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Year : 2016  |  Volume : 59  |  Issue : 2  |  Page : 153-158
p53 and p16 in oral epithelial dysplasia and oral squamous cell carcinoma: A study of 208 cases

1 Graduate and Research Division, Laboratory of Oral Pathology, Dental School, National Autonomous University of, Mexico
2 Department of Oral Public Health, Graduate and Research Division, Dental School, National Autonomous University of , City, Mexico
3 Department of Stomatology, Laboratory of Oral Pathology, Biomedical Sciences Institute, University of Ciudad Juárez, Ciudad Juárez, Mexico
4 Department of Head and Neck Pathology, Hospital Calixto García, Habana, Cuba

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Date of Web Publication9-May-2016


Background: The use of p16 and p53 as biomarkers of malignant transformation of oral epithelial dysplasia (OED) and biological behavior of oral squamous cell carcinoma (OSCC) is controversial. Aim: To determine the immunoexpression of p16 and p53 in OED and OSCC and to establish their possible relation to histopathological grading of OED/OSCC. Materials and Methods: Ninety-six OEDs (40 mild, 36 moderate, and 20 severe dysplasia); and 112 OSCCs (64 well-differentiated, 38 moderately differentiated, and 10 poorly differentiated) coming from archives of four centers of oral pathology were included. Histological slides from all cases were processed with immunohistochemical technique using anti-p53 and anti-p16 antibodies. The intensity of the immunoreactivity were classified using the ImageLab®MCM systemas follows: <60 mild, >60–<90 moderate, and >90 strong. Forstatistical purposesa χ2 test (P < 0.05) was performed. Results: Severe dysplasia show highest relative frequency of p16-positive (35.5%), whereas p53 is associated with mild dysplasia (P = 0.04). Moderately differentiated OSCC had larger relative frequency of p16-positive and p53-positive cases (47.3% both circumstances) (P > 0.05). Statistical association of p16-positive and p53-positive cells to basal stratum of OED (P = 0.0008; P = 0.0000, respectively) and p16-positive cells and p53-positive cells to perivascular zone of OSCC (P = 0.001; P = 0.0000, respectively) was found. Conclusions: p16 and p53 could be not specific enough to identify patients suffering OED with high risk to malignancy; however, the evaluation of the presence of p16 and p53 in the tumoral invasive front of OSCC could contribute to establish the tumor progression.

Keywords: Oral cancer, oral epithelial dysplasia, oral squamous cell carcinoma, p16, p53

How to cite this article:
Cuevas Gonzalez JC, Gaitan Cepeda LA, Borges Yanez SA, Cornejo AD, Mori Estevez AD, Huerta ER. p53 and p16 in oral epithelial dysplasia and oral squamous cell carcinoma: A study of 208 cases. Indian J Pathol Microbiol 2016;59:153-8

How to cite this URL:
Cuevas Gonzalez JC, Gaitan Cepeda LA, Borges Yanez SA, Cornejo AD, Mori Estevez AD, Huerta ER. p53 and p16 in oral epithelial dysplasia and oral squamous cell carcinoma: A study of 208 cases. Indian J Pathol Microbiol [serial online] 2016 [cited 2022 Dec 9];59:153-8. Available from:

   Introduction Top

Oral squamous cell carcinoma (OSCC) ranks eighth in frequency of cancers of whole body and an increase in the irate of mortality has been reported in developing countries.[1],[2],[3] On the other hand, oral epithelial dysplasia (OED) is a modified epithelial tissue that shows cytological changes, specifically severe dysplasia, related to an increased risk in developing OSCC. In spite of important technological advances in cancer research, the risk of malignant transformation of OED and the biological behavior of the OSCCs are still established by morphological parameters. However, it has been suggested that histopathological grading is not accurate due to its subjectivity,[4] and that severe dysplasia is not necessarily related to malignant transformation.[3] Therefore, it is necessary to establish biological markers both, malignant transformation of OED and biological behavior of OSCC. Specific regulator proteins of cellular cycle have been proposed to be useful as biomarkers.[5]

