Odontogenic keratocysts (OKCs) are developmental odontogenic cysts of epithelial origin, first identified and described in 1876 and further characterized by Phillipsen in 1956.  Pindborg and Hansen suggested the histologic criteria necessary to diagnose OKC in 1962.  The initial terminology for an odontogenic keratocyst (OKC) was "primordial cyst," as the origin of the lesion was thought to be the tooth primordium. In 1992, the World Health Organization (WHO) histologic typing of odontogenic tumors listed "odontogenic keratocyst" (OKC) as the preferred terminology for such cysts with a keratinized lining. 
The odontogenic keratocyst (OKC) is known for its high recurrence rate, aggressive behavior, and its occasional association with the nevoid basal cell carcinoma syndrome (NBCCS).  Three histologic variants were recognized initially: a parakeratinized variant, an orthokeratinized variant, and combination of the two. The less aggressive clinical behavior and recurrence pattern of the orthokeratinized variant ultimately warranted the designation of the orthokeratinized variant as a separate entity, "orthokeratinized odontogenic cyst" (OOC). 
NBCCS, also referred to as Gorlin-Goltz syndrome, is associated with a gene level disturbance of chromosome 9 and is transmitted as an autosomal dominant trait with high penetrance.  This syndrome was established as an entity by Gorlin and Goltz in 1960 and has a low incidence of 1 in 56,000 people. 
NBCCS is an ectomesodermal polydysplasia with numerous manifestations, characterized most often by cutaneous abnormalities, including multiple basal cell carcinomas, benign dermal cysts, palmar-plantar pits; craniodentofacial anomalies, such as odontogenic keratocyst (OKC), malocclusion, broad nasal bridge, and increased head circumference; skeletal anomalies, including frontal and parietal bossing and mandibular prognathism, as well as costal anomalies involving the rib and vertebrae; ophthalmologic abnormalities, including hypertelorism, congenital blindness, and strabismus; and neurologic anomalies, including calcifications of the falx cerebri, bony bridging of the sella turcica, and medulloblastoma. 
The components of NBCCS can be divided into 2 groups, as suggested by Evan et al  and Kimonis et al  : with so-called major and minor criteria. The final diagnosis of the syndrome is achieved upon finding any 2 of the major criteria, or 1 major criterion plus 2 minor criteria.
Multiple odontogenic keratocysts (OKCs) are a well-recognized feature of NBCCS (see the image below).  Usually, odontogenic keratocyst (OKC) development, which comprises one of the major criterions, occurs before the observation of other clinical findings in NBCCS, enhancing early diagnosis of the disease. Odontogenic keratocysts (OKCs) associated with this syndrome have a familial tendency, and early family detection and genetic counseling are critical.  These cysts arise earlier in patients with NBCSS than in those who are unaffected by the syndrome.
Odontogenic keratocysts (OKCs) associated with NBCCS have occasionally been reported to transform into aggressive neoplasms such as ameloblastomas and squamous cell carcinoma.  The cyst lining seen in the NBCSS-related odontogenic keratocyst (OKC) is classically parakeratinized and does not appear to be associated with the orthokeratinized variant of the OKC.
Many odontogenic tumors have been described to have extraosseous equivalents, and although odontogenic keratocysts (OKCs) are regarded primarily as intraosseous lesions, they can also occur in a peripheral location  ; 16 such cases have been reported in the literature with a mean patient age of 57.8 years and a female predilection.  Peripheral odontogenic keratocysts can be seen in association with NBCCS. 
