Med Oral Patol Oral Cir Bucal. 2020 May 1;25 (3):e388-94.
Primordial odontogenic tumor
Journal section: Oral Medicine and Pathology
Publication Types: Review
doi:10.4317/medoral.23432
http://dx.doi.org/doi:10.4317/medoral.23432
Primordial odontogenic tumor: A systematic review
Ronell Bologna-Molina 1,2, Vanesa Pereira-Prado 1, Celeste Sánchez-Romero 1, Rogelio González-González 2,
Adalberto Mosqueda-Taylor 3
1
Molecular Pathology Area, School of Dentistry, Universidad de la República, Montevideo, Uruguay
Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango, México
3
Health Care Department, Universidad Autónoma Metropolitana, Ciudad de México, México
2
Correspondence:
Health Care Department
Universidad Autónoma Metropolitana
Calzada del Hueso 1100, Col Villa Quietud
Delg. Coyaoacan, C.P.04960 Ciudad de México
mosqueda@correo.xoc.uam.mx
Received: 09/09/2019
Accepted: 11/11/2019
Bologna-Molina R, Pereira-Prado V, Sánchez-Romero C, GonzálezGonzález R, Mosqueda-Taylor A. Primordial odontogenic tumor: A
systematic review. Med Oral Patol Oral Cir Bucal. 2020 May 1;25
(3):e388-94.
Article Number:23432
http://www.medicinaoral.com/
© Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946
eMail: medicina@medicinaoral.com
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Abstract
Background: The primordial odontogenic tumor (POT) is a recently described benign entity with histopathological
and immunohistochemical features suggesting its origin during early odontogenesis. Aim: To integrate the available
data published on POT into a comprehensive analysis to better define its clinicopathological and molecular features.
Material and Methods: An electronic systematic review was performed up to September 2019 in multiple databases.
Results: A total of 13 publications were included, representing 16 reported cases and 3 molecular studies. The
mean age of the affected patients was 11.6 years (range 2-19), with a slight predominance in males (56.25%). The
posterior mandible was the main location (87.5%), with only two cases affecting the posterior maxilla. All cases
appeared as a radiolucent lesion in close relationship to an unerupted tooth. Recurrences have not been reported
to date. Microscopically, POT comprises fibromyxoid tissue with variable cellularity surrounded by a cuboidal to
columnar odontogenic epithelium but without unequivocal dental hard tissue formation. A delicate fibrous capsule
surrounds (at least partially) the tumor. The epithelial component shows immunohistochemical positivity for amelogenin, CK19, and CK14, and variable expression of Glut-1, Galectin-3 and Caveolin-1, Vimentin, p-53, PITX2,
Bcl-2, Bax and Survivin; the mesenchymal tissue is positive for Vimentin, CD90, p-53, PITX2, Bcl-2, Bax, and
Survivin, and the subepithelial region exhibits the strong expression of Syndecan-1 and CD34. The Ki-67 index
is low (<5%). The negative or weak expression of dentinogenesis-associated genes could explain the inhibition of
dentin and subsequent enamel formation in this neoplasm.
Conclusion: POT is an entity with a well-defined clinicopathological, immunohistochemical and molecular profile
that must be properly diagnosed and differentiated from other odontogenic lesions and treated consequently.
Key words: Primordial odontogenic tumor, systematic review.
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Primordial odontogenic tumor
Introduction
- Study selection
The titles and abstracts of all studies found in the database search were independently reviewed by two
authors; subsequently, the articles that met the inclusion criteria and those lacking information in the title
or abstract were completely evaluated using the EBLIP
Critical Appraisal Checklist. The studies selected by
each author were crossed to ensure that they were properly chosen, according to the inclusion criteria and the
checklist (Fig. 2).
In 2014, the primordial odontogenic tumor (POT) was
described for the first time (1), and subsequently this
entity was included in the World Health Organization
(WHO) Classification of Head and Neck Tumours in the
group of benign mixed neoplasms (2). The name was
coined due to its possible development from the early
stages of odontogenesis (Fig. 1).
Fig. 1: Process of odontogenesis and suggested location of primordial odontogenic tumor (POT) origin according to developmental
stages: late cap and early bell.
