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Eur Arch Otorhinolaryngol

DOI 10.1007/s00405-016-3899-3

HEAD AND NECK

Treatment of ameloblastoma and ameloblastic carcinoma


with radiotherapy
William R. Kennedy1 John W. Werning2 Frederic J. Kaye3 William M. Mendenhall1

Received: 12 August 2015 / Accepted: 7 January 2016


Springer-Verlag Berlin Heidelberg 2016

Abstract The purpose of this study is to report our


institutional experience using radiotherapy in the treatment
of ameloblastoma and ameloblastic carcinoma. Three
patients with ameloblastoma and 3 patients with
ameloblastic carcinoma were treated with radiotherapy
alone (2 patients) or surgery and postoperative radiotherapy (4 patients) at the University of Florida between 1973
and 2007. Follow-up ranged from 4.0 to 13.1 years with a
median of 7.8 years. Radiotherapy complications were
scored using the Common Terminology Criteria for
Adverse Events, version 4.0. Local control was achieved in
4 of the 6 patients. One patient treated with RT alone for an
unresectable ameloblastoma developed a local recurrence
and metastases in both the cervical lymph nodes and lungs,
but had excellent response to dual BRAF/MEK inhibition
with dabrafenib and trametinib. Another patient treated
with surgery and postoperative radiotherapy for an
ameloblastic carcinoma recurred locally without metastasis, but was not salvaged. No significant treatment-related
complications were observed. For patients with local
recurrence or inadequate margins after surgery, adjuvant
radiotherapy provides the potential for disease control. In
the setting of metastatic disease, targeted therapies may
provide an additional opportunity for salvage.

& William M. Mendenhall


mendwm@shands.ufl.edu
1

Department of Radiation Oncology, University of Florida


College of Medicine, 2000 SW Archer Rd.,
PO Box 100385, Gainesville, FL 32610-0385, USA

Department of Otolaryngology, University of Florida College


of Medicine, Gainesville, FL, USA

Department of Medicine, University of Florida College of


Medicine, Gainesville, FL, USA

Keywords
therapy

Head and neck  Outcomes  Radiation

Introduction
Ameloblastomas are rare benign tumors that comprise
approximately 19 % of all odontogenic neoplasms. Behind
odontomas, they are the second most common tumor in the
odontogenic family of tumors. They are slow-growing,
locally invasive tumors that arise primarily from the molarramus region of the mandible (80 %), with almost all
remaining cases occurring in the maxilla [1]. There have
been rare reports of tumors arising from soft tissues as well,
representing 2 % of cases, designated peripheral
ameloblastomas [2].
These tumors typically manifest as a painless swelling
mass of the mandible or maxilla. Less common presenting symptoms include paresthesias and tooth displacement. A history of a painful lesion exhibiting rapid
growth is more suggestive of ameloblastic carcinomas.
As these tumors arise from the bone itself, ameloblastomas may present incidentally via routine dental
X-rays, up to one-third of the time in one series [3].
These tumors typically arise in middle adulthood, with a
median age of 35 years with no apparent sex predilection, although these tumors most likely begin growing
many years prior as there have been reports of diagnosis
in children as young as 12 years [4]. The risk of
developing these tumors is fivefold greater among
African Americans than among whites [5].
While several theories have been presented suggesting
the origin of these tumors, ameloblastomas likely arise
from enamel epithelium and the ectomesenchymal cells
that play an important role in odontogenesis. They are