The cystic nature of odontogenic keratocyst (OKC) has long been debated, with some investigators classifying the OKC as a benign tumor.  In recent years, the WHO has recommended that the term "keratocystic odontogenic tumor" (KCOT) replace the term "odontogenic keratocyst" (OKC), as it better reflects the neoplastic nature of the lesion. [14, 15] Several factors, such as the cyst's aggressive behavior, high mitotic activity histologically, and evidence of associated genetic and chromosomal abnormalities (eg, mutation of the PTCH gene) often seen in neoplasia, serve as the basis for this new classification. [6, 15, 16]
Ehler-Danlos syndrome is a hereditary disorder of the connective tissue related to collagen metabolism. Rare occurrence of multiple odontogenic keratocysts (OKCs) has been reported in this syndrome. [17, 18]
Odontogenic keratocysts (OKCs) account for approximately 3-11% of all cysts in the jaws. [1, 19] They occur in all ages, with a peak incidence in the second and fourth decades of life, [9, 19] with the youngest patient reported at age 5 years.  The mean age of patients with multiple odontogenic keratocysts (OKCs), with or without NBCCS, is younger than those with single nonrecurrent OKCs.
Odontogenic keratocyst (OKC) is predominantly a disease of white individuals, primarily Northern Europeans, and there is a reported male-to-female ratio of 1.6:1, [1, 19] although Chirapathomsakul et al reported that OKCs are slightly more common in women than men.  Peripheral odontogenic keratocysts (OKCs) have a female predominance with a female-to-male ratio of 2.2:1. 
Odontogenic keratocysts (OKCs) are generally thought to be derived from remnants of the dental lamina (rests of Seres), traumatic implantation or down growth of the basal cell layer of the surface epithelium,  or reduced enamel epithelium of the dental follicle.  Studies have suggested a genetic cause, specifically a PTCH gene aberration, in the etiology of these cysts.
Odontogenic keratocysts (OKCs) can be found in the mandible and the maxilla but are twice as common in the mandible, with a predilection for the angle and ascending ramus. [1, 20] Rare examples of these cysts arising from the temporomandibular joint (TMJ) have been reported.  Mandibular cysts can cross the midline, and maxillary cysts may involve the sinus and floor of the nose.  Although most odontogenic keratocysts (OKCs) are encountered as intraosseous lesions, peripheral manifestations have been reported, primarily involving the buccal gingival soft tissue  in the canine area of the mandible. 
Clinical Features and Imaging
Clinically, odontogenic keratocysts (OKCs) generally present as a swelling, with or without pain. [14, 20] The cyst classically grows within the medullary spaces of the bone in an anteroposterior direction, causing expansion that is at first minimal.  Buccal expansion is noted in approximately 30% of maxillary and 50% of mandibular lesions.  It has been demonstrated that the collagenase activity in the cysts' epithelium with its resorbative properties appears to regulate the ability of the lesion to grow expansively in bone. 
Radiographically, odontogenic keratocysts (OKCs) present as a well-defined radiolucent lesion that is either unilocular or multilocular, with smooth and usually corticated margins, unless they have been secondarily infected (see the images below).  In 25-40% of cases, there is an unerupted tooth involved with the lesion  ; adjacent teeth may be displaced, but root resorption is rarely seen. Maxillary lesions tend to be smaller than mandibular lesions; however, more extensive involvement can be appreciated in the maxilla because of the cancellous nature of the bone.  Larger lesions can cause bony expansion with or without perforation of the cortical plates. 
Radiographically, differentiation between an odontogenic keratocyst (OKC) and other odontogenic cysts and tumors can be challenging. The radiographic features of odontogenic keratocysts (OKCs) are not pathognomonic, and the presentation can be similar to that of other odontogenic cysts and tumors. Odontogenic keratocysts (OKCs) can present as dentigerous cysts, primordial cysts, residual cysts, lateral periodontal cysts, or cysts in a nasopalatine location.  Misinterpretation of an odontogenic keratocyst (OKC) as a lesion of endodontic or periodontal origin can confuse treatment planning  ; thus microscopic assessment is the key to diagnosis (see Microscopic Findings).
When odontogenic keratocysts (OKCs) are seen in a pericoronal location, differentiation from a dentigerous cyst may be difficult. Radiographic connection of a cyst to a tooth at a point apical to the cementoenamel junction, with no expansion, favors an odontogenic keratocyst (OKC). The typical multilocular appearance of an OKC can be mistaken for that of ameloblastoma or odontogenic myxoma, although ameloblastomas typically present with significant clinical expansion. The scalloped margin of a simple bone cyst and its tendency for minimal expansion can be similar to that of an odontogenic keratocysts (OKCs); however, the margins of a simple bone cyst are more delicate and difficult to detect. 
