the surgeon xxx (xxxx) xxx

Ameloblastoma: A succinct review of the

classification, genetic understanding and novel
molecular targeted therapies

Hongyi Adrian Shi*, Chee Wee Benjamin Ng, Chong Teck Kwa,
Qiu Xia Chelsia Sim
Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore

article info abstract

Article history: Ameloblastomas are benign but locally invasive neoplasms which may grow to massive
Received 15 May 2020 proportions and cause significant morbidity. Although some types of ameloblastoma can
Accepted 15 June 2020 be treated predictably with aggressive surgical treatment, recurrent ameloblastoma and
Available online xxx metastasising ameloblastoma are still difficult to treat. Recent studies have identified
recurrent somatic and activating mutations in the mitogen-activated protein kinase
Keywords: (MAPK) and sonic hedgehog (SHH) signalling pathways in ameloblastoma. This develop-
Ameloblastoma ment provided a possibility that molecular targeted therapies can be used as neoadjuvant
Odontogenic tumours treatment. In this review, we provide a summary of the latest WHO classification of
Immunohistochemistry ameloblastoma, the current understanding of genetic mutations and novel molecular
BRAF targeted therapies arising from the recent developments.
Molecular targeted therapy © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and
Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Introduction Classification of ameloblastoma

Ameloblastomas are benign but locally invasive neoplasms.1
It is an epithelial neoplasm arising from enamel organ, rem-
nants of the dental lamina, the lining of an odontogenic cyst,
or possibly from the basal epithelial cells of the oral mucosa.2
Ameloblastoma constitutes 1e3% of all tumours and cysts of
the jaws, with 80% occurring in the mandible and 20% in the
maxilla.3,4 It often presents as a slow-growing, asymptomatic
swelling which causes expansion and/or perforation of
cortical bone. If left untreated, ameloblastoma may grow to
massive proportions and cause facial deformity.
The World Health Organisation (WHO) updated its classi-
fication of ameloblastoma in 2017.5,6 Recent studies have also
provided a breakthrough in the understanding of the genetic
mutations in ameloblastoma and a possibility that molecular
targeted therapies can be used as neoadjuvant treatment.7e9
In this review, we will provide a summary of the update in
the WHO classification of ameloblastoma, the current under-
standing of genetic mutations and novel molecular targeted
therapies arising from the recent developments.
* Corresponding author. 5 Second Hospital Avenue, 168938,
Singapore.
E-mail address: adrian.shi.h.y@ndcs.com.sg (H.A. Shi).
https://doi.org/10.1016/j.surge.2020.06.009
1479-666X/© 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland.
Published by Elsevier Ltd. All rights reserved.
In the previous edition of classifications published in 2005,
WHO divided ameloblastoma into four types and used the
terms: solid/multicystic, unicystic, extraosseous/peripheral
and desmoplastic. Amongst other changes in 2017, the WHO
discontinued the use of the term solid/multicystic5 because
most conventional ameloblastomas show cystic degeneration
with no biologic difference in behaviour.6
Despite its distinctive histological appearance, desmo-
plastic type of ameloblastoma also does not exhibit behaviour
different from the other histologic variants. Therefore, sepa-
rate use of this term has been discontinued and the desmo-
plastic ameloblastoma is grouped together with the other
histologic variants including the follicular, plexiform, acan-
thomatous, granular cell and basaloid types.
Peripheral ameloblastoma and unicystic ameloblastoma
both exhibit distinct behavioural and clinic-pathological
characteristics from ameloblastomas; they are retained as
subtypes of ameloblastoma.
Unicystic ameloblastoma continues to be described as
having three histological variants: luminal, intraluminal and
mural variants.
The WHO naming convention has therefore been simplified
to conventional ameloblastoma, unicystic ameloblastoma,