Since its original description in 2014, sixteen cases of
POT have been reported in the literature, presenting as
a well-defined radiolucent lesion in close proximity to
the crown of an unerupted tooth, producing bone expansion, radicular resorption and tooth displacement of
variable extent (3-9).
The aim of this systematic review is to collect and integrate the available data published on POT into a comprehensive analysis to better define its clinicopathological, radiological and molecular features.
Fig. 2: Study selection flowchart, according to PRISMA guidelines.
- Data extraction
All relevant information, such as reference, year of publication, patient nationality or country of publication,
number of cases, patient sex and age, tumor location,
signs and/or symptoms, imaging presentation, treatment, follow-up, immunohistochemical and molecular
features, were extracted (when available) using a specific table.
- Analysis
The abovementioned data were analyzed with descriptive statistics. Since POT is a benign tumor with indolent behavior and no recurrences reported to date, it was
not necessary to perform statistical tests to evaluate the
association of clinicopathological variables with prognosis or survival.
Material and Methods
This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses)
guidelines (10).
- Search strategies
An electronic search was performed up to September
2019, with date restriction since 2014 (first description
of the POT). The following databases were accessed:
PubMed/MEDLINE, Cochrane, and SpringerLink. The
search strategy used in all databases consisted of the
following keywords: primordial odontogenic tumor.
- Inclusion and exclusion criteria
The inclusion criteria were as follows: 1) cases diagnosed as POT with sufficient clinical, microscopic, and
immunohistochemical information to confirm a definite
diagnosis based on the WHO histological classification
of odontogenic tumors (2), including case reports and
molecular studies, 2) articles in English language, and
3) articles included in PubMed/MEDLINE, Cochrane,
and SpringerLink databases.
The exclusion criteria were as follows: 1) case reports
without sufficient information to confirm a definite diagnosis, 2) book chapters, reviews and meta-analyses,
3) documents in a different language from English, or
4) articles published before 2014.
Results
- Literature search
The process of searching and screening the articles is
summarized in Fig. 2. The initial search recorded a total
of 277 articles; of these, 116 articles were excluded due to
duplication. Subsequently, two reviewers, independently, with a substantial concordance indicated by a kappa
coefficient of k = 0.76, assessed the titles and abstracts,
resulting in the exclusion of 146 publications. In the
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Primordial odontogenic tumor
evaluation of the 16 remaining papers, 2 were excluded
because they were reviews and 1 was excluded for not
meeting the criteria to confirm the diagnosis of POT.
- Description of the selected studies
A total of 13 publications were included, representing
16 reported cases and 3 molecular studies (Table 1).
The studies and cases originated from nine countries.
The study of Mosqueda-Taylor et al., 2014 included six
cases from four different countries (México, Guatemala, Brazil and Spain), and additional cases were reported in the U.S.A., Japan, Egypt, India, México, Brazil
and the Philippines (Table 2).
- Descriptive analysis of the clinical and radiographic
features
The age of the patients varies in a range of 2-19 years old,
with a mean of 11.6. Males were slightly more affected
(56.25%) with a male to female ratio of 9:7. All cases
occurred in the posterior region of the jaw, mainly in the
mandible (87.5%). All patients were asymptomatic, with
most presenting swelling in the affected region, and in
only two cases, the tumor was discovered as an incidental radiographic finding (4,8). Radiographically, all
cases were associated with at least one unerupted tooth,
with the majority presenting as unilocular and welldefined radiolucencies, and approximately one-third of
the cases exhibiting biloculated or multiloculated appearances. Tooth displacement and root resorption were
commonly found (in 75% and 87.5% of cases, respectively). Most of these cases involved unerupted teeth,
particularly the third molar (62.5%), followed by the
second deciduous molar. The size of the lesions ranged
from 9 to 90 mm; however, most of these anomalies
were ≥ 30 mm, with a mean of 41 mm (Table 2, Table 3).
Table 1: Selected articles for the systematic review.
