Open Journal of Stomatology, 2013, 3, 520-526 OJST
http://dx.doi.org/10.4236/ojst.2013.39086 Published Online December 2013 (http://www.scirp.org/journal/ojst/)
Ki-67 immunohistochemical expression in mandibular
ameloblastoma: A prognostic indicator for local
recurrence
Ayman Hegab1*#, Mohmmad Shuman2†, Mohammed Abd El-Akher1#, Delaram Arwlan3
1Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Al-Azhar University, Cairo, Egypt
2Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Al-Azhar University, Assuit, Egypt
3Medcal City Teaching Hospital, Teaching Laboratory, Baghdad, Iraq
Received 12 September 2013; revised 12 November 2013; accepted 29 November 2013
Copyright © 2013 Ayman Hegab et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Objective: This study used Ki-67 to evaluate the pro-
liferative activity of ameloblastoma in an attempt to
provide a scientific basis for any differences in the
biologic behaviour that exists between the different
types of ameloblastoma and correlate the results with
the recurrence rate. Study design: We assessed Ki-67
expression by immunohistochemistry in 32 cases of
mandibular ameloblastoma. Formalin-fixed, paraffin-
embedded blocks were sectioned and used for Hae-
matoxylin & Eosin (H&E) staining. H&E slides were
used to re-evaluate the histological types of the amelo-
blastoma. Immunohistochemical analysis for Ki-67
with a labelled streptavidin-biotin-peroxidase com-
plex technique was performed on tumour sections
using Monoclonal Mouse Anti-Human Ki-67 Antigen
(clones MIB1, code M7240, Dako Corporation). Lym-
ph nodes (lymphoma) were used as positive control
for Ki-67. Results: The specimens comprised 18 cases
of Follicular ameloblastoma, 7 cases of Cystic amelo-
blastoma, 4 cases of plexiform ameloblastoma, and 3
cases of Acanthotic ameloblastoma. The results show-
ed that cellular proliferative ac tivity varied within the
ameloblastoma types. There was no statistically sig-
nificant difference in the Ki-67 Acanthotic, cystic and
follicular types of ameloblastoma, while plexiform
type showed statistically significantly higher levels
than the other 3 types. The mean Ki-67 labelling in-
dex of plexiform ameloblastoma ranged from 13 to 30
with a mean of 19.75. The mean values of Ki-67 were
statistically significantly higher in recurrent than
non-recurrent cases. Conclusion: The significant ex-
pression of Ki-67 could provide useful prognostic
markers for proliferative activity and good prognostic
indicators for recurrence rate of mandibular amelo-
blastoma.
Keywords: Mandibular Ameloblastoma; Recurrence;
Immunohistochemistry; Ki-67
1. INTRODUCTION
Ameloblastoma is a Benign Tumour of Odontogenic
epithelium with mature fibrous stroma without odonto-
genic ectomesenchyme. In the updated World Health Or-
ganization (WHO) classification, it was classified into
solid/multicystic type, extra-osseous/peripheral type, des-
moplastic type and unicystic type [1].
Histologically, there are two main patterns, follicular
and plexiform, in which various cellular changes such as
squamous metaplasia and granular transformation are
commonly seen, and when these are extensive, the terms
acanthomatous type and granular cell type are applied,
respectively. Cyst formation within the epithelial islands
of the follicular type is common. Other rare histological
variants, including basal cell ameloblastoma, desmoplas-
tic ameloblastoma and kerato ameloblastoma, have also
been described. Despite numerous studies, correlation
between these histological patterns and tumour behav-
iour has not been consistently established [2]. The me-
chanisms of oncogenesis, cytodifferentiation and tumour
progression of ameloblastoma are still largely unknown
[3,4].
*Corresponding author.
#Associate Professors of Oral and Maxillofacial Surgery, Faculty o
f
Dental Medicine, Al-Azhar University, Cairo, Egypt.