Please cite this article as: Shi HA et al., Ameloblastoma: A succinct review of the classification, genetic understanding and novel
molecular targeted therapies, The Surgeon, https://doi.org/10.1016/j.surge.2020.06.009
2 the surgeon xxx (xxxx) xxx
extraosseous/peripheral ameloblastoma and metastasising
(malignant) ameloblastoma. The new classification is shown in
Table 1.
The odontoameloblastoma has been removed from the
new classification because of a lack of evidence that it repre-
sents a true mixed neoplasm of odontogenic epithelium and
mesenchymal tissues. Metastasising ameloblastoma has also
been moved from the section on ameloblastic carcinomas to a
type of benign conventional ameloblastoma. It is now clearly
defined as a histologically benign typical ameloblastoma
which metastasises to distant sites.
Genetic mutations in ameloblastoma
Recent genetic studies using tumour tissue, cell lines, and
transgenic mice have shown several genetic mutations in
ameloblastoma. The studies identified recurrent somatic
and activating mutations in the mitogen-activated protein
kinase (MAPK)10 and sonic hedgehog (SHH) signalling
pathways.11
Mutations in MAPK pathway identified in ameloblastoma
include the BRAF, RAS and fibroblast growth factor receptor 2
(FGFR2) genes.7,8,12 These mutations have previously been
detected in other tumours, most notably, in malignant mela-
noma.13 Collectively, approximately 79% of ameloblastoma
show BRAF, RAS and FGFR2 mutations.5
BRAF is a serine/threonine protein kinase which activates
downstream signalling and increases cell proliferation, sur-
vival and neoplastic transformation.14 This mutation is a
crucial component in the pathogenesis of odontogenic tu-
mours with an ameloblastomatous component.9 Kurppa et al.
first described a high frequency of BRAF mutations when they
revealed that 15 out of 24 samples (63%) showed BRAF 600E
mutations.7 Subsequently, more studies found similarly high
occurrence of BRAF V600E and wild-type mutations in ame-
loblastoma.8,12 The BRAF V600E mutation involves a substi-
tution of valine for glutamate at codon 600. The incidence of
the BRAF V600E mutation ranged from 43% to 82% of the tu-
mours studied.7,8,10,12,15e19
Brown et al. found that BRAF mutation is present in 88% of
their cases.8 The authors noted that 62% of the mutations are
BRAF V600E and these patients have a younger age of onset
(mean 34.5 years) compared to BRAF wild-type cases (mean
Table 1 e Classification of Ameloblastoma in WHO 2017 update.5,6
Classification of Ameloblastoma
Conventional Unicystic
Ameloblastoma Ameloblastoma
Histological Variants: Histological Variants:
 Acanthomatous  Luminal
 Basaloid  Intraluminal
 Desmoplastic  Mural
 Follicular
 Granular cell
 Plexiform
Please cite this article as: Shi HA et al., Ameloblastoma: A succinct review of the classification, genetic understanding and novel
molecular targeted therapies, The Surgeon, https://doi.org/10.1016/j.surge.2020.06.009
53.6 years). Ameloblastomas with BRAF wild-type mutations
also occurred more frequently in the maxilla than the
mandible and suffered earlier recurrences.10
RAS is a gene that acts upstream of BRAF while FGFR2 is a
membrane-bound activator of MAPK signalling. RAS and FGFR2
mutations occurred in 28% of the ameloblastoma studied.5
Mutations in the SHH signalling pathway identified in
ameloblastoma include the smoothened (SMO) gene. SMO
encodes a G protein-coupled receptor and is a signalling
effector component of the SHH signalling pathway.11,16 A
study by Gültekin et al. analysed 62 patients with amelo-
blastoma, and genetic mutations were identified in 92% of
these patients.16 SMO mutations were detected in 14% of the
patients while 60% of the patients had BRAF V600E mutation.
