Introduction
Cysts are abnormal, closed sac-like formations that contain a liquid, gaseous, or semisolid substance and are surrounded by tissue. Based on odontogenesis, oral cysts are separated into two categories: odontogenic cysts (OCs) and non-odontogenic cysts (NOCs) (non-OCs).1 The most common lesions found in the jaws are odontogenic cysts. "Cavities filled with liquid, semiliquid, or gaseous fluid with odontogenic epithelial lining and connective tissue on the outside," according to the description.2 They come from the epithelial component of the odontogenic apparatus, or fragments of it, which are implanted in the bone or the gingival tissues around it.2 Oral pathological lesions are dominated by odontogenic cysts.3
OCs are best characterized as inflammatory or developmental based on their origin and etiology.3 Inflammatory cysts form as a result of inflammation; however, the triggering elements that cause developmental cysts to form are unknown.3
Over 50 years ago, Philipsen (1956) coined the name "odontogenic keratocyst" (OKC) to characterize a category of odontogenic cysts with a distinctive histological appearance.4 It makes up around 11% of jaw cysts.5 (Figure 1)
In the World Health Organization (WHO) classifications of 1971 and 1992, the term "keratocyst" was used to designate any cyst with keratinization, and it was suggested as the official terminology for a specific form of an odontogenic cyst. OKC was classified into two histological types: parakeratinized and orthokeratinized.6 Orthokeratinized variation was detected in 12% of instances while the parakeratinized form was seen in 90% of cases.6
Classification of OKC
The classification of odontogenic keratocysts (OKCs) is still a topic that many dental researchers discuss. While the first two WHO classifications of odontogenic lesions (Pindborg et al., 1971; Kramer et al., 1992) classified OKCs as developmental odontogenic cysts, the 2005 edition of the World Health Organization Classification of Head and Neck Tumours reclassified OKCs as neoplastic lesions under the name "keratocystic odontogenic tumors" (KCOTs).7 Because KCOTs are locally aggressive jaw cystic lesions with theoretical growth potential and a proclivity for recurrence, it was classified as a benign neoplasm rather than a cyst by the WHO in 2005.8, 9 (Figure 2)
OKC was recategorized by the World Health Organization in 2017 as an odontogenic cyst of developmental origin, with orthokeratinized cyst being classed separately. (Figure 3)
Etiopathogenesis
The formation of the dental lamina, and particularly remnants of it after this organ has served its job, is likely to be linked to the etiology of OKC.10 Due to the improbable probability of remains or offshoots of this dental lamina being situated in the mucosa posterior to the final molar, the common presence of OKC posterior to the 3rd molar region is difficult to describe if dental lamina is supposed to be the etiological derivation.11 This may also arise from basal cells of overlying epithelium. The tendency for this illness to proliferate along the cancellous channels with relatively little cortical expansion is one of its distinguishing traits. To explain this, several theories of OKC expansion have been offered. Intraluminal hyperosmolality, active epithelial proliferation,12 cyst wall collagenolytic activity,13 and keratinocyte production of interleukin 1 and 6 are among them.
Autophagy, a lysosome-dependent catabolic process, plays a critical role in tumor growth regulation by degrading cellular proteins and organelles. Autophagy is a noteworthy finding in KCOTs, as it is induced during tumor formation and plays a crucial role in anti-apoptosis and tumor cell proliferation.14
GENETICS Ptch gene
Sonic Hedgehog (SHH), bone morphogenetic protein (BMP), Wnt, HGF, and FGF, as well as tumor suppressor genes functioning as cell growth regulators, influence the morphogenesis and cytodifferentiation of teeth. Tumor formation occurs when these genes are inactivated by mutations and/or loss of heterozygosity (LOH). 15 PTCH ("patched") is a tumor suppressor gene found on chromosome 9q22.3-q31.36–40 in both NBCCS and sporadic KCOTs. The binding of PTCH to SMO prevents the transmission of growth signals. This inhibition is released when SHH binds to PTCH. If PTCH's usual function is gone, SMO's proliferation-stimulating effects are permitted to take over. Atypical activation of the SHH signaling system during adulthood has been linked to the development of tumors.
Immunohistochemical examination of PTCH, SHH, and SMO expression patterns in sporadic KCOTs revealed that SMO expression is linked to KCOT recurrence. 15
Growth factors
Ki-67, PCNA, and p53
Various studies of the proliferative activity of the lining epithelium of KCOTs have focused on the expression of p53, proliferating cell nuclear antigen (PCNA), and Ki67. 15
Clonality analysis
A neoplasm's origin from a single clone of genetically identical cells is a distinguishing feature. Gomes et al. (2009) investigated the clonal genesis of 19 odontogenic tumors, including 6 OKC patients.15 Twelve of the 16 instances with information indicated a monoclonal pattern. The remaining two OKCs were polyclonal, while four of the six were monoclonal. While the authors stressed that most odontogenic tumors, including OKCs, are clonal, they did attribute the four polyclonal occurrences to stromal or inflammatory cell contamination of samples. A substantial scattered inflammatory cell component was found in both polyclonal OKCs.
