137

Dental Journal
(Majalah Kedokteran Gigi)
2022 September; 55(3): 137–141

Original article

Immunohistochemical differential expression of p16 proteins in 
follicular type and plexiform type ameloblastoma

Haris Budi Widodo1, Anung Saptiwulan2, Helmi Hirawan3, Christiana Cahyani Prihastuti1, Tirta Wardana4,5
1Department of Oral Biology, Dental Medicine Study Programme, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Indonesia
2Undergraduate Student, Dental Medicine Study Programme, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Indonesia
3Department of Oral Surgery, Dental Medicine Study Programme, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Indonesia
4Department of Biomedicine, Dental Medicine Study Programme, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Indonesia
5Integrative Laboratory, Faculty of Medicine, Jenderal Soedirman University, Purwokerto, Indonesia

ABSTRACT
Background: Differences in histopathological features that describe the growth mechanism and biological behaviour of follicular 
and plexiform ameloblastomas are associated with benign, aggressive and destructive tumour markers. p16 has inhibitory interactions 
between cyclin D and CDK 4/6 to block the cell cycle and alterations related to severity. Purpose: This study intends to evaluate and 
determine differential expressions of p16 protein in follicular and plexiform ameloblastomas. Methods: This is a descriptive analytics 
study. A total of 21 specimens consisting of follicular and plexiform ameloblastomas and healthy gingiva tissues as the negative control 
were examined using the immunohistochemistry assay. The analysis of p16 protein expression was interpreted by immunoreactive 
scoring. Statistical analysis was conducted using SPSS software with the Mann–Whitney test. A p-value <0.05 shows the significance 
of the change in expression. Results: An increased expression of p16 protein was found in the follicular ameloblastoma type (2.13 ± 
1.808) and the plexiform type (4.44 ± 2.506) in comparison to the negative control group (0 ± 0). The increase of p16 expression in 
the follicular and plexiform ameloblastomas was significant compared to the negative control group (p-value <0.05); however, there 
was no significant difference between either type of ameloblastoma (p-value >0.05). Conclusion: The highest intensity of p16 protein 
expression was found in the plexiform type, even though it was not significantly different from the follicular type ameloblastoma.

Keywords: ameloblastomas; follicular; immunohistochemistry; plexiform; p16 protein expression

Correspondence: Tirta Wardana, Department of Biomedicine, Dental Medicine Study Programme, Faculty of Medicine, Jenderal 
Soedirman University, Purwokerto, Indonesia. Email: tirta.wardana@unsoed.ac.id

INTRODUCTION

The most common types of ameloblastomas are follicular 
and plexiform, whose clinical findings and specific 
clinical behaviours are associated with histopathological 
appearance. Given that appearance, this tumour shows 
signs of being a benign tumour, although clinically, it 
is aggressive and destructive.1 Ameloblastoma is an 
odontogenic tumour in tooth-forming tissue that grows 
slowly and locally invasive. Usually, the patient is unaware 
until the inflammation enlarges. Its recurrence is high, 
and its spread is expansive and infiltrative, giving the 
impression of malignancy.2

Ameloblastoma is commonly found in the mandibular 
and maxillary areas, with swelling resulting in facial 

deformity. On clinical examination, ameloblastoma does 
not have a specific feature because the stain of the tumour 
tissue is the same as the surrounding tissue.3 In addition, 
the consistency can be soft or hard, with no pain and 
paraesthesia and no ulceration of the mucosa around the 
tumour tissue.4 The growth of ameloblastoma is influenced 
by oral infection, tooth extraction, trauma to the teeth or 
jaws and genetic factors, such as tumour suppressor genes 
(TSG) and oncogenes (c-myc gene and ras gene). The 
loss of function of TSG, which plays a role in controlling 
cell proliferation and preventing cells from becoming 
malignant, causes tumour formation.5–7 

p16 is a group of TSG called MTS1 (multiple tumour 
suppressor 1), CDKN2 (cyclin-dependent kinase inhibitor 
2) and p16INK4a, which functions as an inhibitor of 

Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 158/E/KPT/2021. 
Open access under CC-BY-SA license. Available at https://e-journal.unair.ac.id/MKG/index
DOI: 10.20473/j.djmkg.v55.i3.p137–141

mailto:tirta.wardana@unsoed.ac.id
https://e-journal.unair.ac.id/MKG/index
https://doi.org/10.20473/j.djmkg.v55.i3.p137-141


138Widodo et al./Dent. J. (Majalah Kedokteran Gigi) 2022 September; 55(3): 137–141

the interaction between cyclin D and cyclin-dependent 
kinase (CDK) 4 and 6; it blocks the cell division cycle in 
G1 phase-control points.8,9 High throughput technology 
analyses using microarray gene expression profiling offer 
a technology to classify the tumour subtypes, such as breast 
cancer,10 bladder cancer11 and pancreatic adenocarcinoma.12 
However, because of the high cost and complexity of 
laboratory procedures, alternate immunochemistry (IHC) 
assay is used to identify subtypes of tumour classification. 
The identification of the subtype and the clinical impact of 
the tumour can be used to determine the success of treatment 
due to tumour biological properties and behaviour.13 

Based on its role, p16 can be used as a marker of the cell-
cycle phase to study pathophysiological conditions, such 
as abnormal cell differentiation and tumour prognosis.14,15 
This study aims to determine the differential expression 
of p16 mutant proteins in the formation of follicular 
and plexiform ameloblastomas. This may inform future 
investigations into the molecular mechanism and increase 
potential therapeutics for Indonesian ameloblastoma.

MATERIALS AND METHODS 

This descriptive analytics study uses 21 paraffin block-
stained specimens from the Department of Anatomical 
Pathology Laboratory of Prof. Dr. Margono Soekarjo 
Hospital, Purwokerto and the Asri Medical Centre 
(AMC), Yogyakarta. The paraffin blocks were cut with a 
microtome, deparaffinised, rehydrated and then subjected 
to IHC staining to observe the p16 expression using the 
anti-CDKN2A/p16INK4a antibody (Abcam ab108349, 
USA) with a 30-minute incubation using 1:100 dilution. 
Counterstaining using Mayer’s hemalum was performed 
to determine the differences in three groups: follicular 
and plexiform types of ameloblastomas as well as healthy 
gingiva tissue as a negative control.16,17 All procedures 
followed the manufacturer’s recommendations.

Observation of the p16 protein expression was 
performed by 400x magnification in five viewpoints using a 
light microscope camera with Optilab® (Motic® B2-series, 
USA) and software Raster Image (US National Institutes 
of Health, USA). Observation with a grading picture of 
cells recorded as positive and the reaction intensity were 
as follows:13,18 grade 0 (no cells recorded) and negative 
reaction intensity; grade 1 (>10%–50% of recorded cells) 
and weak staining intensity; grade 2 (>10%–50% of 
recorded cells) and medium staining intensity (2); grade 3 
(>50%–80% of recorded cells) and strong staining intensity; 
and grade 4 (>80% of recorded cells) and powerful staining 
intensity.

Based on a previous study, immunohistochemistry p16 
expression analysis was carried out based on grading status 
and intensity scores, with expression scores ranging from 
0 to 12.18 Immunoreactive scores are categorised as 1–4 
positive scores (+), weak definition; 5–8 positive scores 
(++), moderate definition; and 8–12 positive scores (+++), 
strong definition. Data analysis was carried out using SPSS 
software version 22 (IBM Corp Version 23, Chicago, IL). 
Cohen’s kappa coefficient was used to test the validity of the 
examination by two observers. The analysis of differences 
in p16 expression was carried out using the Kruskal–Wallis 
non-parametric test. The Mann–Whitney test was performed 
to determine significant differences between groups; a 
p-value <0.05 indicates a significant difference.