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Eur Arch Otorhinolaryngol

composed of a central stellate reticulum and a peripheral


layer of vacuolated columnar epithelial cells, known as
reserve cells. The World Health Organization (WHO)
divides ameloblastoma into 4 variants in the current 2005
classification system, with the solid/multicystic type comprising over 90 % of cases, and the unicystic, extraosseous,
and desmoplastic ameloblastomas representing the
remaining cases [6]. Of note, the unicystic type exhibits
lower rates of recurrence compared to the other 3 members
within this group [7].
While ameloblastomas are generally considered to be
benign, approximately 2 % exhibit malignant behavior and
are classified as either ameloblastic carcinoma or malignant
ameloblastoma [8]. Ameloblastic carcinoma is histologically distinguishable from ameloblastoma in that it exhibits
malignant epidermoid features. Conversely, malignant
ameloblastoma primaries and distant metastases are characterized by benign features identical to ameloblastoma.
Malignant ameloblastoma and ameloblastic carcinoma
have a tendency to metastasize to the lung in 75 % of
cases, followed by bone, the liver, and, least commonly,
the brain with a median disease-free interval from diagnosis to first metastasis of 918 years, depending on the
series; regional metastases to lymph nodes are also known
to occur in some cases [9, 10].
The mainstay of treatment is surgical management via
wide local excision with 1.5- to 2-cm margins for the
most common solid/multicystic type and 2- to 3-cm
margins for ameloblastic carcinoma. Depending on the
extent of disease, surgery may require a marginal
mandibulectomy, segmental mandibulectomy, or partial
maxillectomy [11]. More conservative surgical efforts
such as enucleation and curettage have been employed in
an effort to minimize morbidity, but the local recurrence
rates are at least 65 % using conservative approaches as
opposed to 11 % with wide local excision methods
according to a recent review of pooled surgical data
encompassing 818 patients [12]. Although initially
believed to be radioresistant tumors, radiotherapy (RT)
for ameloblastoma may be utilized in patients with postsurgical microscopic or gross residual disease, poor surgical candidates, or those with disease not amenable to reresection. In addition to RT, a variety of chemotherapies
have been evaluated in the settings of metastatic disease,
with either no response or partial responses being
achieved following treatment with regimens including
platinum-based agents [1].
The aim of our study is to update our current institutional experience with RT in the management of patients
with ameloblastomas and ameloblastic carcinomas, and to
review the relevant body of literature to date [13].

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Materials and methods


In accordance with an institutional review board-approved
protocol and the Health Insurance Portability and
Accountability Act, we retrospectively reviewed the medical records of 6 consecutive patients who received RT at
the University of Florida for either ameloblastoma or
ameloblastic carcinoma. All 6 patients were treated with
curative intent with either RT alone (2 patients) after previous operations at outside institutions or following surgery
at the University of Florida (4 patients) between 1973 and
2007. A tissue diagnosis was available in all patients. Two
patients had mandibular lesions, while four had primaries
arising from the maxilla. All but one patient was treated
after a recurrence despite one or more operations. No
patient in our series presented with regional nodal
involvement or distant metastatic disease. Upon presenting
at our institution, four patients underwent resection. Margins were close in two and microscopically positive in the
other four. One elderly patient was treated with RT alone
for a locally advanced recurrent maxillary ameloblastic
carcinoma, and another young patient was treated with RT
alone for an unresectable lesion following several resections. Three patients received RT with once-daily fractionation, two patients received twice-daily fractionation
with a minimum of 6 h between fractions, and 1 patient
was treated with a combination of once- and twice-daily
fractionation. Altered fractionation, particularly hyperfractionation, has been employed at our facility since 1978
to treat patients with head and neck cancer [14]. The
rationale is to intensify the RT without increasing the risk
of late complications. The decision whether to treat once
daily or with altered fractionation was at the discretion of
the attending physician. One of these patients was treated
with intensity-modulated radiotherapy (IMRT). The median radiation dose was 66.2 Gy (range 6374.4 Gy).
Follow-up was calculated from the date that the patient
began RT. Patients had a median observed follow-up time
of 7.8 years (range 2.113.1 years). All patients had routine
follow-up with physical examination and surveillance axial
radiographic imaging; living patients were contacted
within 1 month of data analysis. Patient, tumor, and
treatment characteristics are presented in Table 1. Local
control was defined as no evidence of disease at the primary site clinically and/or radiographically until last follow-up or death. Death from intercurrent disease was
defined as death without any evidence of recurrent tumor.
RT complications were scored using the Common Terminology Criteria for Adverse Events, version 4.0
(CTCAEv4.0). Severe RT complications were considered
grade 3? toxicities using these guidelines.