Apoptotic mechanisms
Recent research has found that bcl-2 positive cells are mostly found towards the base of the lining epithelium, supporting the idea that apoptosis does not occur in these cells. TUNEL-positive cells have only been seen at the surface layer of KCOTs, indicating that they have experienced severe apoptosis. Thus, bcl-2 prevents apoptosis in the basal and supra-basal layers to enhance cellular proliferation, whereas apoptosis maintains the thickness of the lining epithelium and allows the development of vast amounts of keratin in the surface layer of KCOTs. Given that in this type of lesion, there is a regulated equilibrium between cell proliferation, cell differentiation, and cell death, this could explain why KCOTs, despite having a neoplastic nature and a high proliferative capacity, do not form tumor masses. 15
Incidence, Clinical Presentation, and Natural History
OKCs account for around 10% of all odontogenic cysts, with a wide age range (from 8 to 82 years) and a peak in the third decade of life.16 Males have a minor majority in most series. OKCs are found in tooth-bearing areas. In the mandible, they occur twice as frequently as in the maxilla.17 The posterior sextant, the angle, or the ramus are the most common sites where OKCs originate from the jaw.9, 18 The most typical locations of origin in the maxilla are the anterior sextant, primarily between the canine and lateral incisors, and the third molar region.19, 20 (Figure 4)
In most situations, despite their aggressive activity, OKCs induce modest bone extension due to their propensity to expand through the intramedullary region, "increasing the length of the bone." 21 Asymptomatic patients may have large lesions that cause significant erosion of cortical plates and involvement of adjacent structures. OKCs rarely induce root resorption of adjacent teeth, unlike other odontogenic lesions with comparable aggressive tendencies, such as ameloblastomas. 22
Imaging Techniques
Conventional radiography (primarily panoramic radiography), computed tomography (CT), and magnetic resonance imaging (MRI) are the most popular radiological imaging modalities employed in the study of OKCs.
Panoramic radiography
OPG is useful for determining the location, size, form, margins, and extension of odontogenic lesions such OKCs.
OKCs emerge on radiography as a well-defined unilocular or multilocular radiolucency with corticated edges. Around the roots of teeth, these cortices are frequently scalloped. Unilocular lesions are the most prevalent, but multilocular lesions are found in around 30% of patients, most typically in the mandible.23
Approximately 30% of OKCs are linked to at least one unerupted tooth, the third molars being the most prevalent. This link is more common in younger patients.
However, because it provides a two-dimensional picture of maxillofacial structures with magnification, geometric distortion, and overlapping, this radiography technique has a restricted role. As a result, a three-dimensional imaging modality is frequently necessary for preoperative planning, especially in bigger lesions, to overcome these constraints.
Cone beam and multi-detector computed tomography
When examining an OKC, CBCT is thought to be more effective at demonstrating bony alterations in the cortical plates of the jaws (buccal, palatal, or lingual cortices), but MDCT is better at demonstrating internal density and soft tissue extension. The primary radiological aspects of an OKC, including size, shape (hydraulic or scalloping), edges (well-defined and corticated), internal appearance (unilocular or multilocular), and effects on nearby structures, may all be seen on a CT scan (tooth displacement, root resorption, maxillary sinus floor elevation, inferior displacement of mandibular canal).
CT also shows bony alterations (expansion in the buccolingual/palatal direction and erosion), internal density, and extension into soft tissue, which are all characteristics of OKCs. The OKCs in the mandible grow primarily mesiodistally throughout the length of the bone, resulting in limited enlargement of the buccal and lingual cortical plates. 24 (Figure 5 ) Furthermore, when OKCs arise from the alveolar bone next to the maxillary sinus, the sinus's floor is raised and its lumen is diminished.
Magnetic resonance imaging (MRI)
MRI is most commonly used as a supplement to CT (CBCT or MDCT), and it can be useful in some circumstances to provide a better view of interior characteristics and soft tissue involvement. The majority of OKCs had moderate or high signal intensity on T1-weighted sequences and heterogeneous signal intensity (from low to high) on T2-weighted sequences, according to several publications.25
Histopathology
The gross specimen analysis reveals a fluid-filled, thin-walled, friable cyst with derbies. The content's viscosity ranges from a straw-colored liquid to purulent, cheese-like materials. According to one study, a protein content of less than 4.0gm/100ml indicates an OKC diagnosis.