Sweeney et al. examined 28 ameloblastomas and found
that 39% had SMO mutations, and 46% had BRAF muta-
tions.12 Their study also showed that SMO and BRAF muta-
tions tended to be mutually exclusive with only one case
showing both mutations. SMO mutations predominated in
the maxilla (57%), while BRAF mutations occurred mainly in
the mandible (75%). SMO mutation also appears to be asso-
ciated with higher recurrence of ameloblastoma. It can be
postulated that having a SMO mutation might confer a
poorer prognosis in patients with ameloblastoma.8 However,
with the current evidence available, it cannot be determined
if SMO and BRAF mutations correspond to specific histologic
subtypes of ameloblastoma.
Heikinheimo et al. reported that BRAF V600E mutation was
found in all three histopathological subtypes of unicystic
ameloblastoma and with a similar frequency as conventional
ameloblastoma.20 In their sample, 94% (29 out of 31 cases) of
mandibular unicystic ameloblastomas had BRAF V600E mu-
tation while only 33.3% (1 out of 3 cases) of the maxillary
unicystic ameloblastomas had BRAF V600E mutation. One of
the mandibular unicystic ameloblastoma harboured a SMO
mutation while the other one showed no mutation. The au-
thors also did not find RAS and FGFR2 mutations in their
unicystic ameloblastoma cases, although they were present in
conventional ameloblastoma cases. Another study by Pereira
et al. found that 62.5% of the mandibular unicystic amelo-
blastoma showed BRAF V600E mutation and none of them had
a mutation in SMO.21 Taken together, the data suggest that
BRAF V600E mutation is more common than SMO mutation in
unicystic ameloblastoma.
Extraosseous/Peripheral Metastasising
Ameloblastoma (Malignant)
Ameloblastoma
Histological Variants: Histological Variants:
Same as conventional Same as conventional
ameloblastoma ameloblastoma
 the surgeon xxx (xxxx) xxx
Treatment of ameloblastoma
To date, surgery is the standard treatment for amelo-
blastomas. The ideal surgical option is resection as conser-
vative surgical methods such as enucleation have an
unacceptably high recurrence rate.22 Resection involves en
bloc tumour removal with a wide bone margin and immediate
or delayed bony reconstruction of the defect with tissue grafts
and/or prosthetic rehabilitation. Albeit being the current
standard of care, this “radical” treatment approach can cause
a high degree of morbidity in patients. Despite this, the risk of
recurrences still exists.23 Recurrent ameloblastoma can be
difficult to treat especially if it recurs at an anatomical region
with limited surgical access or is detected late.
Conventional ameloblastoma in the mandible is usually
treated with a segmental resection which includes 1e2 cm
bone margins and at least one adjacent uninvolved anatomic
barrier for proper margins. Segmental resection of the
mandible results in a discontinuity defect, which is usually
reconstructed with a free fibula flap (Fig. 1) to restore bone
continuity and allowing for soft tissue coverage with the skin
paddle where there is soft tissue defect after wide excision of
overlying mucosa in cases of cortical perforation. In addition,
the fibula also allows for the placement of dental implants for
oral rehabilitation.
Conventional ameloblastoma in the maxilla can be resec-
ted via various midface approaches, depending on the size of
the lesion, with the resultant defect a unification of the oral
cavity, paranasal sinuses, and/or nasal cavity, causing alter-
ations in speech, mastication and deglutition. These defects
are commonly not reconstructed with a free flap but are fitted
Figure 1 e Right mandibular ameloblastoma. (A)
Preoperative panoramic radiograph. (B) Postoperative
