malignant transformation of the laryngeal mucosa are not clear. It has been suggested that the process of tumorigenesis is based on the accumulation of various stages of genetic damage, which impairs the mechanisms of cell cycle regulation. [5] Disruption of two major pathways controlling the cell cycle, tumor-suppressor gene p53 and pRb pathway are important. [6] The p53 gene product, which is able to block the cell cycle in G1 after encountering genotoxic stress, plays a central role in the G1 phase of the cell cycle. [5] Disruption of the pathways regulated by p53 leads to increased cell proliferation and additional genetic damage. Mutations in p53, resulting in expression of a non-functional protein, appear to be the most common abnormality in human neoplasms and are present as an early event in laryngeal carcinoma. [6] pRb regulates the passage of cells from G1 to S phase and is itself regulated by feedback loops involving p16 and cyclin D1 proteins. [6] Although a relation was shown between p53 expression and shorter survival of the patients, conflicting results have been reported regarding its clinicopathological implications in laryngeal cancers. [7],[8],[9] On the other hand, expression of p53 has been associated with progression from dysplastic lesions to invasive carcinoma. [10]

Proliferating cells express the non-histone nuclear Ki67 proteins of 345 and 395 kDa. [11] Ki67 is not detected during the G0 phase of the cell cycle; its expression being restricted to the G1 through M phases, but its function remains unknown. [12] It is a potential prognostic biomarker in a variety of tumors, including laryngeal neoplasms. [8] Expression of this proliferation marker was found to be increased in poorly differentiated laryngeal carcinomas and in those carcinomas associated with lymph node metastases, [13],[14] but these correlations were not confirmed by other studies. [15],[16],[17] It has been suggested that Ki67 expression increases with the severity of dysplastic changes in pre-neoplastic lesions. [18]

In this retrospective study, we investigated the relation of p53 and Ki67 expression with demographic and pathological findings in patients with laryngeal SCC. The relationship between the Ki67 index and p53 expression in non-tumoral tissue was also evaluated.


   Materials and Methods Top


We analyzed tissue samples from 54 men and one woman with laryngeal SCC (mean age 60 years, age range 40-80 years) between 2005 and 2008 at the Oncology Department in Khalili Hospital, affiliated to Shiraz University of Medical Sciences. Cervical lymph node samples were available for 24 patients and the uninvolved vocal cord was evaluated as a non-tumoral sample in 49 cases. The ethics committee of Shiraz University of Medical Sciences approved the study. All patients were from the same geographic region (southern Iran). We selected cases for inclusion among patients whose disease had been diagnosed at our department and for whom complete medical records were available. None of them had been treated previously. The TNM classifications were based on the 1992 recommendations of the American Joint Committee on Cancer.

Immunohistochemical Analysis


All specimens were fixed in 10% formalin and routine histologic paraffin sections were made and stained with hematoxylin and eosin. Sections were cut to 3-4-μm thickness and mounted on poly-L-lysine-coated slides. The sections were deparaffinized in xylene and rehydrated in alcohol. Then, the sections were heated in a microwave oven for 10 min in 0.01 M sodium citrate buffer (pH 6.0). Endogenous peroxidase was blocked with 3% hydrogen peroxide/methanol. The sections were incubated overnight with a mouse monoclonal antibody against Ki67 antigen (MIB-1, 1:100; Dako, Glostrup, Denmark) and a mouse monoclonal antibody against the p53 antigen clone JC70A (pre-diluted, Dako) as primary antibodies. After that, the slides were rinsed gently with phosphate-buffered saline and an Envision Dual link system-HRP (ready to use, Dako) was used as the secondary antibody. Incubation with 3,3-diaminobenzidine tetrahydrochloride was performed for 10 min as a substrate chromogen solution to produce a brown color. Finally, the sections were counterstained with Mayer's hematoxylin. Appropriate positive and negative control sections were processed in parallel.

Immunohistochemical Evaluation


Sections were evaluated under a light microscope and staining intensity of the tumor cells was classified semiquantitatively. P53 staining was considered negative if the staining was below 10% and positive if it was above 10% [8] . P53 staining reactions were analyzed by counting 1,000 cancer cells in each sample (original magnification, x 400) and assessing the percentage of labeled cells. The Ki67 labeling index was determined by counting at least 1,000 tumor cells and the index was calculated as a percentage. In non-tumoral tissues, the Ki67 labeling was weak when it was limited to the basal layer, but expression was higher in the upper layers.