No. Reference
1
Mosqueda-Taylor et al.,
2014 (1)
2
Slater et al., 2016 (4)
3
Ando et al., 2017 (3)
4
Bologna-Molina et al.,
2017 (17)
5
Mikami et al., 2017 (5)
6
7
8
9
10
11
12
13
Type of study
Case report and immunohistochemical analysis
Case report
Case report
Immunohistochemical
analysis
Case report and immunohistochemical analysis
Mikami et al., 2018 (12) Immunohistochemical and
next generation sequencing
analysis
Bologna-Molina et al., Immunohistochemical
analysis
2018 (18)
Case report
Amer et al., 2018 (7)
Case report
Pardhe et al., 2018 (6)
Almazyad et al., 2018 (8) Case report
Bomfim et al., 2018 (9) Case report
Teixeira et al., 2019 (14) Case report
Poomsawat et al., 2019 (11) Case report
Table 2: Clinicopathological and radiographic features of primordial odontogenic tumor.
No. Reference
1
2
3
Country Age /
or na- gentionality der
MosquedaTaylor et Mexico 18/M
al., 2014
MosquedaTaylor et
Spain 16/M
al., 2014
MosquedaTaylor et
Brazil 16/M
al., 2014
Location
Clinical find- Imaging
ings
findings
RL, UL,
Asymptomatic
WD, TD,
swelling
RR
Asymptomatic, RL, UL,
Left posterior
cortical expan- WD, TD,
mandible
sion
RR
RL, UL,
Left posterior Asymptomatic
WD, TD,
mandible
swelling
RR
Left posterior
mandible
Involved
unerupted
tooth
Size
Treatment
(mm)
Third molar
45 x
40 ^
Third molar
55 x
50 ^
Third molar
65 x
50 ^
Followup
20
Enucleation
years,
and tooth
NED
extraction
Enucleation
13
and tooth
years,
extraction NED ~
Enucleation
10 years,
and tooth
NED
extraction
4
MosquedaGuateTaylor et
mala
al., 2014
3/F
Left posterior Asymptomatic RL, BL,
mandible and
bony expan- WD, TD,
ascending ramus
sion
RR
Second deciduous and
first permanent molars
90 x
70 ^
Enucleation
9 years,
and tooth
NED
extractions
5
MosquedaTaylor et
al., 2014
Brazil
13/F
RL, BL,
Left posterior
Asymptomatic
WD, TD,
mandible and
swelling
RR
ascending ramus
Third molar
80 x
50 ^
Enucleation
3 years,
and tooth
NED
extractions
6
MosquedaTaylor et Mexico
al., 2014
3/F
35 x
30 ^
Enucleation
6
and tooth months,
extractions
NED
7
Slater et
al., 2016
U.S.A.
19/M
8
Ando et
al., 2017
Japan
8/F
Second decidRL, UL,
uous and first
Asymptomatic
WD, TD,
permanent
bony swelling
RR
molars
Asymptomatic,
RL, UL,
Right posterior
Third molar
radiographic
WD, RR
mandible
finding
Left posterior
maxilla
Left posterior
maxilla
25 x Excision and
7
19 x tooth extrac- months;
15 Ӻ
tion
NED
16
Asymptomatic RL, WD, First decidu- 16 x
Enucleation months,
swelling
TD
ous molar,
15
NED
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Primordial odontogenic tumor
Table 2 cont.: Clinicopathological and radiographic features of primordial odontogenic tumor.
9
Mikami et
al., 2017
Japan
5/M
Right posterior
mandible
10
Amer et
al., 2018
Egypt
2/M
Posterior mandible
11
Pardhe et
al., 2018
India
17/M
Left posterior
mandible, and
ascending ramus
12
Almazyad U.S.A. /
15/F
et al., 2018 hispanic
Right posterior
mandible
13
Almazyad Mexico /
18/M
et al., 2018 hispanic
Right posterior
mandible
14
Bomfim et
al., 2018
4/M
Left posterior
mandible
13/F
Left posterior
mandible
17/F
Left posterior
mandible
Brazil
Novaes
15 Teixeira et Brazil
al., 2019
PoomPhilip16 sawat et al.