p53 is a phosphoprotein that promotes cellular arrest and apoptosis,[6] and in response to cellular stress helps avoid mitosis of cells with damaged DNA.[7] The alteration of its expression in early stages of OSCC, event that precedes the continuous tumoral growth, has been related to loss of proapoptotic function.[7] p16 is an inhibitor of cellular division, product of CDKN2 gene, located on the 9p21 chromosome. The inactivation of the locus is an early event in oral carcinogenesis [8] related to loss of senescence and to cell immortalization. In spite of the intense study of the role played by p16 and p53 on oral carcinogenesis [5] their use as biomarkers of malignant transformation of OED and as a predictor of biological behavior of OSCC is still controversial. In order to contribute to better understanding of this issue the main objective of this study was to determine the immunoexpression of p16 and p53 in areas of cell proliferation of OED (basal and parabasal epithelial stratum) and OSCC (tumoral invasive front). In addition, the immunoexpression of p16 and p53 were correlated to histopathologic degrees of OED and OSCC. The assessment about the use of p16 and p53 as biomarkers will help the early identification of patients at high risk of malignancy or patients suffering high-grade malignancy which undoubtedly will contribute to establishing a better and earlier therapy.

   Materials and Methods Top

Archives of four centers of oral pathology (Laboratory of Clinical and Experimental Pathology, Research and Graduate Department, Dental School, National Autonomous University of México; Stomatology Department of the Institute of Biomedical Sciences, Autonomous University of Ciudad Juarez; General Hospital “Calixto García, Havana, Cuba and Madero's Clinicopathological Unit, Durango, Mexico) were reviewed from January 1989 to December 2010 to identify and select all records with diagnosis of OED or OSCC. To be included in the present study, the cases should have histological slides stained with hematoxylin and eosin technique and also sufficient biological material embedded in paraffin. Two hundred and thirty-two cases were identified and selected. All cases were reviewed independently by two experts in oral pathology (JCCG/ERLH) to confirm the diagnosis. Of the total cases (n = 232) 24 were excluded due to insufficient biological material or inconsistence in the diagnoses. Therefore, the total sample was 208 cases; 96 OED and 112 OSCC. Gender, age at the time of diagnosis and topography of the lesion were obtained from the medical record.

The principal observers (JCCG/ERLH) were under calibration (interobservator kappa value = 0.91 and intraobservator kappa value = 0.92 and 0.93, respectively) in regard to histopathological parameters to grading OED and OSCC. OEDs were classified into mild, moderate, and severe according to the criteria proposed by the workshop on precancer and oral cancer by the World Health Organization.[9] OSCCs were classified as Grade I (well-differentiated), Grade II (moderately differentiated), and Grade III (poorly-differentiated) according to the classification of Broders.[10]

Additional histologic slides cuts at 3 µ were obtained and processed with immunohistochemical technique. Briefly, after primary antibody incubation, samples were rinsed and incubated in the following secondary antibodies anti-p53 (BIOCARE ®; 1:100 dilution) and anti-p16 prediluted (blasticidin S deaminase). Anti-p16 and anti-p53 antibodies were chosen to identify the immunoexpression of p16 and p53, respectively. The immunoexpression of these antibodies was assessed in the basal and parabasal epithelial stratum of OEDs, as well as in different histological parameters of tumor invasion front (TIF) of OSCCs. In order to achieve objective evaluation of the immune reactivity the digital index of immunoreactivity expression (DIIE) was establishedas follows: Three random optical fields of ×40 of each histological slide were analyzed using the ImageLab ® MCM version 2.2.4 system analysis of imaging, and adjusted to micrometric scale (µm) in an optical microscope Olympus digital ×b40. The DIIE was considered mild if the value was <60, moderate when the value was >60–<90; and strong when the value was >90. The percentage of positive cells in relation to DIIE was obtained.

A data base was build exprofesso using the software program SPSS ® version 20 (IBM ®, North Castle, New York, USA). The possible association between immunoexpression of p16 and p53, and histopathological features of OED or OSCC was established using the statistical test of χ2 with as significance level of 95% (P < 0.05).