Eur Arch Otorhinolaryngol


Table 1 Patient and treatment characteristics
Patienta

Age
(years)

Histology

Primary
site

Treatment prior to
presenting at our
institution

Surgery at our
institution

Resection
margins

Radiotherapy
dose

Outcome

70

Ameloblastic
carcinoma

Maxilla

One operation

Partial
maxillectomy

Close

66.4 Gy in 46 fx
QD/BID

NED at
11.1 years

70

Ameloblastic
carcinoma

Mandible

None

Segmental
mandibulectomy

Close

66 Gy in 33 fx
QD

DID at
11.2 years

56

Ameloblastic
carcinoma

Maxilla

One operation

Total
maxillectomy

Positive

72 Gy in 60 fx
BID

DWD at
4.0 years

82

Ameloblastoma

Maxilla

Multiple operations

None

None

66 Gy in 39 fx
QD

DID at
2.1 years

61

Ameloblastoma

Maxilla

Multiple operations

Maxillectomy

Positive

63 Gy in 35 fx
QD

NED at
13.1 years

32

Ameloblastoma

Mandible

Multiple operations

None

None

74.4 Gy in 62 fx
BID IMRT

AWD at
7.8 years

fx fractions, QD once daily, BID twice-daily, IMRT intensity-modulated radiotherapy, NED no evidence of disease, DID death of intercurrent
disease, DWD dead with disease, AWD alive with disease
a

All patients were male

Results

Discussion

Local control after RT was observed in four of six patients


(67 %). Of these four, two are alive with no evidence of
disease and two died of intercurrent disease. Two patients
developed both a local recurrence as well as metastases. Of
these, the first patient recurred locally and simultaneously
developed neck and superior chest dermal metastases at
3.7 years after surgery and postoperative RT for an
ameloblastic carcinoma, at which point the patient opted for
best supportive care. The patient passed away several months
later with evidence of disease. The second patient was treated
with RT alone for a locally recurrent incompletely
resectable ameloblastoma after multiple surgical procedures
at outside institutions. He subsequently developed tumor
recurrence in the region of his mandibular reconstruction as
well as the bilateral neck including the left level V, and right
level IB at 5.7 years after RT. At 6.3 years after RT, CT
imaging revealed an obstructing right middle lobe endobronchial lesion as well as multiple subcentimeter intrapulmonary and left hilar nodules, confirmed as metastatic
disease via biopsy. He was then treated with dabrafenib and
trametinib, resulting in a complete resolution of all pulmonary metastatic disease and a partial response in the jaw
and neck disease as confirmed by positron emission
tomographycomputed tomography scan 8 weeks after
treatment [15]. This patient is currently alive with sustained
complete response of pulmonary metastases and continued
partial response in the jaw and neck.
No patient suffered a severe treatment-related
complication.

Surgery is well established as the primary initial treatment


modality, preferably with wide local excision taking adequate margins. Literature reporting experiences with lessextensive operations, such as enucleation, electrocautery,
and marsupialization, have resulted in very high rates of
local recurrence, ranging from 65 % to over 90 % in a
series of 92 patients with ameloblastoma treated with
curettage alone [16]. More extensive wide local excisions
with up to 1- to 2-cm margins for ameloblastoma and up to
3 cm for ameloblastic carcinoma with bone reconstruction
provide much more acceptable rates of local control and
are considered the cornerstone of primary ameloblastoma
management. Olaitain et al. have published the largest
surgical ameloblastoma series to date. They reported 229
cases treated with wide local excision with a recurrence
rate of 10 % at 218 years after surgery (median follow-up
was not reported) [17]. All six of our patients underwent at
least one surgical excision either at our institution or an
outside institution before RT.
As these tumors are rare and surgery is the primary
modality of treatment, data reporting outcomes after RT
remain scarce. The initial Memorial Sloan-Kettering Cancer Center (New York, NY) experience reporting patients
treated with RT between 1921 and 1951 is one of the
earliest and largest series published [16]. They reported
eventual recurrences in all 11 patients treated, although
dose and fractionation details were not described [16]. In
another older series published in 1937, Robinson found a
recurrence rate of 72 % in 18 patients treated with RT [18].