pines
2019
Excision and
RL, UL,
Second decid- 8 x 8
Delayed eruptooth extracWD, TD,
uous molar x 9 Ӻ
tion
tion
RR
Excision and
Asymptomatic RL, ML, “Developing 30 x
tooth extracfleshy swelling WD, TD
tooth”
40 ^
tion
Enucleation
RL, ML,
N/A
Painless swelland tooth
WD, TD, Third molar
⍚
ing
extraction
RR
Excision and
Swelling of
RL, ML,
35 x
tooth extracright mandibu- WD, TD, Third molar
20 ^
tion
lar vestibule
RR
Curettage
Asymptomatic,
17 x
RL, UL,
and tooth
Third molar
radiographic
12 Ӻ
WD
extraction
finding
Excision and
RL, UL,
Second decid- 30 x
Asymptomatic
tooth extracWD, TD,
uous molar 20 ^
swelling
tions
RR
RL, UL,
Mandibular
WD, TD, Third molar N/A
Excision
swelling
RR
Partial
25 x
Asymptomatic RL, UL,
mandibulecThird molar
34 ^
cheek swelling WD, TD
tomy°
7
months,
NED
2 years,
NED
6
months,
NED
3
months,
NED
20
months,
NED
N/A
N/A
18
months,
NED
Abbreviations. M: male, F: female, NED: no evidence of disease, N/A: not available, *: when available, ~: data obtained after the original
publication, RL: radiolucent, UL: unilocular, BL: biloculated, ML: multilocular, WD: well-defined, TD: tooth displacement, RR: root resorption, ^: assessed by imaging, Ӻ: measure of surgical specimen, ⍚: the size reported correspond to intraoral swelling, which is not representative, °: treatment indicated by the diagnosis of odontogenic myxoma in the incisional biopsy.
Table 3: Summary of clinical data of POT.
Variable
Age (years)
< 10
≥ 10
Range: 2 – 19
Mean: 11,7 ± 6,3
Gender
Female
Male
Location
Posterior mandible
Posterior maxilla
Size (higher measure in mm)
< 30
≥ 30
Range: 9 - 90
Mean: 41 ± 23.9
Imaging findings
WD
RL, UL
RL, ML
RL, BL
RR
TD
Involved tooth
3rd molar
1st PM & 2nd DM
Developing tooth NS
All cases, except one, were treated with simple excision/enucleation with extraction of the involved teeth
and to date, there are no reports of recurrences (followup range: 3 months to 20 years) (Table 2). One case was
treated with a partial mandibulectomy due to a misdiagnosis of odontogenic myxoma in the incisional biopsy
(11). Macroscopically, POT is a solid, multilobulated
whitish and glossy mass, without cystic spaces, and this
tumor is surrounded by a capsule or at least well demarcated from the surrounding structures (1,2,9). In some
cases, the dental follicle can be identified in the surgical
specimen with a dark reddish color (4,5,9).
The demographic, clinicopathological and radiographic
features of the 16 POT cases are summarized in Table 2,
and the descriptive statistics are summarized in Table 3.
- Histopathological features
POT comprises mesenchymal fibromyxoid tissue with
variable cellularity that in most cases resembles the
dental papilla, surrounded at the periphery by a cuboidal to columnar epithelium similar to the inner epithelium of the enamel organ. Occasionally, suprabasal stellate reticulum-like areas may be observed. The tumor
is at least partially enclosed by a thin fibrous capsule
(Fig. 3). A condensation of mesenchymal cells in the
subepithelial region is also commonly observed (Fig.
3). Invaginations of the surrounding epithelium can be
focally present within the mesenchymal component, resulting in ameloblastic fibroma-like islands on tangential sections.
n = 16 / %
6 / 37.5
10 / 62.5
7 / 43.8
9 / 56.2
14/ 87.5
2 / 12.5
(n=14)
4 / 28.6%
10 / 71. 4 %
16 /100
13 / 81.3
3 / 18.7
2 / 14.2
12-75
14 / 87.5
12-75
3 /18.8
1 / 6.2
Abbreviations: RL: radiolucent, UL: unilocular, BL: biloculated, ML:
multilocular, WD: well-defined, RR: root resorption, TD: tooth displacement, PM: permanent molar, DM: deciduous molar, NS: not specified.
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Primordial odontogenic tumor
for BRAF V600E and calretinin by immunohistochemistry.
- Molecular characterization
To date, 151 cancer- and 42 odontogenesis-associated
genes have been analyzed in POT by next-generation
sequencing, and no mutations were detected. Nevertheless, the expression of the dentinogenesis-associated
genes Bglap, Ibsp and Nfic was negative or very weak.
DSPP mRNA is highly expressed in POT (12).
