| |

Received: 6 June 2017    Revised: 10 June 2017    Accepted: 12 June 2017

DOI: 10.1111/odi.12702

P R O F S C U L LY M E M O R I A L I S S U E

Ameloblastoma—Clinical, radiological, and therapeutic findings

M Kreppel  | J Zöller

Department for Oral and Craniomaxillofacial

Plastic Surgery, University of Cologne, Ameloblastoma are the most common odontogenic tumor. As they usually do not form
Cologne, Germany metastasis, they are considered as benign tumors with a locally invasive growth pat-

Correspondence
Matthias Kreppel, Department for Oral and
Craniomaxillofacial Plastic Surgery, University
of Cologne, Cologne, Germany.
Email: mattheskreppel@yahoo.de
tern and destruction of the jaws and the surrounding tissue (Oral Diseases, 23, 2017,
199). This article focuses on clinical, radiological, and therapeutic findings, which may
influence diagnosis and treatment of ameloblastoma in the future.
KEYWORDS
ameloblastoma, B-RAF mutation, CBCT, prognosis

1 |  EPIDEMIOLOGY AND ETIOLOGY
FACTORS
With an annual incidence of 0.5 new cases in 1,000,000 people, am-
eloblastoma is considered to be a rare disease. However, there are
geographical differences: Higher incidences are found in Africa, China
and India in comparison with the Western World (McClary et al., 2016).
Generally, ameloblastomas are found at an age of 30-­60 years with
an average of 36 years and a peak around the fifth decade (Effiom,
Ogundana, Akinshipo, & Akintoye, 2017; Gundlach, 2000; McClary et al.,
2016). The male to female ratio is 1.2:1. Ameloblastomas account for 1%
of all head and neck tumors (Milman, Ying, Pan, & LiVolsi, 2016). With a
fraction of approximately 18%, ameloblastomas are the most common
type of odontogenic tumors (Reichart, Philipsen, & Sonner, 1995).
Ameloblastomas are derived from the epithelium involved in tooth
formation, the enamel organ. They were first described by Malassez in
1890 and named Adamantinoma (Baden, 1965). The term “ameloblas-
toma” was introduced in 1929 as the name Adamantinoma was mis-
leading, as ameloblastomas by definition do not produce any enamel.
Very little is known about potential risk factors so far. Occasionally
ameloblastomas are associated with follicular cysts and impacted and
ectopic teeth (Figure 1) (Shin, Choi, & Moon, 2016).
2 |  CLINICAL PRESENTATION AND
LOCALIZATION
Clinical presentation of an ameloblastoma is usually limited, and symp-
toms are non-­specific. They typically show a painless swelling of the
involved region of the jaw. Pain is usually caused by hemorrhage in the
adjacent soft tissue (Milman et al., 2016). Most often however, amelo-
blastomas are found by coincidence in radiographs taken for other
reasons (Esser, Horger, Ioanovicu, & Bosmuller, 2015). In comparison,
ameloblastic carcinomas present more often with pain, paresthesia,
and ulceration due to perineural tumor growth (Kallianpur, Jadwani,
Misra, & Sudheendra, 2014).
About 80% of all ameloblastomas are located in the mandi-
ble, mainly in the third molar region; 20% of ameloblastomas arise
in the maxilla, particularly in the posterior region (Gundlach, 2000;
Mendenhall, Werning, Fernandes, Malyapa, & Mendenhall, 2007).
Desmoplastic ameloblastomas, a rare subtype (2% of all ameloblasto-
mas), arise most frequently in the premolar and anterior regions of the
mandible and the maxilla (McClary et al., 2016).
3 | HISTOLOGICAL PATHOLOGY
Four different types of ameloblastoma are described in the WHO
classification for odontogenic tumors: The solid/multicystic type is
the most common type and accounts for 90% of all ameloblastomas.
Within this group, the plexiform and the follicular histological pat-
terns are found most frequently. The follicular type can show differ-
ent kinds of cytological differentiation such as granular, basal cell, and
spindle cell types (McClary et al., 2016; Milman et al., 2016). The gran-
ular cell type only accounts for 3.5% of ameloblastomas, but tends to
show the most aggressive biological behavior with high relapse rates
and a relatively high potential for metastasis (Babu, Sankari, Anitha, &
Mohideen, 2015).