Keratoameloblastoma, a rare histologic variant of the ameloblastoma, can resemble an odontogenic keratocyst (OKC). The epithelium lining of keratoameloblastoma differs from the OKC in that it is not always of uniform thickness, and there is typically separation and edema between the basal cell layer and the rest of epithelium in the keratoameloblastoma. 
The epithelial lining and connective tissue wall of the odontogenic keratocyst (OKC) is characteristically thin and friable, thus causing the specimen to fragment when treated.  Grossly, the lesion often has a bosselated, gray, cystic appearance mimicking the appearance of a glove.
In 1962, Pindborg and Phillipsen and Henriksen established strict histologic criteria for the diagnosis of an odontogenic keratocyst (OKC). These criteria include an epithelial lining that is usually thin and uniform in thickness, with little or no evidence of rete ridges; a well-defined basal cell layer, the component cells of which are cuboidal or columnar in shape and often fashioned in a palisaded arrangement; a thin, spinous cell layer which often shows a direct transition from the basal cell layer; spinous-cell layer intracellular edema; surface keratinization that is corrugated and predominantly parakeratotic; and a fibrous connective tissue cyst wall that is thin and usually uninflamed (see the following images). 
Additionally, satellite cysts, solid epithelial proliferations, odontogenic rests (see the image below), and basal layer budding have been described in association with the odontogenic keratocyst (OKC).  The incidence of daughter cysts in the cyst wall is reported to range from 7% to 30.1%. Mineralization in the fibrous connective tissue wall may occur, along with inclusion of cholesterol crystals and Rushton bodies. 
A number of studies have discussed the histologic variants of the odontogenic keratocyst (OKC): (1) parakeratinized (see the first image below), (2) orthokeratinized (see the second image below), and (3) combined. There appear to be no statistical differences between orthokeratinized and parakeratinized odontogenic keratocysts (OKCs) when age, race, sex, symptomatology, and the clinical impression are compared. The recurrence rate, however, is much higher in the parakeratinized variant,  thus, some investigators have suggested that the orthokeratinized variant be classified as a separate entity. [4, 27]
Limited data exist regarding the recurrent rate of the combined orthokeratinized and parakeratinized variants.  In a series of 449 cases of odontogenic keratocyst (OKC) assessed by Crowley et al, 86% of cases were parakeratinized, 12.2% were orthokeratinized, and 1.6% had features demonstrating both orthokeratin and parakeratin variants.  The recurrence rate of the parakeratinized variant in that study was 47.8%, whereas that of orthokeratinized OKCs was 2.2%.  Subsequently, the orthokeratinized variant of the odontogenic keratocyst (OKC) was separated as an entity and termed "orthokeratinized odontogenic cyst."
Some histopathologic features are thought to help in the diagnosis of odontogenic keratocysts (OKCs) associated with NBCCS. Budding of the basal cell layer of the lining epithelium and the presence of a high number of daughter cysts in the connective tissue wall tend to favor an association with NBCCS, 
In a review of 183 cases of odontogenic keratocysts (OKCs), 17.1% of cases showed koilocytosis, which raises the possibility of a papillomavirus (HPV) etiology for the lesion  ; however, HPV has not been identified in odontogenic keratocysts (OKCs) using molecular and immunohistochemical methods. The OKC lining may rarely show epithelial dysplasia, and the lesion does have the potential to evolve into ameloblastoma or squamous cell carcinoma. 