†Lecturer of Oral and Maxillofacial Surgery, Faculty of Dental Medi-
cine, Al-Azhar University, Assuit, Egypt.
Determination of epithelial proliferative activity is
apotentially useful means of investigating differences in-
biologic behaviour between tumours [5-7]. Assessment

A. Hegab et al. / Open Journal of Stomatology 3 (2013) 520-526 521
of cell proliferation in many types of tumours is an im-
portent adjunct to histologically based tumour classifica-
tion and has potential relevance as an indicator of tu-
mour-behaviour and treatment response and relapse.
Immunohistochemical assessment of cell proliferation
has advantages over the other techniques, such as tritiat-
edthymidine incorporation and flow cytometry; because
the tissue architecture remains intact and proliferating
cells can be visualized in relation to other histologic
characteristics [8]. The interpretation, merits, and clinical
value of the methods of proliferation assessment in tu-
mours are detailed by van Diest et al. [9].
The Ki-67 antigen, which is coded by a geneon chro-
mosome 10, is expressed in the G1, S, and G2 phases in
cycling cells [10,11]. The Ki-67 score partly correlates
with other proliferation markers like %S-phase cells, and
mitotic count [12-15]. Originally, the Ki-67 antigen
could only be studied in frozen sections. Recently, a se-
ries of Ki-67 antibodies has been developed by the Kiel
group that also works on paraffin embedded tumour ma-
terial after antigen retrieval [10,11]. The Ki-67 labelling
index was found to be prognostically relevant in several
studies [16,17].
The aim of the present study is to evaluate the Ki-67
labelled index in different histologic types of mandibular
ameloblastoma and their relation to proliferative activity
and local recurrence.
2. MATERIAL AND METHODS
2.1. Patients and Tissue Selection
A retrospective study of patients who underwent treat-
ment for mandibular ameloblastoma at Al-Azhar Univer-
sity Hospital, Cairo, Egypt from 2001 to 2009 was per-
formed. The study approved by the institutional ethics
committee and written informed consent was obtained.
Thirty two formalin-fixed, paraffin-embedded archival
biopsy specimens were randomly obtained from the De-
partment of Oral and Maxillo facial Surgery at Al-Azhar
University Hospital. Patient’s files were reviewed to re-
trieve clinical data, pathology reports, surgical treatment,
clinical follow-up and recurrence. All histologic slides
were re-evaluated, applying the criteria of the World
Health Organization for histological typing of ameloblas-
toma.
2.2. Histopathology and Immunohistochemistry
Formalin-fixed, paraffin-embedded blocks were sec-
tioned (3 - 4 µm in thickness) and used for Haematoxy-
lin & Eosin (H&E) staining. H&E slides were used to re-
evaluate the histological types and characteristics of the
ameloblastoma.
The paraffin-embedded tissue sections were also used
for Immunohistochemical staining for the antigens Ki-67.
Sectioning: 3 - 4 micrometer section is done on the par-
affin block on special glass slide and put in oven on 56
degree.
Deparaffinization with xyline and dehydrated with de-
creasing grades of ethanol alcohol. Demasking of the
antigen: Pre-treatment of formalin-fixed, paraffin-em-
bedded tissue sections with heat-induced epitope retrie-
val (HIER) is required for 20 minutes.
Immunohistochemical analysis for Ki-67 with a la-
belled streptavidin-biotin-peroxidase complex technique
was performed on tumour sections using Monoclonal
Mouse Anti-Human Ki-67 Antigen (clone MIB1, code
M7240, Dako Corporation) is used at a dilution range of
(1:75 - 1:150) for 20 minute at room temperature.
Visualization: The recommended visualization system
is Peroxidase/DAB+, Rabbit/Mouse using 20 minutes in-
cubation at room temperature.
 Proper positive and negative controls were performed.
Lymphnodes (lymphoma) were used as positive con-
trol for Ki-67 and using 20 minutes heat-induced epi-
tope retrieval in Target Retrieval Solution, and 20
minutes incubation at room temperature with the Pri-
mary antibody.