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Unsurprisingly, ameloblastomas and ameloblastic carcinomas were long considered radioresistant tumors, as older
methods failed to provide appreciable benefit to patients.
However, more recent reports suggest RT may benefit
postoperative patients who have locally recurred or those
with residual disease after resection. This may be in part
owing to improvements in treatment techniques, as older
series often used orthovoltage irradiation and radium needles
instead of megavoltage irradiation. Princess Margaret Cancer Center (Toronto, Ontario) reported their series of 10
patients treated with RT from 1958 to 1982, with a recurrence rate of 20 % [19]. Miyamoto et al. reported local
control in a patient treated with RT and provided treatment
guidelines in 1991, proposing that doses of at least 4550 Gy
in conventional 1.8-Gy fractions were necessary, and that
lymph nodes need not be included unless clinical involvement was apparent [20]. A more recent French series by
Pinsolle et al. reported a 50 % local control rate when using
postoperative RT [21]. In our current series, two of six
patients developed local recurrences after RT. One patient
passed away after opting for supportive care, while the other
is currently alive with dramatic response to dabrafenib and
trametinib, as described above.
As with RT, the literature on chemotherapy for the
treatment of these tumors is more limited than that on surgical excision, with experiences being limited to isolated
case reports in the setting of metastatic disease. Gall et al. and
Campbell et al. found no tumor response to cyclophosphamide-based regimens [22, 23]. Partial responses using
platinum-based chemotherapy in combination with other
agents have also been reported in the literature [1, 24].
However, a recent investigation into the molecular biology
of these tumors has revealed pivotal roles in the Hedgehog
(SHH) and mitogen-activated protein kinase (MAPK) signaling pathways. Three separate series have reported the
frequency of mutations and potential molecular therapeutic
targets, which have been summarized by McClary et al. [12].
Interestingly mutations in each pathway seem to be mutually
exclusive and location-dependent. The V600E BRAF
mutation in the MAPK pathway appeared in 75 out of 106
(71 %) mandibular ameloblastomas but only 3 of 27 (11 %)
of maxillary ameloblastomas. Conversely, L412F mutations
of Smoothened (SMO) in the SHH pathway were present in
17 of 27 (63 %) maxillary tumors but only 3 of 45 (7 %)
mandibular ameloblastomas [2527]. Our institution was the
first to report a clinical response to BRAF inhibition via
dabrafenib and trametinib in a patient with mandibular
ameloblastoma [15]. In our current series with longer followup, we confirm sustained elimination of pulmonary metastases and continued localregional response to treatment.
Our study updates the University of Floridas experience
managing ameloblastoma and ameloblastic carcinoma with
RT, and demonstrates its feasibility in the setting of locally

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recurrent disease when combined with surgery. While


platinum-based chemotherapeutic regimens have resulted
in either no response or partial response, agents such as
dabrafenib/trametinib and arsenic trioxide targeting
molecular aberrations in the SHH and MAPK pathways,
respectively, may serve as important modalities in either
locally recurrent or distant disease.
Compliance with ethical standards
Conflict of interest

None.

References
1. Amzerin M, Fadoukhair Z, Belbaraka R, Iraqui M, Boutayeb S,
MRabti H, Kebdani T, Hassouni K, Benjaafar N, El Gueddari
BK, Errihani H (2011) Metastatic ameloblastoma responding to
combination chemotherapy: case report and review of the literature. J Med Case Rep 5:491. doi:10.1186/1752-1947-5-491
2. Wesley RK, Borninski ER, Mintz S (1977) Peripheral
ameloblastoma: report of case and review of the literature. J Oral
Surg 35:670672
3. Becelli R, Carboni A, Cerulli G, Perugini M, Iannetti G (2002)
Mandibular ameloblastoma: analysis of surgical treatment carried
out in 60 patients between 1977 and 1998. J Craniofac Surg
13:395400 (discussion)
4. Ord RA, Blanchaert RH Jr, Nikitakis NG, Sauk JJ (2002)
Ameloblastoma in children. J Oral Maxillofac Surg 60:762770
(discussion 7071)
5. Regezi JA, Kerr DA, Courtney RM (1978) Odontogenic tumors:
analysis of 706 cases. J Oral Surg 36:771778
6. Reichart PA, Philipsen HP, Sonner S (1995) Ameloblastoma:
biological profile of 3677 cases. Eur J Cancer B Oral Oncol
31B:8699
7. Mehlisch DR, Dahlin DC, Masson JK (1972) Ameloblastoma: a
clinicopathologic report. J Oral Surg 30:922
8. Slootweg PJ, Muller H (1984) Malignant ameloblastoma or
ameloblastic carcinoma. Oral Surg Oral Med Oral Pathol 57:168176
9. Laughlin EH (1989) Metastasizing ameloblastoma. Cancer
64:776780
10. Van Dam SD, Unni KK, Keller EE (2010) Metastasizing (malignant) ameloblastoma: review of a unique histopathologic entity
and report of Mayo clinic experience. J Oral Maxillofac Surg
68:29622974. doi:10.1016/j.joms.2010.05.084
11. Mendenhall WM, Werning JW, Fernandes R, Malyapa RS,
Mendenhall NP (2007) Ameloblastoma. Am J Clin Oncol
30:645648. doi:10.1097/COC.0b013e3181573e59
12. McClary AC, West RB, Pollack JR, Fischbein NJ, Holsinger CF,
Sunwoo J, Colevas AD, Sirjani D (2015) Ameloblastoma: a
clinical review and trends in management. Eur Arch Otorhinolaryngol. doi:10.1007/s00405-015-3631-8
13. Philip M, Morris CG, Werning JW, Mendenhall WM (2005)
Radiotherapy in the treatment of ameloblastoma and ameloblastic
carcinoma. Hong Kong J Radiol 8:157161
14. Mendenhall WM, Riggs CE, Vaysberg M, Amdur RJ, Werning
JW (2010) Altered fractionation and adjuvant chemotherapy for
head and neck squamous cell carcinoma. Head Neck 32:939945.
doi:10.1002/hed.21261
15. Kaye FJ, Ivey AM, Drane WE, Mendenhall WM, Allan RW
(2015) Clinical and radiographic response with combined BRAFtargeted therapy in stage 4 ameloblastoma. J Natl Cancer Inst
107:378. doi:10.1093/jnci/dju378