   Results Top

Two hundred and eight cases (110 women; 98 male; meanage 56.5 years; standard deviation ±17); 96 OEDs and 112 OSCCs, were included. The distribution with respect to anatomical regions was: 57 (27.4%) in the tongue, 46 (22.1%) in the gingiva, 42 (20.1%) in buccal mucosa, 22 (10.5%) in lip, 16 (7.6%) in palate, 13 (6.2%) in retromolar area, and 12 (5.7%) in floor of mouth. In accordance to their histopathological characteristics OEDs were classified as follows: 40 (41.6%) were mild dysplasias, 36 (37.5%) moderate, and 20 (20.8%) as severe. In the case of the OSCCs 64 (57.1%) were classified as well-differentiated, 38 (33.9%) as moderately differentiated, and 10 (8.9%) were classified as poorly differentiated.

Oral epithelial dysplasia

From 96 OED, 28 (29.1%) of them were positive to p16. In respect to histological grading 32.5% of mild dysplasias; 22.2% of moderate dysplasias; and 35.5% of severe dysplasias were p16-positive [Table 1]. p16-positive Neoplasic cells were observed principally in the stratum basal of OED [Figure 1]a and [Figure 1]b, this association was statistically significant (P = 0.0001) [Table 2]. On the other hand, 32 (33.3%) of OEDs were p53 immunepositive. Forty-five percentage of mild dysplasias; 27.7% of moderate dysplasias; and 75% of severe dysplasias showed immunereactivity to p53. The association of mild dysplasia and p53 was statistically significant (P = 0.04) [Table 2]. The highest amount of p53-positive cells was found in the stratum basal and parabasal (93.7% and 46.8%, respectively) [Figure 2]a,[Figure 2]b,[Figure 2]c. This association also was statistically significant (P = 0.0001). In regard to intensity of immunereaction severe dysplasia showed the greatest amount of cases with strong expression (20%) top 16, while mild dysplasia showed most cases with strong expression to p53. However, in both circumstances these were not statistically significant. The frequency of distribution of OEDs in relation to DIIE in both antibodies is shown in [Table 2].
Table 1: Distribution and relative frequency of oral epithelial dysplasia and oral squamous cell carcinoma with p16 and p53 positive immunoreactions in relation to histological grading

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Figure 1: p16 and oral epithelial dysplasia. (a) Mild dysplasia shows p16-positives cells in their stratum basal, ×400. (b) Mild dysplasia with p16-positive cells in their strata basal and suprabasal, ×400. (c) Moderate dysplasia shows p16-positive cells located in the stratum spinosum, ×400. (d) Severe dysplasia with p16-positive cells in all epithelia strata, ×400

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Table 2: Frequency and intensity of immunereaction to anti-p16 and anti-p53 antibodies in oral epithelial dysplasia in relation to histological grading

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Figure 2: p53 and oral epithelial dysplasia. (a) Mild dysplasia with p53-positive cells in the stratum basal, ×400. (b) Moderate dysplasia with p53-positive cells in strata basal and suprabasal, ×200. (c) Notice that this severe dysplasia had p53-positive cells in the strata basal and suprabasal, ×400

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Oral squamous carcinoma cell

From total OSCCs (n = 112), 50 cases (44.6%) showed positive immunoreactivity to p16. Out of OSCC p16-positive, 29 (45.3%) were well-differentiated; 18 (47.3%) moderately differentiated [Figure 3]a and [Figure 3]b, and 3 (30%) were poorly differentiated. In relation to p53, 45 (40.1%) of all OSCCs were positive. From OSCC p53-positive, 24 (37.5%) were well differentiated; 18 (47.3%) moderately differentiated [Figure 3]c and [Figure 3]d, and 3 (30%) were poorly differentiated. We cannot establish statistical association of any histological grading with any biological marker [Table 1]. The highest relative frequency of OSCC with strong expression to p16 was observed in moderately differentiated cases whereas strong expression to p53 was observed in poorly differentiated cases [Table 3]. However, the association between both variables was not statistically significant in both circumstances.
Figure 3: p16 and p53 in oral squamous cell carcinoma. (a) Malignant epithelial nests show p16-positive. Moderately differentiated oral squamous cell carcinoma, ×400. (b) p16-positive neoplastic cells in the tumor invasion front in close association to inflammatory cells. Well-differentiated oral squamous cell carcinoma, ×400. (c) p53-positive malignant epithelial nests moderately differentiated oral squamous cell carcinoma, ×400. (d) p53-positive malignant epithelial nests in the tumor invasion front in perivascular location. Well-differentiated oral squamous cell carcinoma, ×400

