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13 Advancements inFacial Trauma
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Fig. 13.4 Assessment of facial fracture reduction and/or xation workow, using post-op CT (a),
using ICT (b). CT computed tomography, GA general anesthesia, post-op post-operative, OR operating room
253
Patient-Specic Implant
Advances of technology such as CASS and selective laser melting (SLM) have led
to patient-specic implant (PSI) for craniomaxillofacial surgery. Several studies
have shown that PSI led to decrease time to OR, intraoperative time, accurate fracture reduction, and superior outcome [17].
However, SLM technology or PSI is exceedingly expensive with long production
time (7–14days). Fracture reduction is time sensitive to prevent unfavorable longterm sequela; thus, this technology has limitation in acute setting and used in posttraumatic deformity (Fig.13.5).
254
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a b
c
D. Amin and N. Demian
Fig. 13.5 A 35-year-old male patient sustained rearm injury (FI). FI caused right open and comminuted frontal sinus, superior orbital wall, nasoethmoidal ZMC, orbital oor, zygomatic arch
fractures. Frontal view (a) at presentation to emergency department (ED). Frontal view of 3D
reconstruction of pre-operative CT scan (b) showing comminuted fractures. Frontal view of a summary of CASS plan and PSI design (c), the right ZMC (area shaded in light blue) was reduced digitally, and three PSIs were designed to span different fractures, notice several fractures (frontal
sinus, superior orbital wall, nasoethmoidal fractures) was reconstructed with one large PSI (yellow
arrow), one PSI for ZMC (green arrow), and one PSI for orbital oor fracture (red arrow).
Intraoperative view of two PSIs (yellow and green arrows) (d). Frontal view of 3D reconstruction
of post-operative CT scan (e) showing reconstruction of the frontal sinus, superior orbital wall,
nasoethmoidal, and ZMC fractures
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255
References
1. Septa D, Newaskar VP, Agrawal D, Tibra S.Etiology, incidence and patterns of mid-face fractures and associated ocular injuries. J Maxillofac Oral Surg. 2014;13(2):115–9.
2. Lim LH, Lam LK, Moore MH, Trott JA, David DJ.Associated injuries in facial fractures:
review of 839 patients. Br J Plast Surg. 1993;46(8):635–8.
3. Kieser J, Stephenson S, Liston PN, Tong DC, Langley JD.Serious facial fractures in New
Zealand from 1979 to 1998. Int J Oral Maxillofac Surg. 2002;31(2):206–9.
4. Hsieh T-Y, Funamura JL, Dedhia R, Durbin-Johnson B, Dunbar C, Tollefson TT.Risk factors
associated with complications after treatment of mandible fractures. JAMA Facial Plast Surg.
2019;21(3):213–20.
5. Bell RB. Computer planning and intraoperative navigation in cranio-maxillofacial surgery.
Oral Maxillofac Surg Clin North Am. 2010;22(1):135–56.
6. Girod S, Keeve E, Girod B.Advances in interactive craniofacial surgery planning by 3D simulation and visualization. Int J Oral Maxillofac Surg. 1995;24(1 Pt 2):120–5.
7. Azarmehr I, Stokbro K, Bell RB, Thygesen T. Contemporary techniques in orbital reconstruction: a review of the literature and report of a case combining surgical navigation,
computer-aided surgical simulation, and a patient-specic implant. J Oral Maxillofac Surg.
2020;78(4):594–609.
8. Marschall JS, Dutra V, Flint RL, etal. In-house digital workow for the management of acute
mandible fractures. J Oral Maxillofac Surg. 2019;77(10):2084.e2081–9.
9. Façanha de Carvalho E, Alkmin Paiva GL, Yonezaki F, Machado GG.Computer-aided surgical
simulation in severe atrophic mandibular fractures: a new method for guided reduction and temporary stabilization before xation. J Oral Maxillofac Surg. 2021;79(4):892.e891–7, 892.e1.
10. Markiewicz MR, Bell RB.Modern concepts in computer-assisted craniomaxillofacial reconstruction. Curr Opin Otolaryngol Head Neck Surg. 2011;19(4):295–301.
11. Mezger U, Jendrewski C, Bartels M. Navigation in surgery. Langenbecks Arch Surg.
2013;398(4):501–14.
12. Schmelzeisen R, Gellrich NC, Schramm A, Schön R, Otten JE.Navigation-guided resection
of temporomandibular joint ankylosis promotes safety in skull base surgery. J Oral Maxillofac
Surg. 2002;60(11):1275–83.