RESULTS

In this study, the specimen sample consisted of follicular and 
plexiform ameloblastomas (Table 1). Immunohistochemical 
staining was conducted to evaluate the expression of 
p16 by discolouration. The brown and dark brown 
discolouration in follicular and plexiform ameloblastoma 
specimens showed mutant p16 expressions (Figure 1). The 
differential in colour intensity indicated weak positive, 

    

 

Table 1. Mean of p16 mutant protein expression

Tissue specimens Total sample Average Std. deviation Std. error mean
Plexiform ameloblastoma 9 4.44 2.506 0.835
Follicular ameloblastoma 8 2.13 1.808 0.639
Healthy gingiva epithelial tissue control group 4 0 0 0

A B C

Figure 1. Positive p16 mutant protein expression by immunohistochemical staining in study groups (A) plexiform type ameloblastoma
(x400); (B) follicular type Ameloblastoma (x400); and (C) healthy gingival epithelium tissue (x40).

Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 158/E/KPT/2021.
Open access under CC-BY-SA license. Available at https://e-journal.unair.ac.id/MKG/index
DOI: 10.20473/j.djmkg.v55.i3.p137–141

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139 Widodo et al./Dent. J. (Majalah Kedokteran Gigi) 2022 September; 55(3): 137–141

moderately positive and strong positive differences in 
immunosuppression scores (Figure 1). The mean value 
of the difference in the expression of mutant p16 from 
the results of immunohistochemical examinations in the 
sample group are shown in Table 1. Two observers analysed 
mutant p16 expression by multiplying the positive cell 
grading and the reaction intensity from five fields of view 
observations.

The kappa coefficient test analysis showed a significance 
value of p = 0.000 with an ideal value of 0.598. In 
our study, the mean p16 expression for the follicular 
ameloblastoma group was 2.13 ± 1.808, for the plexiform 
ameloblastoma group 4.44 ± 2.506 and for the healthy 
gingival epithelium control group 0 ± 0. The analysis of 
differences in the expression of p16 showed a significant 
difference (p-value <0.05) in the follicular ameloblastoma, 
the plexiform ameloblastoma and the control groups (can 
be seen in Table 2). The expression of p16 mutant proteins 
showed differences between the control group compared 
with the follicular type ameloblastoma (p-value <0.05) 
and the control group compared with the plexiform type 
ameloblastoma (p-value <0.05), whereas the follicular 
type ameloblastoma compared with the plexiform type 
ameloblastoma group showed no significant difference 
(p-value = 0.071; p-value >0.05) (Figure 2). 

DISCUSSION

Ameloblastoma is a tumour with a high incidence, unrelated 
to age and gender and with no specific clinical symptoms. 
Histopathological and radiographic examinations are 
the gold standard for diagnosis in the incidence of 
ameloblastoma, with several types often found, namely 
follicular, plexiform and adenomatous. Different types 
of ameloblastomas can represent characteristics such 
as aggressiveness, recurrence and severity. Increased 
p16 expression in the incidence of ameloblastoma can 
provide an overview of the severity of its role as a 
tumour-suppressor gene in inhibiting the uncontrolled                                                                                   
proliferation process.19,20 This study found a significant 
increase of p16 expression in both types of ameloblastomas 
compared to the healthy gingival tissue, with the 
highest expression of p16 shown in the plexiform type 
ameloblastoma. 

Increased expression of the p16 mutant ameloblastoma 
indicated the incidence of a malignancy. On the other hand, 
the wild-type p16 protein is difficult to detect in normal 
conditions because it has a short half-life.21 Increased 
expression of mutant p16 causes failure of cell proliferation 
in the G1 phase so that it is often found in follicular and 
plexiform types of ameloblastomas.22,23 The imbalance 
of cell cycle regulatory pathways involving p16-RB can 
impair cell proliferation, ultimately leading to unrestricted 
proliferation and tumourigenesis.22,24,25 Mutant p16 
expression was not found in the regular gingival epithelial 
control group in normal cell proliferation, implying there 
were no malignant changes in cells. 