Statistical Analyses

The chi-squared and Mann-Whitney tests were used to compare categorical variables. Analyses were performed with SPSS software (Statistical Package for the Social Sciences, version 15; SSPS Inc., Chicago, IL, USA), with P <0.05 as the cut-off value for significance.


   Results Top


The clinicopathological features of the patients are listed in [Table 1]. Tumor location was glottic in 49 (90%), supraglottic in two (4%) and epiglottic in three (6%) patients. Tumors were graded as grade I (well-differentiated) in 27 patients, grade II (moderately differentiated) in 19 patients [Figure 1] and [Figure 2] and grade III (poorly or undifferentiated based on degree of keratinization, nuclear pleomorphism and presence or absence of intercellular bridges) in eight patients. There was a significant correlation between tumor differentiation (grade) and mitosis (P < 0.001). Cervical lymph node metastases were present in 14 patients (one supraglottic and 13 glottic). There was a significant correlation between tumor size and lymph node involvement (P = 0.015) and between stage with lymph node involvement (P = 0.028).
Table 1 :Demographic, clinical and pathological characteristics in 54 Iranian patients with laryngeal squamous cell carcinoma


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Figure 1 :Moderately differentiated squamous cell carcinoma (grade II). (Hematoxylin and esoin, ×400)

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Figure 2 :p53 expression in squamous cell carcinoma tumoral cells. (Immunohistochemical staining, ×400)

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Overall, p53 expression was found in 35 (64.81%) of the 54 patients [Figure 2]. This marker was observed in three supraglottic (5.5%), three epiglottic (5.5%) and 29 glottic tumors (53.7%). In cases with lymph node involvement, p53 expression was seen in nine patients and no expression in the remaining five patients. There was a significant correlation between tumoral p53 expression and tumor location (P = 0.004), tumor stage (P = 0.02) and lymph node involvement (P = 0.008). There was no correlation between p53 immunohistochemical staining and age (P = 0.72), sex (P = 1.0), tumor size (P = 0.39), grade (P = 0.7) or mitosis (P = 0.45).

The Ki67 labeling index was <50% in 42 (78%) cases [Figure 3] and ≥50% in the remaining 12 (22%) cases [Figure 4]. Most grade I tumors had a labeling index <50%, and a labeling index ≥50 was found mainly in high-grade tumors. There were significant correlations between tumoral Ki67 expression and tumor grade (P = 0.017) and tumor mitotic count (P = 0.001). There was no correlation between Ki67 labeling index and tumor region (supraglottic or glottic) (P = 0.4), age (P = 0.1), tumor size (P = 0.1), stage (P = 0.2) or lymph node involvement (P = 0.247). The patterns of Ki67 and p53 immunostaining according to histological findings are summarized in [Table 2].
Table 2 :Correlation of tumoral expression of p53 and Ki67 with tumoral size, grade and stage in Iranian patients with laryngeal squamous cell carcinoma


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Figure 3 :Ki67 labeling index <50% in squamous cell carcinoma. (Immunohistochemical staining, ×400)

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Figure 4 :Ki67 labeling index ≥50% in squamous cell carcinoma. (Immunohistochemical staining, ×400)

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Non-tumoral tissue was available from 49 patients: two (4%) cases with severe, seven (14%) with moderate, 16 (31%) with mild dysplasia and 24 others (51%) with normal findings. For the statistical analysis, the first two groups were combined for comparison with the other two groups. The patterns of Ki67 and p53 immunostaining according to histological findings in non-tumoral tissue are summarized in [Table 3]. There was no significant correlation between non-tumoral p53 expression and histological findings. Low Ki67 expression was detected in 94% of normal to low-grade lesions. On the other hand, 95% of the high-grade lesions revealed high Ki67 expression (P < 0.001). This parameter also correlated significantly with tumor size (P = 0.008).
Table 3 :Pattern of p53 and Ki 67 expression in nontumoral tissues from Iranian patients with laryngeal squamous cell carcinoma


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   Discussion Top


It has been suggested that laryngeal tumorigenesis is based on the accumulation of multiple genetic lesions in the sequence of dysplasia-carcinoma. The p53 protein plays an important role in apoptosis and cell growth regulation. This pathway is frequently inactivated by gene mutations that account for increased cell proliferation and makes cells susceptible to additional genetic damage. [3],[8],[9] Disruption of the pRb pathway is another important event in carcinogenesis. [6]

In this study, we found a statistically significant correlation between p53 expression and tumor location, stage and lymph node status in patients with laryngeal SCC. Ki67 expression also correlated with tumor grade.