Discussion
Although POT is a recently described and accepted entity (1,2), this systematic review showed that the 16 cases reported to date exhibit a well-defined profile of clinicopathologic, radiographic, immunohistochemical and
molecular features that can be summarized as follows:
this tumor occurs in the first and second decades of life,
affecting the posterior region of the jaw, particularly
the mandible. Radiographically, POT appears as a welldefined radiolucent unilocular lesion always associated
with unerupted teeth, such as deciduous or third molars,
with a mean size of 4.1 cm, showing tooth displacement
and frequent root resorption (Table 1, Table 2).
Considering that most lesions appear as unilocular
radiolucencies in close relationship with the crown of
an unerupted tooth, the main radiographic differential diagnosis includes a dentigerous cyst and an ameloblastic fibroma; however, multilocular lesions with
tooth displacement and root resorption could mimic
other odontogenic tumors and cysts, such as ameloblastoma, odontogenic myxoma and odontogenic keratocyst (2,4,11). POT is a benign tumor with an indolent
course, as there are no reported recurrences after conservative excision (Table 1).
Macroscopically, POT is a solid, multilobulated whitish and glossy mass with no evidence of cystic changes,
and this tumor is well demarcated from the surrounding
structures. Considering these aspects, it is convenient
to rule out the possibility of ameloblastic fibroma in excision specimens and of odontogenic myxofibroma in
incisional biopsies (1,2,9,11).
Microscopically, POT essentially shows mesenchymal
fibromyxoid tissue resembling in large areas the dental
papilla, surrounded by a cuboidal to columnar epithelium that resembles the inner epithelium of the enamel
organ (Fig. 3) (2,4,5). These features differ from their
main histopathological differential diagnoses: ameloblastic fibroma, hyperplastic dental follicle and odontogenic myxoma (1,4). In the last case, it is mandatory to
identify the highly distinctive features of POT to avoid
the misdiagnosis of odontogenic myxoma, particularly
in small incisional biopsies and subsequent overtreatment, a situation that has been reported previously (11).
In a representative biopsy or a complete surgical specimen of POT, it is possible to exclude an odontogenic
Fig. 3: Histological features of POT. A: The fibromyxoid mesenchymal tissue is completely surrounded by cuboidal to columnar odontogenic epithelium. A subepithelial cellular condensation of the mesenchyme is observed; additionally, higher vascularization is observed
adjacent to this region. B: In this magnified region, the tumor is covered by an odontogenic epithelium with ameloblastic and cuboidal
morphology. The subepithelial mesenchymal condensation (arrows)
is observed next to a prominent vascularized area (hematoxylin and
eosin staining, zoom of digitalized slide A: 2x, B: 20x).
This tumor is devoid of dental hard tissues; nevertheless, four authors have described the presence of small
foci of calcifications within the epithelial tissue, specifically, the stellate reticulum-like areas. However, no evidence of odontoblastic differentiation or the induction
of dental hard tissue deposition has been described thus
far. These intraepithelial calcifications are round small
masses of hard material with a globular or concentric
appearance (5,8,9,11).
- Immunohistochemical features
The epithelial component shows consistent immunohistochemical positivity for CK14, CK19, amelogenin,
ameloblastin and dentin sialophosphoprotein precursor (DSPP). However, other markers, such as Glut-1,
Vimentin, MOC-31, Caveolin-1, Galectin-3, PITX2,
p53, Bax, Bcl-2, Survivin and PTEN, are variably and
focally expressed. The mesenchymal tissue is strongly
positive for Vimentin, Syndecan-1, PITX2, Endoglin
(CD105), CD34, Cyclin D1, Bax, Bcl-2, Survivin and
p53, while PTEN, CD90 and DSPP were detected with
moderate positivity. The proliferation index assessed
by Ki-67 is <5%. The condensed mesenchymal tissue
adjacent to the epithelium presents the strong expression of CD34 and Syndecan-1. This tumor is negative
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Primordial odontogenic tumor
myxoma, since this tumor is not surrounded by an
odontogenic epithelium, and to differentiate it from an
ameloblastic fibroma, which presents cords and islands
of odontogenic epithelium within the dental papilla-like
myxoid stroma (2). Some authors have stated that the
areas of ameloblastic epithelium of POT are similar
to those of the lining of unicystic ameloblastoma (4);
however, POT presents as a tumor mass and not as a
cystic lesion. Additionally, the differences in the mesenchymal component (fibrous tissue for ameloblastoma
and fibromyxoid for POT) are helpful in confirming the
diagnosis (Fig. 3) (2,4).