 The recommended negative control is Dako Mouse
IgG1, diluted to the same mouse.
IgG concentration as the primary antibody.
2.2.1. Interpretation
Slides were scanned by ×40 magnification. Ten cellular
are as selected (i.e. the so-called hot spots) and evaluated
at ×400 magnification. Staining is seen as a dark brown
to black nuclear signal in cells expressing the Ki-67 an-
tigen. Ki-67 is expressed in all phases of the cell cycle
and is therefore considered a marker of proliferating
cells.
Ki-67 proliferation index is assessed by point counting
and reported as percent positive.
2.2.2. Assessmen t o f Ki-67
Ki-67 labelling index was done by calculating the ratio
of positive nuclei in relation to total number of neoplastic
nuclei in 10 HPFs. The labelling index (number of posi-
tive tumour cells/total number of tumour cells expressed
as a percentage) was calculated in every specimen.
2.3. Statistical Analysis
Microstat7 for windows statistical package (Microstat
Co.) was used for statistical analysis of this study. One-
Way ANOVA was used to evaluate the mean values of
the Ki-67 in different types of ameloblastoma while in-
dependent “t” test was used to compare Ki-67 levels in
recurrent and non-recurrent cases.
Difference between mean values was considered sta-
tistically significant when p ≤ 0.05.

A. Hegab et al. / Open Journal of Stomatology 3 (2013) 520-526 522
3. RESULTS
This study was carried out on retrospective 32 cases of
mandibular ameloblastoma treated in oral and maxillofa-
cial surgery department-Al-Azhar university hospital
from the period from 2001 to Jan. 2009 with follow up
period until 2011. The male: female ratio was 3:1, with
24 (75%) males and 8 (25%) females. Age distribution
ranged from 21 to 78 years, with a mean age of 35.7
years. Most of the cases occurred in the second and third
decades of life. The specimens comprised 18 cases of
Follicular ameloblastoma (56.2%), 7 cases of Cystic
ameloblastoma (21.8%), 4 cases of Plexiform ameloblas-
toma (12.5%), and 3 cases of Acanthotic ameloblastoma
(9.4%). Tumours were predominantly located in the mo-
lar-angle and angle-ramus regions of the mandible (Ta-
ble 1).
Recurrence of the ameloblastoma occurred in 8 cases
out of 32. The recurrence was higher in male more than
female.
4 cases of the recurrence were plexiform ameloblas-
toma (100%) and the other 4 cases occurred in the Fol-
licular ameloblastoma (22%).
The results showed that cellular proliferative activity
varied within the ameloblastoma types. There was no
statistically significant difference in the Ki-67 Acan-
thotic, cystic and follicular types of ameloblastoma,
Table 1. Summary of clinico-pathologic finding of the studied cases.
