Odontogenic Keratocyst

• Benign but aggressive intraosseous lesions of odontogenic origin
• Reclassified back to odontogenic keratocyst in the WHO 2017 classification (previously classified as keratocystic odontogenic tumour [KCOT] from 2005 to 2017)
• Subtypes:
  1. Odontogenic Keratocyst (OKC) - parakeratinised
  2. Orthokeratinised Odontogenic Keratocyst (OOKC)

Epidemiology

• Account for 5-10% of jaw cysts
• Peak incidence 20-30yrs
• ♂ > ♀ (slightly)
• Commonest site — angle of the mandible
  • 70-80% occur in the mandible
  • 50% at the angle of the mandible

Clinical Features

• Usually asymptomatic (commonly incidental findings)
  • When large/infected can cause pain/swelling/discharge/pathological fracture/tooth displacement/buccal expansion
• Characteristic insidious pattern of growth
  • Unlike other cysts, OKCs do not have a high internal pressure ∴ they preferentially expand along the medullary cavity (the path of least resistance)
  • A cyst in the mandible may extend through much of the ramus and body without significant expansion of the jaw
  • Clinical signs often fail to appear until the cyst is well advanced
• Usually solitary cysts (consider Nevoid basal-cell carcinoma syndrome (Gorlin-Goltz Syndrome))
• High recurrence rate

Differential Diagnosis

Memory Aid - Multilocular lesions of the mandible (MACHO)
Mxyoma Amelobastoma Central giant cell tumour Haemangioma/vascular malformation Odontogenic Keratocyst

• Other cysts of the jaws
• Radiological differentials:
  1. Odontogenic myxoma
  2. Ameloblastoma
  3. Central giant-cell granuloma
  4. Haemangioma/Vascular malformations
  5. Adenomatoid odontogenic tumor
  6. Dentigerous cyst
• Histological differentials:
  1. Radicular cyst
  2. Ameloblastoma

Aetiology and Pathogenesis

Aetiology

• Developmental cyst - arises from dental lamina and its remnants (cell rests of Serres)
• Can be sporadic or syndromic
• Syndromic cases:
  • Associated with mutation/inactivation of PTCH gene (which activates SHH pathway)
  • 5% occur as part of Nevoid basal-cell carcinoma syndrome (Gorlin-Goltz Syndrome)

Pathogenesis

• Mutation of PTCH
  • PTCH is a tumour suppressor gene that encodes the PTCH protein
  • PTCH protein is a receptor for sonic hedgehog (SHH)
  • In adult tissue, SHH plays a role in cell cycle regulation (SHH dysfunction is implicated in various cancer types)
  • ↓ PTCH gene activity → release of the break on cell cycle (mediated by SHH) → ↑ proliferative activity in epithelial lining of keratocysts
  • This increase in proliferative activity causes enlargement of the cyst by mural growth (as opposed to osmotic growth seen in other cysts)
  • Increase in proliferative activity may also contribute to recurrence rates
• Mural growth of cysts
  • Growth is by extension of finger-like processes into marrow spaces rather than by expansion (growth is said to be "neoplastic")
  • Growth of the wall is faster than the expansion of cyst cavity ∴ the lining becomes folded
  • Cyst enlarges slowly along the pathway of least resistance

Investigations

Unilocular odontogenic keratocyst

Large multilocular odontogenic keratocyst

Intermediate magnification of an odontogenic keratocyst showing a folded cyst.

High magnification of an odontogenic keratocyst.