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved

Oral Diseases. 2018;24:63–66. wileyonlinelibrary.com/journal/odi |  63

  
 |
64       KREPPEL and ZÖLLER
Other types of ameloblastoma are the unicystic type, extra-­
osseous-­peripheral type and the desmoplastic type (McClary et al.,
2016). The unicystic type is associated with a smaller risk of relapse
and is the only type that is susceptible for conservative surgery, as it
exhibits an intraluminal growth pattern and rarely infiltrates the sur-
rounding tissue (McClary et al., 2016).
4 |  RADIOLOGICAL PRESENTATION
In contrast to odontogenic cysts and due to the locally aggressive
growth, an infiltration of the surrounding soft tissue can be found
frequently. Radiological features of ameloblastoma are described as
unilocular or multilocular osteolytic lesions leading to a spacious thin-
ning and expansion of the cortical bone (Ariji et al., 2011). Sometimes
resorption of dental roots can be found. 3D imaging is considered
standard today (Figure 1). Various studies have shown advantages for
computed tomography, magnetic resonance tomography, and cone-­
beam computed tomography in comparison with panoramic radio-
graphs (Apajalahti, Kelppe, Kontio, & Hagstrom, 2015).
5 |  TREATMENT
Standard treatment for ameloblastoma today is radical resection with
1-­cm resection margins. Recurrence rates range from 0 to 15%. For
more aggressive types of ameloblastoma, such as the granular cell
type, even greater resection margins may be required (Hong et al.,
2007; Masthan, Anitha, Krupaa, & Manikkam, 2015; Milman et al.,
2016; Sham et al., 2009). Conservative surgery including enuclea-
tion and curettage yield recurrence rates as high as 55% (Almeida
Rde, Andrade, Barbalho, Vajgel, & Vasconcelos, 2016) and is only
F I G U R E   1   Ameloblastoma of the
mandible with an impacted and ectopic
tooth 38. Top left: Coronal section of the
ectopic tooth 38 and the ameloblastoma.
Top right: Panoramic view showing an
ameloblastoma in left posterior mandible.
Bottom left: Sagittal section of the
ectopic tooth 38 and the ameloblastoma.
Bottom right: Transversal section of the
ameloblastoma
considered feasible for unicystic ameloblastoma with a luminal growth
pattern (McClary et al., 2016). Apart from the possibly more aggres-
sive growth pattern, two other major problems are associated with
recurrent ameloblastoma: the development of metastasis, termed ma-
lignant ameloblastoma, and the transformation into an ameloblastic
carcinoma, both with rates of 2% in recurrent ameloblastoma (Hayashi
et al., 1997; Milman et al., 2016). Malignant ameloblastoma describes
ameloblastomas with metastases mainly located in the lungs, but with
the same cytological features as the original ameloblastoma. In con-
trast, an ameloblastic carcinoma exhibits all malignant cytological fea-
tures (Jayaraj et al., 2014).
6 | RECENT MOLECULAR PATHOGENIC
FINDINGS AND IMPLICATIONS FOR
TARGETED THERAPY
Very little is known about molecular risk factors for ameloblastoma.
Multiple genetic mutations can increase the risk of developing cancer
(Effiom et al., 2017). Under normal circumstances, cells have the abil-
ity to correct the mutations or to undergo apoptosis, unless these mu-
tations affect genes, which code for proteins with repair function. One
of these genes is the X-­ray repair cross-­complementing gene (XRCC-­
1), which encodes proteins involved in base excisional repair processes
(Hoeijmakers, 2001). Patch-­1 (PTCH-­1) is a gene involved in human
tooth development and in various types of cancer. Recent studies de-
scribed the XRCC-­1 and PTCH-­1 gene polymorphisms as risk factors
for the occurrence of ameloblastomas. For XRCC-­1, genetic polymor-
phisms at the codons 194 and 399 showed an increased risk of de-
veloping an ameloblastoma (Kawabata et al., 2005; Yanatatsaneejit,