No Age Sex Duration & Site Type Recurrence Ki-67
1 21 Y F 2Y/angle-ramus region Cystic ameloblastoma − 2
2 33 Y M 1Y/angle-ramus region Follicular ameloblastoma − 5
3 36 Y F 6M/molar-ramus region Follicular ameloblastoma − 4
4 30 Y M 18M/body-angle region Plexiform ameloblastoma + 13
5 23 Y M 6M/molar-angle region Cystic ameloblastoma − 2
6 42 Y F 1Y/body-angle region Follicular ameloblastoma + 6
7 36 Y M 1Y/molar region Cystic ameloblastoma − 4
8 28 Y F 6M/body-angle region Cystic ameloblastoma − 6
9 35 Y M 3Y/angle-ramus region Follicular ameloblastoma − 8
10 37 Y F 2Y/canine-premolar region Cystic ameloblastoma − 3
11 31 Y M 18M/molar-ramus region Cystic ameloblastoma − 2
12 78 Y F 10Y/symphysis-angle region Acanthotic ameloblastoma − 2
13 42 Y M 1Y/body molar region Follicular ameloblastoma + 10
14 38 Y F 6M/body molar region Follicular ameloblastoma − 9
15 29 Y F 2Y/molar angle region Follicular ameloblastoma − 3
16 37 Y M 1Y/Molar angle region Cystic ameloblastoma − 4
17 33 Y M 2Y/body region Follicular ameloblastoma − 6
18 24 Y M 1Y/body molar region Follicular ameloblastoma − 3
19 35 Y M 2Y/molar angle region Acanthotic ameloblastoma − 2
20 33 Y M 18M/molar angle region Follicular ameloblastoma − 2
21 42 Y M 6M/molar angle region Plexiform ameloblastoma + 20
22 29 Y M 1Y/body molar region Follicular ameloblastoma − 2
23 65 Y M 3Y/symphysis-molar region Follicular ameloblastoma − 6
24 31 Y M 1Y/molar angle region Follicular ameloblastoma − 4
25 37 Y M 2Y/molar angle region Follicular ameloblastoma − 5
26 29 Y M 1Y/molar angle region Follicular ameloblastoma + 15
27 41 Y M 3Y/body molar region Follicular ameloblastoma + 15
28 35 Y M 1Y/molar angle region Plexiform ameloblastoma + 30
29 36 Y M 2Y/molar angle region Acanthotic ameloblastoma − 6
30 28 Y M 6M/molar angle region Follicular ameloblastoma − 3
31 36 Y M 1Y/molar angle region Plexiform ameloblastoma + 16
32 32 Y M 2Y/molar angle region Follicular ameloblastoma − 4

A. Hegab et al. / Open Journal of Stomatology 3 (2013) 520-526 523
while plexiform type showed statistically significantly
higher levels than the other 3 types (Figure 1). The mean
Ki-67 labelling index (LI) of plexiform ameloblastoma
ranged from 13 to 30 with mean of 19.75 (Table 2 and
Figure 2).
Statistical analysis of the Ki-67 between the recurrent
and non-recurrent cases showed that, the mean values of
Ki-67 was statistically significantly higher in recurrent
than non-recurrent cases (Table 3 and Figure 3).
4. DISCUSSION
Ameloblastoma have been categorized broadly into 3
biologic variants: cystic (unicystic), solid, and peripheral.
(a) (b)
(c) (d)
(e) (f)
(g)
Figure 1. (a) Lymphnode germinal center (Lymphoma ×400)
Ki-67 as a positive control; (b) Acanthotic ameloblastoma (H&
E); (c) Acanthotic ameloblastoma (×400), Ki-67 labeling index
reaching 6%; (d) Follicular ameloblastoma (H&E); (e) Follicu-
lar ameloblastoma Ki-67 labeling index reaching 8%; (f) Plexi-
form ameloblastoma (H&E); (g) Plexiform ameloblastoma
(×400) Ki-67 labeling index reaching 20%.
Table 2. Ki-67 means levels in ameloblastoma different types.
Mean St Dev
Acanthotic 3.33 2.31
Cystic 3.29 1.50
Follicular 6.11 3.94
Plexiform 19.75 7.41
Figure 2. Plexiform type showed statistically significantly
higher levels than the other 3 types.
Table 3. Independent “t” test results comparing Ki-67 levels in
recurrent and non-recurrent cases.
Mean ± St Dev
Non-recurrent Recurrent “t” value Probability
4.042 ± 1.99 15.63 ± 7.15 7.336 3.6E−08
Figure 3. The mean values of Ki-67 was statistically signifi-
cantly higher in recurrent than non-recurrent cases.
The literature indicates that the cystic variant is biologi-
cally less aggressive and has a better response to enucle-
ation or curettage than does the solid ameloblastoma [18,
19].