Laboratory Investigations

Aspiration of cyst contents may be helpful for analysis of protein content (biochemistry) and keratinization (cytology)

Imaging

Plain film

• Well defined radiolucent area with a sharply demarcated and corticated bony wall
• Radiographically usually multilocular
  • Unilocular lesions tend to have a scalloped margin
  • When multilocular, can mimic ameloblastoma if many locules exist
• Can mimic other cysts
  • 40% in a ‘dentigerous’ position
• Adjacent roots/teeth may become displaced by large cysts, but usually the cyst will extend around the roots and inferior alveolar nerve without displacing them or causing significant expansion

Computed Tomography

• Can facilitate diagnosis, and 3D characterisation for surgical planning

Histopathology

• Biopsy is the diagnostic investigation of choice (OKCs have a consistent and unique appearance)
• Features:
  1. Epithelium
     • Regular stratified squamous epithelium
     • 5-8 cells thick
     • Palisaded basal layer (cells are columnar in shape)
     • Lack rete ridges
     • Often have artifactual separation from basement membrane
     • Corrugated surface which can be parakeratinized (83%), orthokeratinized (10%) or both (7%)
  2. Thin fibrous capsule
  3. Satellite (daughter) cells
     • Particularly seen in those with NBCCS
  4. Cyst contents
     • Fluid has protein content <4g/ dL
  5. High mitotic activity
  6. Inflammatory changes
     • Inflamed cysts show hyperplastic epithelium which is no longer characteristic of OKCs and can have resemblance to radicular cysts instead
     • A larger biopsy is needed to confirm OKC if there is inflammation

Management

• !Controversial topic¡
• Diagnosis must be confirmed by biopsy
• Treatment considerations:

Unilocular + small multilocular lesions

• Conservative enucleation and bone curettage
• Difficult to ensure all of cyst lining is removed ∵ friable capsule + complex outline of cyst
• Epithelial remnants and satellite/daughter cysts can easily be left behind after enucleation
• It is currently considered that enucleation alone is an inadequate form of treatment and needs to be used in combination with adjuvant methods (see below)

Large cyst extending around muti-rooted teeth

• Difficult to completely remove, teeth may have to be sacrificed to ensure complete removal
• May require decompression first followed by enucleation
• Decompression is a modified marsupialization technique which causes the cyst to decrease significantly in size and the cystic lining becomes thicker resembling oral mucosa that allows for easier enucleation
• This method decreases the levels of IL-1α which regulates epithelial cell proliferation in OKC; hence, there is immune-histochemical evidence that decompression is superior to enucleation alone

Very large cyst

• Resection and bone reconstruction (free-flap)
• Resection provides the least recurrences

Adjuvant treatment to enucleation

1. Peripheral ostectomy
   • Aggressive form of adjuvant therapy where methylene blue is utilised to stain any cystic remnants and a rosehead bur is used to remove these
2. Carnoy's solution
   • Chemical curettage that causes cell necrosis of the cystic lining
3. Cryotherapy (liquid nitrogen)
   • Liquid nitrogen causes cell necrosis of the cystic lining

Suggested Management Protocol

Management protocol for odontogenic keratocysts (OKC). (CT: computed tomography, MRI: magnetic resonance imaging, IAN: inferior alveolar nerve, Rx: treatment, RR: recurrence rates). Image from Titinchi 2020

Prognosis and Complications

• Recurrence:
  • High recurrence rate (up to 60%)
  • Higher in NBCCS and presence of satellite cells
  • Lower in orthokeratinised odontogenic keratocysts

Summary of recurrence rates (%) for different surgical methods in the management of odontogenic keratocysts - data from 5 large systematic reviews

Study	Enucleation alone	Enucleation & Peri-oestectomy	Enucleation & Carnoy’s solution	Enucleation & cryotherapy	Marsupialization/ decompression alone	Decompression & residual cystectomy	Resection
Al-Moraissi et al. (2017)	23.10	17.40	11.50	14.50	32.30	14.60	8.40
de Castro et al. (2018)	20.80	NA	NA	NA	18.50	11.90	NA
Chrcanovic and Gomez (2017)	22.50	18.60	5.30	20.90	28.70	18.60	2.20
Johnson et al. (2013)	25.60	NA	7.90	30.30	NA	15.80	6.30
Kaczmarzyk et al. (2012)	26.09	18.18	50	NA	40	NA	0
Average	23.60	18.10	18.70	21.90	29.90	15.20	4.20

Follow-up

• Yearly follow-up for at least 5 years
• Orthopantogram every year, MRI every 2 years