Strong p63 staining has been demonstrated in the epithelium of odontogenic keratocysts (OKCs), especially in the suprabasal layer of the epithelium.  It has been postulated that p63 plays a role in blocking apoptosis-inducing and growth inhibitory actions, which may facilitate the proliferative potential of epithelial cells due to its capability of blocking wild type p53, thus enhancing the biologic aggressiveness of these cysts. [30, 31]
Matrix metalloproteinases (MMPs) are enzymes thought to play an important role in regulating the integrity and composition of the extracellular matrix (ECM) and consequently degradation, proliferation, differentiation, and cell death.  MMP-1, synthesized by a variety of normal cells including epithelial cells, is one of the major proteases that can degrade the triple helical domain of type I fibrillar collagen, which is responsible for connective tissue strength and rigidity. MMP-1’s expression is thought to be associated with odontogenic keratocyst (OKC) degradation of the organic bone matrix, favoring dissemination of these cysts through the trabecular spaces.  With immunohistochemistry, MMP-2s have also been observed to reside in the basement membrane of odontogenic keratocysts (OKCs), and they have been implicated in the degradation of the extracellular matrix surrounding the cysts. 
Vascular endothelial growth factors (VEGFs) comprise a family of multifunctional proteins and act as a sensitive measure of the angiogenic potential of a lesion.  VEGFs have been implicated in the pathogenesis of cystic tumors and radicular cysts,  and they have been documented to be intensely expressed in odontogenic keratocysts (OKCs). [14, 32]
A number of studies have examined the expression profile of p53, proliferating cell nuclear antigen (PCNA), and Ki-67 in odontogenic keratocysts (OKCs). These markers have been reported to be expressed more strongly in these cysts than in other types of odontogenic cysts. 
In a study of 30 cases of odontogenic keratocyst (OKC), gp38, an epithelial specific 38-kD cell surface glycoprotein, showed consistent positivity of all basal and suprabasal cell layers and when satellite cysts were present in all parakeratinized OKCs. These findings suggest an alteration in gene expression supporting the view that the odontogenic keratocyst (OKC) has neoplastic potential. 
The biologic mechanism associated with the expression of p53 protein in the epithelium of odontogenic keratocysts (OKCs) is not well understood, but the aggressive behavior and high recurrence rate of these lesions may be related to the expression of this protein.  In a study performed on 37 odontogenic keratocyst (OKC) cases by Gurgel et al, 91.9% of the cases were strongly positive for p53 in the suprabasal layers of the cystic epithelium,  but no significant difference in p53 immunostaining was observed between odontogenic keratocysts (OKCs) associated with NBCCSs or sporadic OKCs [30, 35] It remains unclear whether p53 positive immunostaining in odontogenic keratocysts (OKCs) is because of gene mutation or simply a product of accumulation of normal p53 protein in the site. 
The NBCCS or PTCH gene has been mapped to chromosome 9q22.3-q31, which functions as a tumor suppressor. Studies on NBCCS and occasional solitary odontogenic keratocysts (OKCs) suggest that the PTCH gene might play a role in the development of sporadic OKCs.  Sun et al reported 26 PTCH1 mutations in odontogenic keratocysts (OKCs). 
Prognosis and Predictive Factors
Odontogenic keratocysts (OKCs) are the most aggressive odontogenic cysts that involve the oral cavity,  largely related to their ability to extend into the adjacent soft tissue and bone. Most recurrences take place within 5-7 years after treatment, although some recurrences have been encountered more than 10 years following initial surgical intervention.  The peripheral odontogenic keratocyst (OKC) is far less aggressive than its intraosseous counterpart, and therefore, a more conservative treatment approach is recommended. [12, 21] .
Treatment of odontogenic keratocysts (OKCs) remains controversial, and management modalities can be categorized as either "conservative" or "aggressive,"  based on multiple factors including lesional size, anatomic relationship, recurrence pattern, and the cyst's association with NBCCS.  Multiple surgical management techniques have been reported, including marsupialization, enucleation, enucleation with the use of Carnoy's solution, decompression, marginal or radical surgical resection, and bone implantation. 
There is very little information in the literature defining whether the size of an odontogenic keratocyst (OKC) can affect its potential to recur. [15, 39] In a report by Zhao et al, of 489 patients treated for odontogenic keratocysts (OKCs), 255 had follow-up over a period of 3 to 29 years, in which no correlation could be made as to recurrence potential based on lesion location.