The clinical course in any given patient with an amelo-
blastoma is difficult to predict because there are few fea-
tures to aid the evaluation of the biological behavior of
the tumor. There is no clear evidence that histologic fea-
tures of ameloblastoma, such as follicular or plexiform

A. Hegab et al. / Open Journal of Stomatology 3 (2013) 520-526 524
patterns, determine the degree of invasiveness of indi-
vidual cases or allow prediction of likelihood of recur-
rence or malignant transformation [20]. The only prog-
nostically significant histologic factor is that unicystic
types are less aggressive especially if associated with
impacted molar teeth. Therefore, there is a need for a
predictive marker of clinical behavior inameloblastoma.
The proliferative activity of tumor cells has been
found to be an indicator of aggressiveness and to provide
useful prognostic in formation. Immunohistochemical
detection of the Ki-67antigen has provided a means of
evaluating turnout cell proliferation in a range of ma-
lignancies including carcinomas of the breast and the
head and neck [21-24].
Many investigations of tumor cell proliferative activ-
ity have used PCNA and Ki-67 in oral and other systemic
tumors. However, despite the years of intense research
on these relatively simple immunostaining techniques
and the routine use of such investigations in certain ma-
lignancies such as lymphomas, the routine application of
PCNA and Ki-67 in diagnostic histopathology of oral
tumors is as yet of little value [25].
Ki-67antigen is a more specific marker of proliferating
cells, maximally expressed during S phase, which is rap-
idly degraded after mitosis. The original antibody raised
against this 395 KD Ki-67 protein (pKi-67) is referred to
as Ki-67 antibody, a prototype for other antibodies that
also identify epitopes of pKi67, e.g., MIB-1 [26]. MIB-1
is an antibody that detects Ki-67 antigenin formalin-fixed,
paraffin-embedded tissue after antigen retrieval [27]. Ki-
67 is a nonhistone protein initially expressed in mid G1,
increasing in level through S and G2 and peaking in M.
It has been suggested that Ki-67 staining is more ac-
curate than the counting of mitoses or PCNA staining. Its
estimated half-life is 60 to 90 minutes [26]. However, not
all cells containing the Ki-67 antigen are actively prolif-
erating cells, and the use of Ki-67 to assess proliferative
activity is not advised in tissues over expressing p53 or
p21 [28]. It should further be noted that correlation be-
tween mitotic and Ki-67 labeling indices is variable [29-
34].
The Ki-67 labelling index was found to be prognosti-
cally relevant in several studies [16,17]. More recent stu-
dies using MIB1 paraffin antibody have confirmed its
prognostic value [35,36].
The results of the current study showed that; cellular-
proliferative activity as assessed by Ki-67 labeling indi-
ces varied within recurrent and non-recurrent cases of
ameloblastoma. There was a significant relation between
labeling index of nuclear proliferation marker Ki-67 and
recurrence of ameloblastoma. Also; recurrence rate was
highly significant in the plexiform ameloblastoma (100%)
which associated with the highest Ki-67 labelling index
followed by Follicular ameloblastoma (22%).
The result of Immunohistochemical data in the current
study indicated that the immuno expression of Ki-67 la-
beling index might be a good prognostic indicator for
proliferative activity and the local recurrence of man-
dibular ameloblastoma. The use of Ki-67 before surgical
excision of the ameloblastoma can be considered as an
important step in the treatment plan for evaluation of the
proliferative activity and subsequent the possibility of the
recurrence.
Even though, our results showed that both plexiform
and follicular types expressed the higher proliferative
activity and recurrence rate, but this cannot be consid-
ered as a role because of small sample size of our study.
Histologic types with high Ki-67 label index should be
treated with large safety margin to decrease the incidence
of recurrence.
5. CONCLUSION
The significant expression of Ki-67 could provide useful
prognostic markers for proliferative activity and good
prognostic indicators for recurrence rate of mandibular
ameloblastoma. Preoperative immunohistochemistry with
Ki-67 could be considered as an important step for the
treatment plan. Further studies on large sample size
should be considered.
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