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Table 14.2 Major and minor criteria to establish the diagnosis of BCNS based on the consensus
statement from the rst international colloquium on BCNS
Major criteria Minor criteria
First degree relative with BCNS Rib anomalies
BCC prior to 20years old or excessive
numbers of BCCs out of proportion to prior
sun exposure and skin type
Odontogenic keratocyst of the jaw prior to
20years old
Palmar or plantar pitting Cleft/lip palate
Lamellar calcication of the falx cerebri Ovarian/cardiac broma
Medulloblastoma/neuroectodermal tumor,
typically desmoplastic
a
This is a new major criterion that has led to the early establishment of the BCNS diagnosis as this
is a nding typically diagnosed at 2years or younger
a
Skeletal malformations and radiologic changes
(i.e., vertebral anomalies, kyphoscoliosis, short
fourth metacarpals, and postaxial polydactyly)
Macrocephaly
Lympho-mesenteric cysts
Ocular abnormalities (i.e., strabismus,
hypertelorism, congenital cataracts, glaucoma, and
coloboma)
M. A. Timoshchuk and W. Zaid
from environmental factors such as ultraviolet light and radiation. The inherited
PTCH1 mutation is transmitted as autosomal-dominant inheritance with high penetrance and inconstant expressivity leading to broad phenotypic presentation
[26, 27].
Dened by Gorlin and Goltz in 1960, the classical facial features that are present
in 60% of patients with BCNS include frontal bossing, macrocephaly, overall coarse
facial features, and facial milia [28]. Clinical and radiographic ndings are often
utilized in numerous combinations as diagnostic criteria. These ndings have been
classied as major and minor criteria, and they are summarized in Table14.2. The
consensus from the BCNS Life Support Network suggested that a diagnosis of
BCNS can be established in the following scenarios:
• The presence of one major criterion with molecular conrmation
• Two major criteria
• One major with three minor features
Despite the perception that genetic testing is the gold standard for diagnosis, it is
not recommended and is rarely performed in clinical practice due to its elevated cost.
Treatment ofOKC
Before diving into the treatment of OKC as surgeons, we need to understand the
recurrence rate, which is reportedly between 7% and 28% after surgical treatment
[29]. This recurrence rate has been attributed to various causes: the persistence of
residual epithelium, the retention of daughter cysts in the walls of the original cysts
or from microcysts, and the continuous intrinsic epithelial proliferation due to
genetic mutation. Most recurrences occur before 5years and decrease with time
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[30, 31]. There are three primary surgical treatments employed for OKC: marsupialization and decompression, enucleation, and en bloc resection. Along with these
surgical techniques, there are four main adjunct techniques to help reduce the recurrence rate and they are peripheral ostectomy, Carnoy’s and modied Carnoy’s solution, cryosurgery with liquid nitrogen, and 5-FU.When treatment planning a lesion
that is biopsy-proven or highly suspicious for OKC, it is important to consider the
timeline for dental rehabilitation. Due to the high recurrence rate of OKC, it is typically recommended to postpone reconstructive treatments until after cyst excision
or a period of decompression, though there have been successful case reports of
bone grafting and immediate implant placement after enucleation [32, 33]. Bone
grafting has the advantage of stabilizing the blood clot, provides osteoconductive
properties increasing the migration of progenitor cells, and can potentially reduce
the risk of pathologic fracture. However, bone grafting can be a potential source of
infection and OKCs have been shown to recur in grafted sites leading to costly and
stressful re-treatment for patients [34].
In a multicenter study performed by Lim etal., 305 cysts that had undergone
enucleation and simultaneous bone grafting were retrospectively investigated for
factors associated with bone graft failure [35]. Bone graft failure was observed in 48
cases (15.7%) with a mean duration of surgery time to failure of 38.7days. Graft
failure was associated with younger age, smoking, preoperative infection, large
cysts, impaction of the mandibular third molar in the cystic cavity, perilesional sclerosis, and the use of mixed non-autogenous and autogenous bone grafts. Similarly,
Chacko etal. evaluated 44 consecutive patients with large maxillary and mandibular
cysts, 20 of which were OKCs, treated with either enucleation or marsupialization
with an average max lesion dimension of 58.2mm in max dimension and follow-up
of 6months [36]. Uneventful healing and spontaneous lling of the residual cavities
were obtained in all cases. Without the use of bone grafts, radiodensity of the cystic
cavity recovers approximately 25% at 6months, 58% at 9months, 88% at 12months,
and 91–100% at 2years [36, 37]. If bone grafting is not used, a period of 9–12months
is typically recommended depending on the original lesion size and patient factors
and comorbidities before pursuing implant treatment. When considering dental
rehabilitation with a lesion biopsy-proven or concerning for OKC, the patient must
be informed of the risk of recurrences and weigh these with early return to function.