13. Azarmehr I, Stokbro K, Bell RB, Thygesen T. Surgical navigation: a systematic review of
indications, treatments, and outcomes in oral and maxillofacial surgery. J Oral Maxillofac
Surg. 2017;75(9):1987–2005.
14. Stanley RB Jr. Use of intraoperative computed tomography during repair of orbitozygomatic
fractures. Arch Facial Plast Surg. 1999;1(1):19–24.
15. Alasraj A, Alasseri N, Al-Moraissi E.Does intraoperative computed tomography scanning in
maxillofacial trauma surgery affect the revision rate? J Oral Maxillofac Surg. 2021;79(2):412–9.
16. Ma D, Zhang S, Pang C, Zhang W, Wang B, Liu Y.The application of intraoperative computed
tomography in surgical management of temporomandibular joint ankylosis. J Oral Maxillofac
Surg. 2021;79(1):90.e91–7.
17. Yang WF, Choi WS, Leung YY, etal. Three-dimensional printing of patient-specic surgical
plates in head and neck reconstruction: a prospective pilot study. Oral Oncol. 2018;78:31–6.
Chapter 14
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Advancements inMaxillofacial Benign
Tumors andCysts
MariAlinaTimoshchuk andWaleedZaid
Update onWorld Health Organization (WHO) Odontogenic
Benign Tumors andCysts
The fth edition of the WHO’s Classication of Head and Neck Tumors was published in March 2022 [1]. Experts formulated the guidelines in the eld to provide
more accurate and clinically oriented classication. The main aim of these changes
was to deliver a modern concise classication that properly reects the proper entities of these lesions and reduces the need for complex molecular techniques that
may not be widely available or affordable.
The 2022 fth edition follows many of the same concepts that were introduced
in the 2017 edition. In particular, the 2022 edition continues to use the odontogenic
cyst classication that was introduced in the 2017 guidelines, which was previously
omitted in the 2005 edition [2]. Also like the 2017 edition, the 2022 edition continued to use a simplied classication of odontogenic tumors into three main groups
based on histological origin: (1) epithelial, (2) mesenchymal, and (3) mixed odontogenic tumors. Distinct from the 2017 edition update, the 2022 guidelines added
M. A. Timoshchuk
Department of Oral and Maxillofacial Surgery, School of Dentistry, Louisiana Health
Sciences Center, New Orleans, LA, USA
e-mail: mtimos@lsuhsc.edu
W. Zaid (*)
Department of Oral and Maxillofacial Surgery, School of Dentistry, Louisiana Health
Sciences Center, New Orleans, LA, USA
Site Director Baton Rouge LSUHSC Oral and Maxillofacial Surgery Department, Our Lady
of Lake Regional Medical Center, Baton Rouge, LA, USA
e-mail: wzaid@lsuhsc.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
J. C. Melville et al. (eds.), Advancements and Innovations in OMFS, ENT, and
Facial Plastic Surgery, https://doi.org/10.1007/978-3-031-32099-6_14
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adenoid ameloblastoma among benign epithelial odontogenic tumors and added
surgical ciliated cyst to the list of jaw cysts. Additionally, the new edition text has
added “essential and desirable diagnostic criteria” to simplify and emphasize key
features for each pathologic entity [1].
M. A. Timoshchuk and W. Zaid
Ameloblastoma
Odontogenic tumors (OTs) represent 2–3% of jaw lesions [3]. In the prior 2017
WHO classications, ameloblastoma had a signicant share of debate regarding its
aggressive behavior. The consensus was to keep ameloblastoma as a benign epithelial odontogenic tumor despite the few reported cases of metastasizing ameloblastoma, which is dened as being ameloblastoma that is present at extraoral locations,
most commonly the lungs [4, 5]. In the 2017 WHO classication, ameloblastoma
was simplied to ameloblastoma, unicystic ameloblastoma, and extraosseous/
peripheral ameloblastoma. The adjective “solid/multicystic” for conventional ameloblastoma was eliminated due to the lack of any biological or clinical value.
Odontoameloblastoma was eliminated as it was deemed more of a descriptive term
rather than having any clinical implications [1]. The 2022 WHO classications have
added adenoid ameloblastoma, which is an epithelial odontogenic neoplasm with
essential diagnostic criteria that include ameloblastoma-like component, duct-like
structures, whorls/morules, and a cribriform architecture. There are currently
approximately 40 cases that have been reported in the literature [6]. Reports have
shown locally aggressive behavior with a high recurrence rate of approximately
45.5–70% [7].