We excluded a recently published POT case report from
this study because most of the clinicopathological and
radiographic characteristics did not match the profile of
the POT, such as its location (anterior), lack of association with an unerupted tooth, small size, subepithelial
odontoblastic differentiation, and dentinoid production
(13). Consequently, we consider that this case represents a developing odontoma, which must be included
as another differential diagnosis of POT, mainly in very
small lesions in children. In contrast to odontoma, POT
does not present the production of dental hard tissues or
odontoblastic differentiation (Table 2) (3,5,7,14).
Initially, the term POT was coined due to the histologic
resemblance of the tumor with the appearance of the
epithelial and mesenchymal elements during the early
stages of tooth development (Fig. 3), when the epithelium is located peripherally, mimicking the relation between the inner epithelium of the immature enamel organ and the primitive dental papilla, without inductive
effects over the ectomesenchyme (Fig. 2) but lacking
the ability to follow a normal evolution toward histoand morphodifferentiation (1,12). Heterogeneity in epithelial differentiation within the same tumor has been
documented previously by histopathological analysis,
describing features, such as localized areas of ameloblastic differentiation(3,4) and focal stratum intermedium-like structures, as well as some superficial stellate
reticulum-like areas, which are not necessarily representative of the findings of POT (5,9). The histomorphological variability may reflect the heterogeneity of the
tumor caused by, for example, slight differences in the
state of differentiation among the reported cases (5,12).
Although POT is devoid of dental hard tissues, four
cases showed small foci of calcifications within the epithelial layer (5,8,9,11), which may suggest that alkaline
phosphatase could play a role in the formation of these
calcifications, as occurs in the calcifying epithelial
odontogenic tumor (15,16).
Immunohistochemically, POT has shown a low proliferation index (<5%), which defines this lesion as a
slow-growing benign tumor in which cell proliferation
does not seem to be the main mechanism implicated in
tumoral growth and expansion (17). Nonetheless, one
study has shown that the condensed subepithelial region exhibits higher vascularization and positivity for
Glut-1 and antiapoptotic markers, suggesting a major
participation of metabolic, antiapoptotic and angiogenic
events in tumor growth (5,17).
The immunoexpression patterns described in POT corresponded to those found in the normal early stages of
tooth development: the condensed mesenchymal subepithelial area seems to be the most proliferative and
shows high expression of Syndecan-1 and CD34, which,
along with the epithelial expression patterns of CK14,
CK18 and CK19, and focal PITX2, as well as the mesenchymal and epithelial staining for vimentin, resembles
the initial period of tooth formation, suggesting that
POT origins around the 10th to 20th week of embryonal
development (cap stage to late bell stage of tooth germ)
(Fig. 2) (1,5,12,18).
In fact, the epithelial portion of the tumor consistently
expresses CK14 and CK19, while other markers, such
as Vimentin, Amelogenin, Glut-1, MOC-31, and Caveolin-1. Galectin-3, PITX2, p53, Bax, Bcl-2, Survivin and
PTEN, are variably expressed in focal areas, suggesting a dynamic tissue presenting cells in different stages
of maturation and exhibiting a transition between early
stages of tooth development to those with ameloblastic
maturation but without induction of odontoblastic maturation or production of mineralized tissues (5,17,18).
This immunohistochemical profile supports the denomination of “primordial” for this tumor.
Recently, somatic mutations of cancer-associated genes,
such as BRAF V600E (19), SMO (20), KRAS (21),
PTCH1 (22) and CTNNB1 (23,24), have been reported
in some benign odontogenic tumors and cysts. These
findings indicate that neoplastic proliferation of some
odontogenic tumors may be triggered by genetic alterations affecting oncogenic signaling pathways (25). As
odontogenic tumors are derived from the cells of the
tooth-forming apparatus and their remnants (2), the
evaluation of odontogenesis-associated genes is also
important to elucidate the pathogenesis of POT. The absence of immunoexpression of the mutant protein BRAF
V600E confirms that this mutation is not implicated in
the pathogenesis of POT, excluding it from the category
of the BRAF mutated ameloblastic tumors (17).