panoramic radiograph after resection and reconstruction
with a free fibula flap.
Please cite this article as: Shi HA et al., Ameloblastoma: A succinct review of the classification, genetic understanding and novel
molecular targeted therapies, The Surgeon, https://doi.org/10.1016/j.surge.2020.06.009
3
with an obturator, to allow for easy access for clinical sur-
veillance of a potential recurrence site. Maxillary amelo-
blastoma behaves more aggressive clinically in terms of
disease extent and recurrence than its mandibular counter-
part as it is believed that the relatively thinner maxillary bone
barely affords a weak wall of defence against local spread. It
may not be possible to resect the tumour if there is extension
into vital structures such as the skull base, orbit and paranasal
sinuses (Fig. 2).
The unicystic ameloblastoma is a distinct type of amelo-
blastoma which has different clinical, radiological and histo-
pathological features from conventional ameloblastoma.24
Although luminal and intraluminal variants of unicystic
ameloblastoma are amenable to conservative surgical treat-
ment with low recurrence rate of under 10%, the mural variant
has a high recurrence after conservative surgical treatment
similar to conventional ameloblastoma.25,26 Therefore, the
mural variant of unicystic ameloblastoma requires a more
aggressive surgical management.
Peripheral ameloblastomas, which accounts for 1% of
ameloblastoma cases are amenable to conservative surgical
treatment and show low recurrence rates.27e29
Metastasising ameloblastoma is extremely rare, and there
is currently no established treatment protocol.30 Despite its
benign nature, it can develop metastases to the lungs and
cervical lymph nodes. Attempts at non-surgical treatment
methods using adjuvant radiotherapy with or without
chemotherapy for positive margins of recurrent following re-
sections of recurrent tumours or in patients with unresectable
ameloblastomas have yielded unpredictable outcomes.31
Moreover, the possible risks and sequelae of radiotherapy
must also be considered such as the risks of developing
radiation-induced malignancies and osteoradionecrosis.23
Discovery and elucidation of the activated molecular
pathways discussed in the previous section highlighted the
potential for novel molecular targeted therapies in the man-
agement of ameloblastoma with genetic mutations. The key
benefit of molecular targeted therapies is that it can signifi-
cantly reduce the surgical morbidity seen in resection surgery,
recurrent ameloblastoma and metastasising ameloblastoma.
The drugs which have potential to be used in molecular
targeted therapies of ameloblastoma are those which inhibit
the functions of mutated BRAF and MEK.22 These are vemur-
afenib and dabrafenib, which inhibit mutated BRAF gene;
trametinib, which inhibits the mutated MEK gene; and pona-
tinib and regorafenib which inhibit the mutated FGFR2 genes.
The US Food and Drug Administration has approved three
molecular targeted therapies for BRAF V600E mutation:
vemurafenib and dabrafenib for BRAF mutation and trameti-
nib for MEK mutation.32,33 Vemurafenib and dabrafenib have
also been used successfully in molecular targeted treatment
of melanomas with BRAF V600E mutations.34,35
In vitro studies involving ameloblastomas have also shown
that vemurafenib was effective in the deactivation of the
MAPK signalling pathway and proliferation of ameloblastic
cells with BRAF V600E mutation.8 Apart from in vitro studies,
there are a handful of case reports which reported clinical
effectiveness of using BRAF and/or MEK inhibitors for patients
with BRAF V600E mutations. The six reported cases are sum-
marised in Table 2.
4 the surgeon xxx (xxxx) xxx