Boonsuwan, Mutirangura, & Kitkumthorn, 2013). Another possible
mechanism contributing to tumorigenesis of ameloblastoma seems
KREPPEL and ZÖLLER
to be DNA hypomethylation of transcription related genes. A recent
study showed a lower methylation rate significantly of the promoter
region of BCL-­2 in ameloblastomas in comparison with regular dental
follicles (Costa et al., 2017).
A lack of knowledge of the molecular biology of ameloblastomas
has inhibited the introduction of targeted therapies to their treat-
ment scheme (Ohta et al., 2017). Recently, a number of oncogenic
mutations that are linked to the activation of signal transduction
pathways, which are similar to different developmental stages of
odontogenesis, have been identified by next-­generation sequencing.
The most common genetic mutations found were the BRAF-­V600E
mutation causing an activation of the mitogen-­activated-­protein-­
kinase pathway and an SMO mutation leading to an activation of a
hedgehog pathway (Kurppa et al., 2014; Sweeney et al., 2014). Up to
64% of all ameloblastoma show the BRAF-­V600E mutation (Kurppa
et al., 2014). This mutation is also found in other malignant tumors
such as melanoma, papillary thyroid cancer, and colorectal cancer
(Brown & Betz, 2015). The mutation of BRAF-­V600E results in over-
expression of the BRAF protein resulting in the activation of extra-
cellular signal-­regulated kinase signaling further down the pathway
resulting in activation of transcriptional factors leading to malignant
transformation and growth (Brown & Betz, 2015). Patients display-
ing a BRAF-­V600E mutation may be eligible for target therapy using
a combination of dabrafenib ((BRAF inhibitor) and trametinib (MEK
inhibitor). Case reports have shown excellent responses to this treat-
ment even after formation of metastasis in malignant ameloblastoma
(Brown & Betz, 2015). Although not yet confirmed in larger studies,
this may be a treatment option for the future that might spare rad-
ical surgery and thus reduce the treatment-­associated morbidity in
patients with ameloblastomas.
CO NFLI CT OF I NTE RE ST
The author reports no financial disclosure and no conflicts of interest.
AUT HOR CONTRI B UTI O N
Matthias Kreppel and Joachim Zöller have designed and written this
paper together.
REFERENCES
Almeida Rde, A., Andrade, E. S., Barbalho, J. C., Vajgel, A., & Vasconcelos,
B. C. (2016). Recurrence rate following treatment for primary multicys-
tic ameloblastoma: Systematic review and meta-­analysis. International
Journal of Oral and Maxillofacial Surgery, 45, 359–367.
Apajalahti, S., Kelppe, J., Kontio, R., & Hagstrom, J. (2015). Imaging char-
acteristics of ameloblastomas and diagnostic value of computed to-
mography and magnetic resonance imaging in a series of 26 patients.
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 120,
e118–e130.
Ariji, Y., Morita, M., Katsumata, A., Sugita, Y., Naitoh, M., Goto, M., … Ariji,
E. (2011). Imaging features contributing to the diagnosis of ameloblas-
tomas and keratocystic odontogenic tumours: Logistic regression anal-
ysis. Dento Maxillo Facial Radiology, 40, 133–140.
|
      65
Babu, N. A., Sankari, S. L., Anitha, N., & Mohideen, G. (2015). Aggressive
granular cell ameloblastoma: Report of a rare case. Journal of Pharmacy
& Bioallied Sciences, 7, S276–S278.
Baden, E. (1965). Terminology of the ameloblastoma: History and current
usage. Journal of Oral Surgery, 23, 40–49.
Brown, N. A., & Betz, B. L. (2015). Ameloblastoma: A review of recent mo-
lecular pathogenetic discoveries. Biomarkers in Cancer, 7, 19–24.
Costa, S., Pereira, N. B., Pereira, K., Campos, K., de Castro, W. H., Diniz,
M. G., … Gomez, R. S. (2017). DNA methylation pattern of apoptosis-­
related genes in ameloblastoma. Oral Diseases, http://doi.org/10.1111/
odi.12661.