In the study of Mikami et al., [2018], no somatic mutations were detected when 151 cancer- and 42 odontogenesis-associated genes were examined, and the mRNA
expression level of odontogenesis-associated genes in
POT was determined by next-generation sequencing.
Nevertheless, the expression of the dentinogenesisassociated genes Bglap, Ibsp and Nfic was negative or
very weak, likely due to epigenetic silencing mechanisms, explaining the inhibition of dentin (and consequently, enamel) formation in POT (12).
In tooth germ development, DSPP is immunohistoe393
Med Oral Patol Oral Cir Bucal. 2020 May 1;25 (3):e388-94.
Primordial odontogenic tumor
chemically positive in preameloblasts and preodontoblasts (26). Although DSPP is immunoexpressed in the
epithelium and mesenchyme of POT, and DSPP mRNA
is also highly expressed, neither odontoblast differentiation nor the induction of dentin formation is morphologically observed (12,18).
In brief, with the data obtained by immunohistochemical and genetic studies, we can conclude the following:
POT is a benign, slow-growing odontogenic neoplasm,
which shows a low proliferation rate and moderate vascularization (17). The epithelial tissue surrounding the
tumor mass is nonstatic and shows varying degrees
of maturation, with a transition from an inner enamel
epithelium morphology to areas of ameloblastic maturation, but without evidence of induction leading to
mineralized tissue production (5,17). The subepithelial
area shows the expression of several proteins, suggesting that it is a highly active tumor region (17,18). The
pathogenesis of the tumor does not appear to be linked
with any type of known gene mutation; however, there
is an inhibition of enamel and dentin formation by the
downregulated expression of genes and proteins associated with dentinogenesis (12).
In summary, in this systematic review, we showed that
the 16 cases reported to date exhibit a well-defined profile of clinicopathologic, radiographic, immunohistochemical and molecular features. Despite the indolent
clinical course of POT, it is crucial to identify its highly
distinctive presentation to avoid misdiagnosis, mainly
in small incisional biopsies and subsequent overtreatment.
10. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group.
Preferred reporting items for systematic reviews and meta-analyses:
the PRISMA statement. Ann Intern Med. 2009;151:264-9.
11. Poomsawat S, Ngamsom S, Nonpassopon N. Primordial odontogenic tumor with prominent calcifications: A rare case report. J Clin
Exp Dent. 2019;11:e952-6.
12. Mikami T, Bologna-Molina R, Mosqueda-Taylor A, Ogawa I,
Pereira-Prado V, Fujiwara N, et al. Pathogenesis of primordial odontogenic tumour based on tumourigenesis and odontogenesis. Oral
Dis. 2018;24:1226-34.
13. Sun Q, Lee J-S, Kim O, Kim Y. Primordial odontogenic tumor: a
case report and literature review. Diagn Pathol. 2019;14:92.
14. Teixeira LN, Furuse C, Santos FP, Soares AB, de Oliveira EMF,
de Araújo NS, et al. The Challenging Diagnosis of Primordial Odontogenic Tumor. Case Rep Dent. 2019;2019:6415785.
15. Morimoto C, Tsujimoto M, Shimaoka S, Shirasu R, Takasu J.
Ultrastructural localization of alkaline phosphatase in the calcifying epithelial odontogenic tumor. Oral Surg Oral Med Oral Pathol.
1983;56:409-14.
16. Amm HM, Rollins DL, Ren C, Dong J, DeVilliers P, Rivera H,
et al. Establishment and characterization of a primary calcifying
epithelial odontogenic tumor cell population. J Oral Pathol Med.
2014;43:183-90.
17. Bologna-Molina R, Mikami T, Pereira-Prado V, Pires FR, Carlos-Bregni R, Mosqueda-Taylor A. Primordial odontogenic tumor:
An immunohistochemical profile. Med Oral Patol Oral Cir Bucal.
2017;22:e314-23.
18. Bologna-Molina R, Mikami T, Pereira-Prado V, Tapia-Repetto G,
Pires FR, Carlos R, et al. Primordial odontogenic tumor: Subepithelial expression of Syndecan-1 and Ki-67 suggests origin during early
odontogenesis. Oral Dis. 2018;24:72-7.