Figure 2 e Right unresectable maxillary ameloblastoma (desmoplastic variant) with significant extension. (A) Panoramic
radiograph. (B) Computed tomography (CT) axial view showing maxillary sinus wall perforation and expansion. (C) CT
coronal view showing obliteration of right maxillary sinus. (D) CT coronal view showing extension to middle cranial fossa,
nasopharynx, sphenoid sinus, sellar and right parasellar regions.

Half of the six cases reported in literature using these novel
molecular targeted therapy was performed on patients with
recurrent ameloblastoma36e38 while the other half was for
metastasising ameloblastoma.39e41 Interestingly, all six cases
presented with ameloblastoma in the mandibles. Four cases
used single-agent therapy, while two cases used dual-agent
therapy. All cases showed significant shrinkage and
improvement in symptoms after a treatment period of be-
tween 16 weeks and 26 months. Tan et al. reported a case in
which molecular targeted neoadjuvant therapy was used to
achieve tumour size reduction of >90% after 16 weeks and the
patient underwent subsequent radical resection of the

Table 2 e Summary of case reports using BRAF and/or MEK inhibitors for Ameloblastomas with BRAF V600E mutation.
Authors Age Gender Type of Location Genetic Targeted Drugs Outcome
Ameloblastoma Mutation Therapy
Fernandes 29 Female Ameloblastoma Mandible BRAF V600E Single-agent Vemurafenib Complete resolution
et al.36 (Recurrent) of symptoms and
shrinkage of tumour
after 11 months
Tan et al.37 85 Male Ameloblastoma Mandible BRAF V600E Single-agent Dabrafenib Shrinkage of tumour
(Recurrent) (>90%) after 16
weeks and a
resection of the
remaining tumour
was performed
Faden et al.38 83 Female Ameloblastoma Mandible BRAF V600E Single-agent Dabrafenib Significant shrinkage
(Recurrent) of tumour after 12
months
Broudic- 33 Female Metastasising Mandible with lung BRAF V600E Single-agent Vemurafenib Improvement of
Guibert ameloblastoma metastases symptoms and
et al.39 persistent shrinkage
of tumour and
metastases after 26
months
Kaye et al.40 40 Male Metastasising Mandible with neck BRAF V600E Dual-agent Dabrafenib, Complete resolution
ameloblastoma and lung metastases Trametinib of symptoms and
shrinkage of tumour
and metastases after
20 weeks
Brunet et al.41 26 Female Metastasising Mandible with lung BRAF V600E Dual-agent Dabrafenib, Complete remission
ameloblastoma metastases Trametinib after 30 weeks

Please cite this article as: Shi HA et al., Ameloblastoma: A succinct review of the classification, genetic understanding and novel
molecular targeted therapies, The Surgeon, https://doi.org/10.1016/j.surge.2020.06.009
 the surgeon xxx (xxxx) xxx
remaining lesion.37 The authors concluded that molecular
targeted neoadjuvant therapy for ameloblastoma might be
useful in certain clinical settings of primary ameloblastoma
which could alter the extent of the surgery and when surgical
options are initially limited due to the size of the tumours.
From the literature available, results of molecular targeted
therapies using BRAF and/or MEK inhibitors in ameloblastoma
with BRAF V600E mutations appear to be promising.
The downside to molecular targeted therapies with BRAF
inhibitors is that acquired resistance can develop quickly.
Treatment with BRAF inhibitors alone as single-agent inhibi-
tor therapy can cause the development of resistance through
compensatory activation of the MAPK pathway by epidermal
growth factor receptor and may cause the development of
skin tumours.7,42,43 It has been found that dual-agent inhibitor
therapy with a combination of a BRAF inhibitor and MEK in-
hibitor can delay the development of resistance and reduce
the incidence of BRAF inhibitor-induced skin tumours.44,45
There is currently no evidence available which compares
the effectiveness of single-agent and dual-agent inhibitor
therapy in molecular targeted treatment of ameloblastoma.
From the case reports, there seems to be a preference for dual-
agent inhibitor therapy for metastasising ameloblastoma.
Molecular targeted therapy using SMO inhibitors, such as
vismodegib and itraconazole, have been less successful due to
resistance mechanisms that block the binding of SMO-
targeted drugs.11,12 Drugs inhibiting the SHH signalling
pathway, such as arsenic trioxide and cyclopamine, appear to
be more effective when compared to SMO inhibitors.12 How-
ever, cyclopamine, the most widely used SHH antagonist, can
inhibit osteoblast proliferation and differentiation which af-
fects bone healing.46 This side effect can be particularly
detrimental to the treatment of pathologies in the jaw. The
use of SMO and SHH inhibitors in ameloblastoma patients has
not been reported.
Conclusion
In this review, a summary of the update in the latest WHO
classification of ameloblastoma, the current understanding of
genetic mutations involved and novel molecular targeted
therapies are reported. From the limited literature available,
molecular targeted therapies using BRAF and/or MEK in-
hibitors in ameloblastoma with BRAF V600E mutations appear
to be an effective treatment modality. There is currently no
evidence available which compares the effectiveness of
single-agent and dual-agent inhibitor therapy in molecular
targeted treatment of ameloblastoma.
Funding
No grants.
Authors declaration
All authors have viewed and agreed to the submission.
Please cite this article as: Shi HA et al., Ameloblastoma: A succinct review of the classification, genetic understanding and novel
molecular targeted therapies, The Surgeon, https://doi.org/10.1016/j.surge.2020.06.009
5
Declaration of Competing Interest
The authors declare no competing interest.
Acknowledgements
The authors thank Miss Safiyya Mohamed Ali for her assis-
tance with editing of this manuscript.
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