In previous studies, p53 expression has been found in laryngeal SCC at frequencies ranging from 40% to 90%. [8],[10],[11],[12],[13],[14] The rate of p53 expression in the series of patients studied in the present study (64.8%) was within the range of values reported in the literature.

In the literature, data on the relationship between p53 and Ki67 expression, obtained in different tumor types and from different series, are somehow controversial. In a study of 27 patients by Kazkayasi and colleagues, expression of p53 was significantly associated with the presence of lymph node metastases. These authors found no statistically significant correlation between expression of the p53 protein and age of patients, tumor site, clinical stage or histopathological grade of the tumor. [19] Klatka et al.[20] and Rodrigues et al.[21] found no significant correlation between p53 expression and patients' T or N stage or histological grade. According to previous research, p53 expression was not a significant prognostic predictor in laryngeal SCC. [22],[23],[24],[25]

Zidar et al.[26] found a statistically significant correlation between the grade of carcinoma and the MIB-1 labeling index. Acikalin et al.[27] studied 63 patients with laryngeal SCC and reported a significant correlation between Ki67 index and patient age, tumor stage and lymph node metastases. Ki67/MIB-1 immunostaining, DNA S-phase fraction, proliferating cell nuclear antigen expression and analysis of nucleolar organizer region-associated proteins detected significant correlations with prognosis in 4,806 cases of tumors of the oral cavity, salivary glands, pharynx and larynx. [28] Golusiρski et al.[29] evaluated 120 specimens from previously untreated laryngeal carcinomas and found that p53 and Ki67 scoring correlated with T and N stage.

Liu et al.[17] suggested that Ki67 expression was significantly higher in tumors with lymph node metastases and correlated with pathological stage. In contrast, Mielcarek-Kuchta et al. found no statistically significant correlation between level of p53 expression and regional lymph node metastases. [13] Nevertheless, the correlation between stage and Ki67 staining was significant. [13] Calgaro et al.[30] compared MIB-1 and p27 expression in laryngeal tumors and found the former to be a better predictor of disease recurrence in patients treated for partial laryngectomies.Liu et al.[31] found that the fraction of cancer cells immunolabeled for PCNA or Ki67 in pre-operative biopsy could predict neck metastasis.

In the non-tumoral tissue samples analyzed, there was no correlation between p53 expression and histological findings. However, 77% of high-grade lesions showed a high Ki67 labeling index. Our results indicate that Ki67 expression increased with the severity of dysplastic changes in the laryngeal epithelium. Dolcetti et al.[32] suggested that the detection of p53 immunostaining in pre-invasive areas as well as in pre-neoplastic lesions was a very early event in laryngeal SCC. Maestro et al.suggested a possible pathologic relationship between smoke carcinogen exposure and p53 inactivation in the development of SCC. Pignataro et al.[9] found no significant association between p53 immunoreactivity and evolution toward laryngeal carcinoma, but Ki67 expression was significantly associated with neoplastic progression. There are also several reports of evidence that Ki67 expression increases with the severity of dysplastic changes in the laryngeal and oral epithelium. [10],[18],[26] Ki-67, expressed at all stages of the cell cycle except G0, is a widely used marker of cell proliferation. [6] Our results support the model of carcinogenesis, with increased loss of control of cellular proliferation with the accumulation of genetic alterations in dysplastic lesions.

In conclusion, we suggest that analysis of p53 and Ki67 expression in tumoral tissues may help predict the clinical course in patients with laryngeal SCC and may, therefore, aid in the selection of patients who should be treated more aggressively. In addition, immunohistochemical evaluation of the proliferative index in biopsy samples from dysplastic laryngeal mucosa is potentially useful for predicting the progression of these pre-neoplastic lesions toward carcinoma.



 
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Correspondence Address:
Negar Azarpira
Organ Transplant Research Center, Department of Pathology, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.72019

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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