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Marsupialization andDecompression
The concept of marsupialization and decompression was introduced by the German
surgeon Partsch, who historically proposed marsupialization as a denitive treatment of cysts. Decompression involves any modality that relieves the pressure
within the cyst that causes its expansion. It is alleged that cyst growth occurs from
osmotic pressure and pressure resorption of the adjacent bone associated with prostaglandins and growth factors [38, 39]. The other signicant advantage of marsupialization and decompression is the change in the local intracystic microenvironment
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by decreasing interleukin-α. Surgeons who advocate for this procedure attest to
some of the benets associated with this treatment modality, such as diminishing
the cyst size and shrinking the cyst away from critical structures.
Technically, when performing a marsupialization, the surgeon needs to enter the
cyst lumen and attempt to create a continuous pouch between the cyst lining and
oral mucosa by suturing the cyst lining to the adjacent mucosa. The decision to
marsupialize a cyst could be done during the incisional biopsy. As denitive management of OKC, marsupialization is associated with a 32.3% recurrence rate.
Kolkythas etal. investigated whether decompression is associated with increased
recurrence by comparing 22 patients with OKC treated either by (1) enucleation
with peripheral ostectomy or resection or (2) decompression followed by enucleation and peripheral ostectomy [40]. The study found two recurrences in the decompression group compared to no recurrences in the enucleation and peripheral
ostectomy group. Both recurrences, however, were themselves recurrent lesions that
had previously undergone enucleation. This high recurrence rate has led clinicians
to avoid marsupialization as the only surgical modality. Instead, clinicians favor
combining residual cyst enucleation after the initial decompression, an approach
that has reduced the recurrence rate down to 14.6% [41].
M. A. Timoshchuk and W. Zaid
Enucleation
The denition of enucleation is to try to create a plain of separation between the cyst
and the surrounding bone while preserving the surrounding osseous infrastructure.
Ideally, we advocate for the cyst to be enucleated in its entirety, something that
allows the pathologist to study the complete specimen. Given the lining of OKC is
typically 5–6 cells thick, enucleating the cyst lining may be friable and can cause
the cyst to be enucleated in pieces, especially if the cyst did not undergo previous
marsupialization. Ideally, at the end of the enucleation procedure, the bone cavity
should be clean from any cyst lining. The recurrence rate of enucleation alone as a
surgical modality of OKC is approximately 23.1%; however, enucleation in conjunction with adjuvant therapy decreases the recurrence rate down to 11.5–17.5% [41].
En Bloc Resection
En bloc resection with or without vascularized ap reconstruction is a treatment
typically reserved for cases with multiple recurrences, possibly syndromic cases, or
those that have undergone malignant transformation [41, 42]. Depending on the size
of the lesion, the continuity of the mandible may be preserved by performing a
marginal resection. This technique results in very low recurrence rates (0–8.4%) but
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has a much higher patient morbidity fueling surgeons to nd more conservating
measures that can achieve similar recurrence outcomes [41, 43, 44]. Gosau et al.
reported similar recurrence rates with enucleation with Carnoy’s solution and curettage when compared to that of resection [45]. Lone etal. found a high rate of recurrence in their institution with enucleation and Carnoy’s (66.6%); however, there
were no recurrences in either the peripheral ostectomy with the 5-FU group or the
segmental resection group [46]. Although radical resection remains the most certain
option for obtaining the lowest recurrence rate compared to other modalities, it
produces signicant morbidity with functional and aesthetic compromises and is
typically reserved for select cases.
Since the bula free ap was introduced, the development of computer-assisted
surgery has greatly increased the accuracy of mandibular reconstruction [47].
Computer-aided design and computer-aided manufacturing (CADCAM) allows
surgeons to create personalized surgical devices and physical models, which greatly
increases the accuracy of bula osteotomies with respect to mandibular resections.
The “Jaw in a Day” (“JIAD”) technique consists of completing a virtually guided
resection, a bula reconstruction, and the insertion of an implant-retained dental
prosthesis all in one operation with assistance from CADCAM technology. This
technique establishes immediate restoration of form and function. The immediate
xation of the dental prosthesis also allows the patient to start dental rehabilitation
in the early postoperative period. This technique will be described in greater detail
in a separate chapter of this textbook.