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Table 3: Frequency and intensity of immunereaction to anti-p16 and anti-p53 antibodies in oral squamous cellcarcinoma in relation to histological grading

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The immunexpression of biological markers was found in invasiv enests, islands, and cords of proliferative neoplastice pithelium cells, inclose relation to inflammatory cells [Figure 3]b. The frequency of distribution of immunexpression in different histological zones of OSCCs is shown in [Table 4]. The association of p16-positive neoplastic cells with inflammatory infiltrate and of p53-positive neoplastic cells with lamina propia and perivascular zone was statistically significant (P = 0.001;P = 0.0001, respectively). With respect to TIF, 40 (80%) OSCCs showed perivascular p16-positive neoplastic cells and in 10 cases (20%) p16-positive malignant cells infiltrated blood vessels. For p53,36 (80%) OSCC cases showed p53-positive neoplastic cells near by to blood vessels and 9 cases (20%) showed vascular infiltration [Figure 3]d.{Figure 3}
Table 4: Relative frequency of p16-positive and p53-positive neoplastic cells in different histological areas of oral epithelial dysplasia and oral squamous cell carcinoma

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   Discussion Top

The present report shows the immunoreactivity to antibodies anti-p16 and anti-p53 in different areas of OED and OSCC. The usefulness of p16 and p53 as biomarkers of behavior for malignant neoplasms and potentially malignant oral lesions remains controversial.[11] The inactivation of p16INK4a is an early event in oral carcinogenesis preceding the progression from premalignant to malignant oral lesions.[12] The results obtained donot support this suggestion since we find the highest p16-positivity in severe dysplasia (35%) suggesting that p16 may be associated with increasing risk of malignancy. However, this association is not statistically significant. Information about the role played by p53 in epithelial precancerous oral lesions is controversial. We observe positivity to p53 in basal and suprabasal strata of 33.3% of OED. p53 is circumscribed to basal stratum in normal epithelium and therefore over expression of p53 in suprabasal cells is considered predictive of malignant transformation [13] of severe dysplasia.[14] However, malignant transformation also occurs in absence of p53-expression in suprabasal cells. In consequence p53 could be not sensitive enoughto predict which precancerous lesions will progress to cancer.[15] Our results agree with this assessment, because p53 was associated to mild dysplasia (P = 0.04), and therefore, it could be related to low risk to malignancy.

The interpretation of the presence or absence of p16 and p53 in OSCCs is controversial. On the one hand it has been suggested the presence of p16 with well-differentiated tumors,[16] on the other hand no relationship has been found with the survival time.[2] We find positive identification to p16 in the 44.6% of OSCC's cases, very similar data (44%) to reported in squamous cell carcinoma of the tongue,[17] but less than 64.7% reported by Dragomir et al.[11] In the present paper 40.1% of OSCC were p53-positive, less than reported by Dragomir et al. (82.5%).[11] The presence of p53 in OSCC cases has been associated with the time of survival,[8] even though their relation with the degree of differentiation has not been established.[11],[18] It has been reported that neoplasms without expression of p16 and with expression of p53 have unfavorable diagnosis.[19] Patients with OSCC, where it was not possible to identify p16, presented 2.08 more risk of recurrence than those where the protein was detectable.[8] In a general view, our results agree with this suggestion since poorly differentiated OSCC showed lower frequency of p16 immunepositivity. This could be related to the fact that p16-positive neoplastic cells were located near or even in contact with inflammatory cells including eosinophils. Presence of inflammatory cells, including eosinophils, in malignant neoplasms is a defense mechanism and therefore considered as a factor for favorable prognosis.[20],[21] On the other hand, our results of p53 were very similar to p16 ones, poorly differentiated OSCC showed lower frequency of p53-positivity. However, p53-positive neoplastic cells were observed in perivascular or intravascular location of the TIF. The microvascular invasion at TIF can negatively impact survival.