The p16 protein expressed in the G1 phase is a product 
of the CDKN2A gene, a tumour suppressor gene (anti-
oncogene) that can prevent the overgrowth of cells in the 
G1 phase.26 The p16 protein acts as a negative regulator 
of cell proliferation. In normal cells, wild-type p16 is 
expressed and binds to CDK4 and CDK6 so that free cyclin 
D and protein kinase complexes are inactive.27 Decrease 
or inactivation of p16 causes CDK4/6 to bind to cyclin 
D, causing an active protein kinase complex. The protein 
kinase complex triggers the phosphorylation of pRb so that 
pRb is inactive. Inactivation of pRb causes the release of the 
transcription factor E2F so that the cell enters the S phase. 
Continuous E2F transcription will cause normal cells to 
become ameloblastoma.28–30

The results showed an increase in mutant p16 expression 
in follicular and plexiform ameloblastoma types. These 
results are supported by the research of Kumamoto et 
al.(2001), who demonstrated over-expression of p16 
in most neoplastic cells from ameloblastoma so that 
odontogenic epithelium would be found to be under the 
control of this oncoprotein.31 Another study also showed 
the immunohistochemical expression of p16 in odontogenic 
tumours, including ameloblastomas, finding a particularly 
positive trend in tumour cell nuclei for tumours with low 
recurrence risk and a similar reaction for the nucleus and 
cytoplasm of tumours with high recurrence rates.32

 

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Figure 2. Immunohistochemical expressions of p16 mutant 
proteins on follicular and plexiform ameloblastomas 
and healthy gingiva control group.

Table 2. Different expressions of p16 mutant proteins

Variable I Variable II Significance

Control
Follicular 
Ameloblastoma

0.028

Control
Plexiform 
Ameloblastoma

0.005

Follicular 
Ameloblastoma

Plexiform 
Ameloblastoma

0.071

Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 158/E/KPT/2021. 
Open access under CC-BY-SA license. Available at https://e-journal.unair.ac.id/MKG/index
DOI: 10.20473/j.djmkg.v55.i3.p137–141

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140Widodo et al./Dent. J. (Majalah Kedokteran Gigi) 2022 September; 55(3): 137–141

The difference in p16 expression in follicular type 
ameloblastoma was not significantly different from the 
plexiform type ameloblastoma group. This shows that 
the two groups have similar characteristics of mutant p16 
expression. The results of this study are supported by a 
previous study that showed that there was no statistically 
significant difference in the expression of positive p16 in the 
central cells of low-risk and high-risk odontogenic tumours; 
in both groups, the results were equally high.32 Another 
study showed that the expression of the tumour suppressor 
p16 was not significantly different in odontogenic keratoses 
and unicystic ameloblastomas.13 This suggests that the 
invasive growth of odontogenic keratosis and the cystic 
behaviour of unicystic ameloblastoma are closely related 
to the state of p16 expression in the lesional epithelium. 
A candidate tumour marker can be used to analyse 
mutant p16 protein expression changes in follicular and 
plexiform ameloblastomas. However, it cannot be used 
as a progression marker between follicular and plexiform 
ameloblastoma groups. 

This study has several limitations: the limited number of 
specimens involved and the clinical data that may have risk 
factors associated with p16 protein expression. In addition, 
we believe that our findings impact the understanding of 
p16 protein expression in different types of ameloblastomas. 
There are significant differences in p16 protein expression 
using immunohistochemical analysis between the follicular 
and plexiform types of ameloblastomas compared to 
healthy tissue. In addition, the highest increase in the 
expression of the p16 protein is shown in the plexiform 
type’s ameloblastoma. 

ACKNOWLEDGMENTS

The authors would like to thank the educators and teaching 
staff of the Faculty of Medicine, Jenderal Soedirman 
University; the Anatomical Pathology Laboratory of the 
Regional General Hospital Prof. Dr Margono Soekarjo 
Purwokerto; the Anatomical Pathology Laboratory of 
Faculty of Medicine, Gadjah Mada University Yogyakarta; 
and the Anatomical Pathology Laboratory of Dr Sardjito 
General Hospital Yogyakarta for their help. All authors 
declare there is no conflict of interest in this study. 

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Open access under CC-BY-SA license. Available at https://e-journal.unair.ac.id/MKG/index
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Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 158/E/KPT/2021. 
Open access under CC-BY-SA license. Available at https://e-journal.unair.ac.id/MKG/index
DOI: 10.20473/j.djmkg.v55.i3.p137–141

https://e-journal.unair.ac.id/MKG/index
https://doi.org/10.20473/j.djmkg.v55.i3.p137-141