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Adjunct Therapy
This is a group of surgical steps the surgeon usually performs after the completion
of the enucleation procedure, and this can be subclassied into mechanical and
chemical modalities.
Peripheral Ostectomy
With this procedure, the surgeon aims to mechanically eliminate any remnants of
the cyst wall or any satellite cysts by removing the bone adjacent to the cystic lining.
Rotary instruments are gently applied against the cyst wall. This maneuver reduces
the risk of recurrence from 23.1% to 17.5% [41, 48]. Despite the simplicity of the
peripheral ostectomy maneuver, this cannot be employed in every OKC case, especially with larger cysts approaching the inferior border of the mandible or with large
cysts that are prone to a pathologic fracture by just enucleation of the cyst, thin
lingual cortex, or proximity to adjacent teeth.
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M. A. Timoshchuk and W. Zaid
Carnoy’s Solution andModied Carnoy’s Solution
Carnoy’s solution was proposed by Cutler and Zollinger back in 1933 as a xative
solution, hemostatic agent, and sclerosing agent, for the treatment of cervical cysts
and stulas in general surgery literature. Voorsmit was the rst to describe the use
of Carnoy’s solution as an adjunct therapy in the management of OKC.The solution
was a mixture of 6mL of 100% alcohol/ethanol that allowed hardening of the tissue
by the shrinking process, 3mL of chloroform to increase the xation speed, 1mL
of glacial acetic acid that led to tissue swelling to prevent over-hardening of the tissues, and 1g of ferric chloride that helped with dehydration. The time-dependent
penetration of Carnoy’s solution was a double-edged sword: it penetrated the bone
adjacent to the enucleated cyst allowing xation of OKC remnant lining or daughter
cysts, but it also possessed a risk of nerve injury, approximately 55% [46]. The recommended application time of Carnoy’s solution was between 3 and 5min. It is
expected that with a 5-min application cycle of Carnoy’s solution, there will be
nerve penetration of 0.15mm, 0.51mm mucosal penetration, and approximately
1.54mm bony penetration [49–51]. With all these properties, Carnoy’s solution has
proven to be a successful adjunct modality to decrease the recurrence rate of OKC
between 4.5% and 11.5% [41, 52]. In 2013, the FDA Compliance Policy Guide
prohibited the use of chloroform as it was proven to be carcinogenic and a reproductive toxic agent that led to the abandoning of classical Carnoy’s solution that contained chloroform. This development pushed surgeons to explore the use of modied
Carnoy’s solution, which did not contain chloroform. When compared to classical
Carnoy’s solution, modied Carnoy’s solution only decreased the recurrence rate of
OKC to 35–45% [31]. Donnelly et al. found a similar recurrence rate reduction
between classical and modied Carnoy’s solution. It should be noted, however, that
the group performed extractions of any necessary teeth, enucleation, peripheral
ostectomy, and a 3-min application of either classical or modied Carnoy’s solution
when showing a comparable recurrence rate of 14% [53].
Cryosurgery Using Liquid Nitrogen
Cryosurgery affects the cellular organic component of the contacted bone while
maintaining the inorganic osseous framework [54]. Cryosurgery is usually effective
when the temperature is below -20°C as this leads to the formation of ice crystals,
which cause damage to the intracellular and extracellular components, osmotic disturbance, and electrolyte imbalance. Cryosurgery is useful after conventional enucleation is performed and then the treatment is applied to the surrounding bony bed
[55, 56]. It is expected that 1min of cryosurgery results in approximately 1–3mm
of penetration necrosis. Cryosurgery might be associated with normal local surgical
bed complications like wound dehiscence, swelling, pain, local infection, and even
weakening bone, which may result in pathologic fractures [31, 56].
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Bell and Derick described their cryosurgery technique as follows: after meticulous enucleation with peripheral ostectomy, the osseous bed of the OKC is isolated.
Next, malleable retractors are positioned and sponges of gauze are used to insulate
the soft tissues from the bony bed. Finally, with the use of the ladle and funnel, the
liquid nitrogen is carefully transported to the OKC osseous bed, and a recommended
three rounds of freeze-thaw are performed [55]. Cryotherapy has a higher recurrence rate than Carnoy’s solution, approximately 30%, but that is followed by a
steep negative gradient over time; this same trend is observed with modied
Carnoy’s [31, 56].