Effiom, O. A., Ogundana, O. M., Akinshipo, A. O., & Akintoye, S. O. (2017).
Ameloblastoma: Current etiopathological concepts and management.
Oral Diseases, http://doi.org/10.1111/odi.12646.
Esser, M., Horger, M., Ioanovicu, S. D., & Bosmuller, H. (2015). Imaging di-
agnosis of ameloblastoma. Rofo, 187, 847–852.
Gundlach, K. H. (2000). Odontogene tumoren. Mund-­, Kiefer-­und
Gesichtschirurgie, 4, S187–S195.
Hayashi, N., Iwata, J., Masaoka, N., Ueno, H., Ohtsuki, Y., & Moriki, T.
(1997). Ameloblastoma of the mandible metastasizing to the orbit with
malignant transformation. A histopathological and immunohistochemi-
cal study. Virchows Archiv, 430, 501–507.
Hoeijmakers, J. H. (2001). Genome maintenance mechanisms for prevent-
ing cancer. Nature, 411, 366–374.
Hong, J., Yun, P. Y., Chung, I. H., Myoung, H., Suh, J. D., Seo, B. M., …
Choung, P. H. (2007). Long-­term follow up on recurrence of 305 ame-
loblastoma cases. International Journal of Oral and Maxillofacial Surgery,
36, 283–288.
Jayaraj, G., Sherlin, H. J., Ramani, P., Premkumar, P., Natesan, A.,
Ramasubramanian, A., & Jagannathan, N. (2014). Metastasizing
Ameloblastoma -­ a perennial pathological enigma? Report of a case and
review of literature. Journal of Cranio-­Maxillo-­Facial Surgery, 42, 772–779.
Kallianpur, S., Jadwani, S., Misra, B., & Sudheendra, U. S. (2014).
Ameloblastic carcinoma of the mandible: Report of a case and review.
Journal of Oral and Maxillofacial Pathology, 18, S96–S102.
Kawabata, T., Takahashi, K., Sugai, M., Murashima-Suginami, A., Ando, S.,
Shimizu, A., … Iizuka, T. (2005). Polymorphisms in PTCH1 affect the risk
of ameloblastoma. Journal of Dental Research, 84, 812–816.
Kurppa, K. J., Caton, J., Morgan, P. R., Ristimaki, A., Ruhin, B., Kellokoski, J.,
… Heikinheimo, K. (2014). High frequency of BRAF V600E mutations in
ameloblastoma. The Journal of Pathology, 232, 492–498.
Masthan, K. M., Anitha, N., Krupaa, J., & Manikkam, S. (2015).
Ameloblastoma. Journal of Pharmacy & Bioallied Sciences, 7, S167–S170.
McClary, A. C., West, R. B., McClary, A. C., Pollack, J. R., Fischbein, N. J.,
Holsinger, C. F., … Sirjani, D. (2016). Ameloblastoma: A clinical review
and trends in management. European Archives of Oto-­Rhino-­Laryngology,
273, 1649–1661.
Mendenhall, W. M., Werning, J. W., Fernandes, R., Malyapa, R. S., &
Mendenhall, N. P. (2007). Ameloblastoma. American Journal of Clinical
Oncology, 30, 645–648.
Milman, T., Ying, G. S., Pan, W., & LiVolsi, V. (2016). Ameloblastoma: 25
Year Experience at a Single Institution. Head and Neck Pathology, 10,
513–520.
Ohta, K., Naruse, T., Ishida, Y., Shigeishi, H., Nakagawa, T., Fukui, A., …
Takechi, M. (2017). TNF-­alpha-­induced IL-­6 and MMP-­9 expression
in immortalized ameloblastoma cell line established by hTERT. Oral
Diseases, 23, 199–209.
Reichart, P. A., Philipsen, H. P., & Sonner, S. (1995). Ameloblastoma:
Biological profile of 3677 cases. European Journal of Cancer. Part B, Oral
Oncology, 31B, 86–99.
Sham, E., Leong, J., Maher, R., Schenberg, M., Leung, M., & Mansour, A. K.
(2009). Mandibular ameloblastoma: Clinical experience and literature
review. ANZ Journal of Surgery, 79, 739–744.
Shin, S. M., Choi, E. J., & Moon, S. Y. (2016). Prevalence of pathologies re-
lated to impacted mandibular third molars. Springerplus, 5, 915.
 |
66       KREPPEL and ZÖLLER

Sweeney, R. T., McClary, A. C., Myers, B. R., Biscocho, J., Neahring, L., Kwei,
K. A., … West, R. B. (2014). Identification of recurrent SMO and BRAF How to cite this article: Kreppel M, Zöller J. Ameloblastoma—
mutations in ameloblastomas. Nature Genetics, 46, 722–725. Clinical, radiological, and therapeutic findings. Oral Dis.
Yanatatsaneejit, P., Boonsuwan, T., Mutirangura, A., & Kitkumthorn, N.
2018;24:63–66. https://doi.org/10.1111/odi.12702
(2013). XRCC1 gene polymorphisms and risk of ameloblastoma.
Archives of Oral Biology, 58, 583–589.