Treatment ofAmeloblastoma Using Checkpoint Markers
Surgical resection with a 1cm margin along with one added anatomical barrier is
the current standard of care as more conservative approaches are linked to high
recurrence rates ranging between 55% and 90% compared to 15–25% with resection [8]. Nevertheless, surgical resection is associated with a high morbidity rate
without absolute elimination of the risk of recurrence. Recent invitro studies and
case reports, however, have shown that medication that targets specic genetic
mutations prevalent in ameloblastomas can reduce ameloblastic cells and can potentially be used as therapeutic alternatives for patients unsuitable to undergo standard
surgical resection [9]. Genetic studies show recurrent genetic mutations in the
mitogen- activated protein kinase (MAPK) and sonic hedgehog (SHH) signaling
pathways of ameloblastoma. Approximately 79% of ameloblastoma mutations in
MAPK pathways include BRAF, RAS, and broblast growth factor receptor 2
14 Advancements inMaxillofacial Benign Tumors andCysts
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(MAPK)
Mitogen-Activated Protein
Kinase
• Vemurafenib
• Dabrafenib
259
BRAF V600E
BRAF
RAS
FGFR2
SMOs
Ameloblastoma
Genetic mutations
(SHH) Sonic HedgeHog
• Ponatinib
• Regorafenib
• Vismodegib
• Intraconazole
Fig. 14.1 Tumor markers and potential targeted therapies
(FGFR2) genes. Studies have found a high occurrence of BRAF V600E mutations,
which involves the substitution of valine for glutamate at codon 600. Knowing the
MAPK pathways activated in ameloblastomas with genetic mutations creates the
potential for molecularly targeted therapies that inhibit the functions of mutated
BRAF and MEK (Fig.14.1). Potential drugs include vemurafenib and dabrafenib
(inhibit mutated BRAF gene), trametinib (inhibits mutated MEK gene), and ponatinib and regorafenib (inhibit mutated FGFR2 genes). The US Food and Drug
Administration (FDA) has approved the use of vemurafenib and dabrafenib for
BRAF mutations and trametinib for MEK mutations [9–12]. A treatment approach
has been implemented in melanoma treatment as having been proven to improve
overall disease-specic survival [13].
Similar to MAPK, studies have also shown a high incidence of recurrent mutations in SMOs, a SHH pathway gene in ameloblastoma. However, SMO inhibitors,
such as vismodegib and itraconazole, have not been shown to successfully treat
ameloblastomas [11]. While drugs inhibiting the SHH signaling pathway are more
effective in treating ameloblastomas, the most used SHH signaling pathway inhibitor, cyclopamine, can inhibit osteoblast proliferation. Thus, cyclopamine would
affect bone healing and is not ideal for treating ameloblastomas [14].
The current literature on the use of medication to target specic genetic markers
associated with ameloblastomas is limited to case reports and in vitro studies.
Although there are more studies on the efcacy of FDA-approved medications in
the treatment of melanomas, which have the same genetic mutations observed in
ameloblastomas, further studies with larger sample sizes are required to determine
if this approach will be widely adopted after establishing reliable long-term favorable results from using targeted molecular therapy medications in the treatment of
ameloblastoma, especially with the potential side effects that might be associated
with these medications (Table14.1).
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Table 14.1 Targeted molecular therapy agents and currently documented dosages for the treatment
of ameloblastoma
Generic
Agent
Vemurafenib Zelboraf BRAF kinase
Dabrafenib Tanlar,
name
ranlar
Mechanism
of action Use Dosage Side effects
BRAF-positive
inhibitor
BRAF kinase
inhibitor
unresectable or
metastatic
melanoma
BRAF V600E
mutationpositive
metastatic
melanoma
M. A. Timoshchuk and W. Zaid
• 960mg PO
twice daily
• 960mg PO
twice daily,
then
reduced to
480mg
twice daily
when side
effects
occurred
[15, 16]
• 150mg PO
twice daily
[17]
• 75mg PO
twice daily
[18]
• Increased risk of
squamous cell
carcinoma,
melanoma, basal
cell carcinoma,
keratoacanthomas
• Maculopapular
rash
• Follicular
hyperkeratosis
• Palmar-plantar
erythrodysesthesia
• Arthralgia
• Transaminitis
• QT prolongation
• New primary
malignancies,
increased cell
proliferation in
BRAF wild-type
melanoma
• Hyperkeratosis
• Headache
• Pyrexia
• Arthralgia
• Papilloma
• Alopecia
• Palmar-plantar
erythrodysesthesia
syndrome
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Table 14.1 (continued)