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5-FU
5-FU is a chemotherapy agent classied under the antimetabolic class that was rst
formulated by Heidelberger, Pleven, and Duschinsky in 1957 [31, 57]. 5-FU has
various mechanisms of action: rst by inhibiting the enzyme thymidylate synthase
and second by misincorporation of uorinated nucleoside into both RNA and DNA
instead of uracil. Inamed OKCs are associated with low thymidylate synthase and
high thymidine phosphorylase and therefore may benet more from 5-FU application than non-inamed OKCs [58, 59]. Additionally, 5-FU induces cell apoptosis by
downregulating the SHH pathway and SMO inhibition [60]. As discussed above,
the SHH signaling pathway dysregulation has been identied as the driving factor
for the development of multiple basal cell carcinomas in syndromic and nonsyndromic OKCs, and its treatment as a topical application for basal cell carcinoma
is well established. Clinically, 5% 5-FU is used by coating a ribbon gauze and placing it in the cystic cavity after enucleation to be removed 24h postoperatively. The
advantage of using the topical form is avoiding the side effects associated with
systemic use of 5-FU such as mucositis, nausea, pancytopenia, cardiac toxicity,
neuropathy, and death. The main contraindication for using any form of 5-FU is
dihydropyrimidine dehydrogenase (DPD) deciency, which is the initial and ratelimiting enzyme in the catabolism of 5-FU, thus placing patients at high risk for
developing severe 5-FU-associated toxicity. DPD deciency is seen in approximately 3–5% of the general population and up to three times higher in the AfricanAmerican female population, though how this translates to topical application as
seen with OKC treatment is still unknown [61].
In a retrospective review conducted by Caminiti etal., 34 patients were treated
with 5% topical 5-FU compared to 36 managed with modied Carnoy’s solution
after enucleation and peripheral ostectomy. The median follow-up time was
22months in the 5-FU group and 27months in modied Carnoy’s group. No recurrences were identied in the 5-FU group compared to nine recurrences in modied
Carnoy’s solution cohort. There were no differences in the incidence of permanent
nerve paresthesia between groups [62].
5-FU has been shown to be safe around vital structures. Five percent 5-FU application twice weekly for 1 month after medial maxillectomy and
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M. A. Timoshchuk and W. Zaid
sphenoethmoidectomy showed no adverse effects on the infraorbital nerve or sinus
mucosa [63, 64]. Lone etal. compared 9 patients treated with enucleation and modied Carnoy’s solution and 11 with enucleation, peripheral ostectomy, and 5-FU
with an average follow-up of 3.5years. Five percent 5-FU application was associated with 9% temporary paresthesia and 0 recurrences compared to modied
Carnoy’s solution, which had 44% temporary paresthesia, 11% permanent paresthesia, and a 66.6% recurrence rate. Both 5-FU and modied Carnoy’s solution were
not associated with any function or cosmetic adverse events [46]. While mucosal
absorption rates of 5% 5-FU are currently unclear, 20mg/kg is the reported threshold for toxicity development providing a wide safety prole with the average 70kg
patient requiring 1400mg of 5-FU to develop toxicity [31, 65].
In the authors’ experiences, 5-FU is often more accessible than modied Carnoy’s
solution and technically simpler than cryotherapy allowing for reduced operating
time. For biopsy-proven OKCs at our institution, patients are treated with a combination of enucleation +/− peripheral ostectomy and topical 5-FU application.
During the treatment planning appointment, a script for 5% uorouracil (Efudex)
cream is provided and the patient presents to their surgery date with their prescription. Enucleation of the cyst in its entirety is performed along with concomitant
through peripheral ostectomy and then non-compressed Gelfoam impregnated with
5% 5-FU is packed in the surgical bed and excess 5-FU is removed and closure is
performed in the standard fashion (Fig.14.2). This technique eliminates the need to
a b
Fig. 14.2 Description of the LSU 5-FU application technique. (a) Mandibular OKC postenucleation. (b) Peripheral ostectomy. (c) Non-compressed Gelfoam impregnated with 5%
5-FU. (d) Packing the cyst bed with Gelfoam impregnated with 5% 5-FU
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271
remove the impregnated ¼-in. gauze with 5-FU 24h after the original application of
the technique that was described by Caminiti etal. [62].
While studies are few, they are promising showing decreased morbidity and
recurrence compared to modied Carnoy’s solution. Despite promising initial data,
there is currently an insufcient quantity and follow-up to determine long-term
recurrence rates and efcacy to make denitive conclusions regarding the effectiveness of this technique and the most appropriate protocol for its use in OKC
management.
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