19. Kurppa KJ, Catón J, Morgan PR, Ristimäki A, Ruhin B, Kellokoski J, et al. High frequency of BRAF V600E mutations in ameloblastoma. J Pathol. 2014;232:492-8.
20. Sweeney RT, McClary AC, Myers BR, Biscocho J, Neahring L,
Kwei KA, et al. Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nat Genet. 2014;46:722-5.
21. Gomes CC, De Sousa SF, De Menezes GHF, Duarte AP, Dos
Santos Fontes Pereira T, Moreira RG, et al. Recurrent KRAS G12V
pathogenic mutation in adenomatoid odontogenic tumours. Oral Oncol. 2016;56:e3-5.
22. Qu J, Yu F, Hong Y, Guo Y, Sun L, Li X, et al. Underestimated
PTCH1 mutation rate in sporadic keratocystic odontogenic tumors.
Oral Oncol. 2015;51:40-5.
23. Sekine S, Sato S, Takata T, Fukuda Y, Ishida T, Kishino M, et al.
Beta-catenin mutations are frequent in calcifying odontogenic cysts,
but rare in ameloblastomas. Am J Pathol. 2003;163:1707-12.
24. Yukimori A, Oikawa Y, Morita K-I, Nguyen CTK, Harada H,
Yamaguchi S, et al. Genetic basis of calcifying cystic odontogenic
tumors. PLoS One. 2017;12:e0180224.
25. Diniz MG, Gomes CC, de Sousa SF, Xavier GM, Gomez RS.
Oncogenic signalling pathways in benign odontogenic cysts and tumours. Oral Oncol. 2017;72:165-73.
26. Bègue-Kirn C, Krebsbach PH, Bartlett JD, Butler WT. Dentin
sialoprotein, dentin phosphoprotein, enamelysin and ameloblastin:
Tooth-specific molecules that are distinctively expressed during murine dental differentiation. Eur J Oral Sci. 1998;106:963-70.
References
1. Mosqueda-Taylor A, Pires FR, Aguirre-Urízar JM, Carlos-Bregni R, de la Piedra-Garza JM, Martínez-Conde R, et al. Primordial
odontogenic tumour: clinicopathological analysis of six cases of a
previously undescribed entity. Histopathology. 2014;65:606-12.
2. El-Naggar A, Chan JK, Grandis JR, Takata T, Slootweg PJ.
WHO Classification of Head and Neck Tumours. 4th ed. Lyon:
IARC Press; 2017.
3. Ando T, Shrestha M, Nakamoto T, Uchisako K, Yamasaki S, Koizumi K, et al. A case of primordial odontogenic tumor: A new entity
in the latest WHO classification (2017). Pathol Int. 2017;67:365-9.
4. Slater LJ, Eftimie LF, Herford AS. Primordial Odontogenic Tumor: Report of a Case. J Oral Maxillofac Surg. 2016;74:547-51.
5. Mikami T, Ohashi Y, Bologna-Molina R, Mosqueda-Taylor A, Fujiwara N, Tsunoda N, et al. Primordial Odontogenic Tumor: A case
report with histopathological analyses. Pathol Int. 2017;67:638-43.
6. Pardhe N, Bajpai M. Primordial Odontogenic Tumor of Mandible; A Case with Proposed Diagnostic Criteria. Iran J Med Sci.
2018;43:97-9.
7. Amer H, Hafed L, Ibrahim S. Case Report: A Primordial odontogenic tumor. F1000Res. 2018;7:562.
8. Almazyad A, Li CC, Tapia ROC, Robertson JP, Collette D, Woo S
Bin. Primordial odontogenic tumour: report of two cases. Histopathology. 2018;72:1221-7.
9. Bomfim BB, Prado R, Sampaio RK, Conde DC, de Andrade BAB,
Agostini M, et al. Primordial Odontogenic Tumor: Report of a New
Case and Literature Review. Head Neck Pathol. 2019;13:125-30.
Funding
The present work was partially funded by the program “Grupos I+D,
Comisión Sectorial de Investigación Científica”, UDELAR, Uruguay.
Conflict of interest
The authors have no conflicts of interest to declare.
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