Epithelium
The histological characteristics are distinct and specific. The cysts are lined by a keratinized stratified squamous epithelium that is thin and varies in thickness from 5-to 8.
Basal cells
Basal cells are made up of a palisaded, polarized layer of cuboidal or columnar epithelial cells that are frequently hyperchromatic and have a 'picket fence' or 'tombstone' look.
Suprabasal layers
Suprabasal layer cells are polyhedral, with intracellular edema and intercellular bridges common. Mitotic figures are more frequently seen in the suprabasal layers than in the basal layers.
OKC lining is usually parakeratotic, but it can also be orthokeratotic, and both kinds can be found in different areas of the same cyst. Orthokeratinized OKCs make up 12 percent to 13 percent of keratinizing odontogenic cysts, and they're more common in the second to fifth decades of life, with a male predisposition, and they're more common in the mandible, with a tendency for the back of the jaw. The size can range from less than a centimeter to more than seven centimeters.15
Epithelial connective tissue
The epithelium-connective tissue capsule relationship is prone to failure, and separation occurs in numerous locations. Lysosomal enzyme activity may promote the restructuration of juxta epithelial collagen fibers. As a result of this infolding, the OKC grows.15
Connective tissue capsule
The mucopolysaccharides-rich fibrous capsule is thin and frequently loose or myxoid, with a small number of cells separated by stroma. The cystic epithelium does not differentiate independently of the stroma. As a result, keratocysts’ biologic behavior may be influenced not only by the epithelium but also by the stroma.
Mast cells are found in vast numbers in the connective tissue walls, and they are more abundant just beneath the epithelium (subepithelial zone) than in the deeper sections (intermediate and deeper areas), according to Smith G et al. Mast cells play a significant role in cyst growth. 15
Role of inflammation
Although OKC is classified as a developing lesion, the connective tissue wall is inflamed in the majority of instances. In cases when the cyst is near neighboring teeth, the presence of inflammation may be attributed to communications with the oral mucosa or by the periodontal ligament, which has been demonstrated to be active in recruiting inflammatory cells during a normal response.15
Differential Diagnosis
An OKC associated with an impacted tooth can mimic a dentigerous cyst. Similar to ameloblastoma, an OKC that are multilocular and located in the posterior sextant or ramus of the mandible can be mistaken for one. Finally, an OKC with a periapical location or involving an edentulous area may be mistaken for a radicular cyst or residual cyst. As a result, the most prevalent odontogenic lesions in the differential diagnosis of an OKC are dentigerous cyst, ameloblastoma, and radicular cyst, residual cyst and simple bone cyst.26
Syndromic and non-syndromic multiple OKCs
Multiple OKCs are thought to be one of the most important diagnostic criteria for NBCCS, and their existence may be the disease's initial indication. Multiple nevoid basal cell carcinoma, multiple OKCs, palmar or plantar pits, calcifications of the falx cerebri, and skeletal anomalies such as bifid, fused, or splayed ribs are all symptoms of NBCCS, also known as Gorlin–Goltz syndrome. 27
Treatment of OKC
The therapy of these lesions can be divided into two types: conservative and aggressive. Enucleation with or without curettage, decompression, and marsupialization are all part of the conservative approach. Peripheral ostectomy (with rotating devices), cryotherapy (with liquid nitrogen), and Carnoy's solution application are all aggressive procedures. The goal of all of these procedures is to enucleate the cyst and reduce the risk of recurrence and surgical morbidity. Although, due to the small sample size, retrospective nature of the studies, limitations in the specifics presented of the therapy procedures, and heterogeneity of the control checkups, it is extremely difficult to evaluate the therapeutic results in diverse studies.28 (Figure 6)
Recurrence
The recurrence rate of OKCs following surgery has been reported to be as high as 30%, with the majority of recurrences occurring after conservative treatments such as simple lesion enucleation. Patients with NBCCS and multilocular lesions had higher recurrence rates, according to reports.29 Recurrences could be due to a variety of factors, including insufficient ablation of the epithelial cyst lining's highly active basal layer, the creation of small intramedullary satellite cysts left behind by conservative treatment, and the development of new lesions in the jaws' surrounding region. Some studies suggested that recurrence could be linked to the biological characteristics of the lesion and the presence of proliferative markers like Ki-67.30
Conclusion
Odontogenic keratocysts (OKCs) are odontogenic cysts that are benign but aggressive. They account for around 10% of all odontogenic cysts and are characterized by aggressive behavior. In determining the size of the lesions and their relationship to neighboring structures, a combination of clinical and radiological observations is helpful. With a better understanding of the histological nature, etiology, and recurrence affecting variables, OKC management should now focus on the following principles:
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