TIF should be considered the most representative region for the histopathological diagnosis of OSCC and this histological field is predictive of biological behavior.[11],[22] Mean while the microvascular invasion is the parameter with greater impact on survival.[13] An association between angiogenesis and neoplastic proliferative activity has been well established in premalignant and malignant lesions of the oral mucosa.[23],[24] We found statistically significant association of perivascular and intravascular p16-positive and p53-positive neoplastic cells in TIF.

A probable cause to justify the contradictory reported results could be due to different experimental designs. Because there is no homogeneity in research protocols, to compare results and draw conclusions will be difficult. There should be a consensus among the different research groups to determine the parameters analyzed. Only in this way a rapid translation of basic research results to the clinical field could be attained. The knowledge of defects in cellular cycle involved in oral carcinogenesis should not be limited only to its biological or academic value but they should contribute to the early diagnosis of subjects at high risk of malignancy or suffering with high-grade malignancy. Early diagnosis undoubtedly will contribute to establish a better and earlier therapy for better handling and the eventual establishment of a biologically supported therapy.

Due to contradictory results with respect to possible association of degree of dysplasia and expression of p16 and p53,[20] longitudinal studies of patient suffering from OED could be necessary. However, to our knowledge, there are scarce follow-up studies of potentially malignant oral lesions; presumably due to ethical reasons. Other tests have been proposed like the determination of methylation of p16 in all OED patients.[23] DNA methylation is the best studied epigenetic mechanism implicated in cancer initiation and progression.[24] Fork head box protein M1 (FOXM1) is a member of the fork head superfamily of transcription factor that regulates DNA damage repair, cell proliferation, cell cycle progression, cell renewal, cell differentiation, and cell migration throughout methylation. Because the FOXM1 over regulation is an early event during cancer development in many malignancies, it has been suggested that FOXM1 plays a key role in cancer initiation.[25] In case of oral cancer there are evidences that suggest the existence of epigenetically modified oncogenes in squamous cell carcinomas.[26] Patients afflicted with OED with high p16 methylation possessed high risk to progression to oral carcinoma.[23] This fact would suggest an apparent association between FOXM1 and gen p16. FOXM1 over regulation suppressed p16 gene expression in primary human oral keratinocytes.[24],[25] FOXM1 has showed dose-dependent over regulation during tumor progression from oral dysplasia to head and neck squamous cell carcinoma. Due to the fact of FOXM1 signature gene is retained in head and neck squamous cell carcinoma, it has been speculated that the FOXM1-induced differentially methylated genes possess strong potential as epigenetic biomarkers for early cancer screening, diagnostic, prognostic, and/or therapeutic interventions.[24],[25] An advantage of epigenetic DNA markers is that they enable the possible use of non invasive specimens, such as saliva and buccal scraping.[26] Although these findings are hopeful and it is likely and possible that research groups focused on the molecular biology of cancer might find their clinical application, necessarily, a doses dependent expression of FOXM1 has to be determined to propose a clinical use of FOXM1 targeting. Even more, determination of methylation is an expensive test requiring sophisticated equipment and trained personnel.

Therefore, in some developing countries it is unreachable for routine laboratory work in centers treating cancer patients. Paradoxically, developing countries have a high prevalence of oral cancer.[1],[2] This assumption does not demerit the enormous and very important findings about the role played by FOXM1 in carcinogenesis and their putative use in early detection of malignant cell changes as oral epithelial dysplasia or subjects with high risk to malignancy. The immunohistochemistry technique is a method widely used and could become are liable tool.

In relation to the results obtained in this study p16 and p53 could be not specific enough to identify patients suffering OED with high risk to malignancy; however, the evaluation of the presence of p16 and p53 in the TIF of OSCC could contribute to establish the tumor progression.

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Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Elba Rosa Leyva Huerta
Laboratory of Clinical and Experimental Pathology, Graduate and Research Division, Dental School, National Autonomous University of Mexico, Circuito Institutos s/n, Ciudad Universitaria, Coyoacan, 04510, Mexico City
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.182037

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  [Table 1], [Table 2], [Table 3], [Table 4]

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