Agent
Dabrafenib
and
trametinib
(dual agent)
Generic
name
Tanlar
or
ranlar
and
mekinist
Mechanism
of action Use Dosage Side effects
BRAF kinase
inhibitor and
MEK
inhibitor
Unresectable or
metastatic
melanoma with
PRAF V600E
or V600K
mutations
150mg PO
twice daily
alongside
2mg
trametinib
twice daily
[19, 20]
261
• New primary
malignancies,
increased cell
proliferation in
BRAF wild-type
melanoma
• Major hemorrhagic
events
• Venous
thromboembolism
• Cardiomyopathy
• Embryo-fetal
toxicity, secondary
skin infections
hyperglycemia
• Hemolytic anemia
• Pyrexia
• Chills
• Fatigue
• Rash
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Peripheral edema
• Cough
• Headache
• Arthralgia
• Night sweats
• Decreased appetite
• Constipation
• Myalgia
(continued)
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Table 14.1 (continued)
Agent
Ponatinib Iclusig Multitargeted
Regorafenib Stivarga Multi-kinase
Generic
name
Mechanism
of action Use Dosage Side effects
receptor
tyrosine
kinase
inhibitor
(FGFR2 gene
inhibitor)
inhibitor
(FGFR2 gene
inhibitor)
Refractory
chronic
myelogenous
leukemia
Metastatic
colorectal
cancer,
hepatocellular
carcinoma, and
gastrointestinal
stromal tumors
M. A. Timoshchuk and W. Zaid
No case
studies yet
• Hypertension
• Rash
• Abdominal pain
• Fatigue
• Headache
• Dry skin
• Constipation
• Arthralgia
• Nausea
• Pyrexia
• Hematologic
adverse reactions
included
thrombocytopenia,
anemia,
neutropenia,
lymphopenia, and
leukopenia
• Severe
hepatotoxicity
resulting in
potential liver
damage
• Asthenia/fatigue
• HFSR
• Diarrhea
• Decreased appetite
• Hypertension
• Mucositis
• Dysphonia
• Infection
• Pain (not otherwise
specied),
• Decreased weight
and gastrointestinal
and abdominal
pain, and nausea
• Rash
• Fever
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263
Odontogenic Keratocyst (OKC)
OKC arises from the cell rests of the dental lamina and represents approximately
3–20% of all odontogenic cysts of the jaw [21, 22]. It was rst described by Philipsen
in 1956 and was reclassied back by the WHO in 2017 as a benign cyst from a cystic neoplasm. The previously debated reason for considering it as malignancy is
because of several studies that found evidence of genetic mutations. These mutations ranged between 30% in non-syndromic OKCs and 60–85% of syndromic
OKCs, such as in basal cell nevus syndrome (BCNS), which have mutations in
PTCH1, a marker in the SHH signaling pathway. Agaram etal. found that seven out
of ten OKCs showed loss of heterozygosity in tumor suppressor genes with the most
frequent allelic losses at p16, p53, PTCH, and MCC (75%, 66%, 60%, and 60%,
respectively). Daughter cells were also found to contribute to a higher frequency of
allelic loss [23]. Despite these mentioned factors, it was determined that this did not
warrant the attachment of the tumor title to OKC [2, 24]. Regardless of nomenclature, these lesions are signicant for their local aggressive growth potential, high
recurrence rate, and association with syndromes such as BCNS.
PTCH1 Gene andSonic Hedgehog Pathway
The PTCH1 gene is responsible for producing a sonic hedgehog receptor on the cell
membrane called PTCH1. Normally, PTCH1 maintains smoothened, a transmembrane protein that activates GLI proteins. When SHH ligand/protein binds to
PTCH1, it releases the smoothened suppression, and the activated smoothened promotes activation of transcription factors of glioma-associated oncogenes, including
GLI1 [25]. GLI1 is itself a transcription factor and induces PTCH1 transcription;
thus SHH signaling can create a negative feedback loop [26].
PTCH1 Mutation andBCNS
Understanding how the SHH pathway interacts with PTCH1 also sheds light on the
genetic background of BCNS.BCNS is a rare autosomal-dominant condition caused
by a PTCH1 mutation that releases its smoothened suppression, leading to uninhibited stimulation of the SHH.The uninhibited stimulation then leads to SHH proliferation and carcinogenesis, which explains BCNS’s association with OKC and
basal cell carcinomas [27]. BCNS develops through a “two-hit” mechanism. BCNS
patients inherit the rst “hit” when they are born with a mutation on one of the
PTCH1 gene alleles, where the bulk of the mutations involve truncating the PTCH1
gene in the various germline cells. It takes, however, a second “hit” to the second
and normal PTCH1 gene allele for a patient to have BCNS.This second hit may be
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