Eur Arch Otorhinolaryngol


16. Sehdev MK, Huvos AG, Strong EW, Gerold FP, Willis GW
(1974) Proceedings: ameloblastoma of maxilla and mandible.
Cancer 33:324333
17. Olaitan AA, Adeola DS, Adekeye EO (1993) Ameloblastoma:
clinical features and management of 315 cases from Kaduna,
Nigeria. J Craniomaxillofac Surg 21:351355
18. Robinson HB (1937) Ameloblastoma: a survey of 379 cases from
the literature. Arch Pathol Lab Med 23
19. Atkinson CH, Harwood AR, Cummings BJ (1984) Ameloblastoma of the jaw. A reappraisal of the role of megavoltage irradiation. Cancer 53:869873
20. Miyamoto CT, Brady LW, Markoe A, Salinger D (1991)
Ameloblastoma of the jaw. Treatment with radiation therapy and
a case report. Am J Clin Oncol 14:225230
21. Pinsolle J, Michelet V, Coustal B, Siberchicot F, Michelet FX
(1995) Treatment of ameloblastoma of the jaws. Arch Otolaryngol Head Neck Surg 121:994996
22. Gall JA, Sartiano GP, Shreiner DP (1975) Ameloblastoma of the
mandible with pulmonary metastasis. Oncology 32:118126

23. Campbell D, Jeffrey RR, Wallis F, Hulks G, Kerr KM (2003)


Metastatic pulmonary ameloblastoma. An unusual case. Br J Oral
Maxillofac Surg 41:194196
24. Ramadas K, Jose CC, Subhashini J, Chandi SM, Viswanathan FR
(1990) Pulmonary metastases from ameloblastoma of the mandible treated with cisplatin, adriamycin, and cyclophosphamide.
Cancer 66:14751479
25. Kurppa KJ, Caton J, Morgan PR, Ristimaki A, Ruhin B, Kellokoski J, Elenius K, Heikinheimo K (2014) High frequency of
BRAF V600E mutations in ameloblastoma. J Pathol
232:492498. doi:10.1002/path.4317
26. Arslan H, Akcay M, Yasa B, Hatirli H, Saygili G (2015)
Bleaching effect of activation of hydrogen peroxide using photon-initiated photoacoustic streaming technique. Clin Oral
Investig 19:253259. doi:10.1007/s00784-014-1255-9
27. Brown NA, Rolland D, McHugh JB, Weigelin HC, Zhao L, Lim
MS, Elenitoba-Johnson KS, Betz BL (2014) Activating FGFR2RAS-BRAF mutations in ameloblastoma. Clin Cancer Res
20:55175526. doi:10.1158/1078-0432.CCR-14-1069

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