Escolar Documentos
Profissional Documentos
Cultura Documentos
DOI 10.1007/s00405-016-3899-3
Keywords
therapy
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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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
Results
Discussion
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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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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
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