The results derived from 41 studies including 3 systematic reviews and meta-analyses [ 6, 8, 9] are summarized and presented using a narrative structure/framework. Since majority of the studies included in this analysis are retrospective, we acknowledge that a low level of evidence is derived from such studies and that constitute an unavoidable limitation of this work. The proposed surgical algorithm includes diagnosis and treatments of OKCs (Figs. 1, 2 and 3).
The pathologists have been encumbered with the task of confirming OKCs alleged nature in order to appropriately label it and this informed the choice of treatment modality that will result in low prospect of recurrence. The surgeons, in addition, have explored various treatment modalities in a bid to discover the most suitable approach to preventing its persistently high recurrence rate .
The neoplastic nature of OKC was largely attributed to both its association with patched (PTCH) gene alterations and its destructive growth pattern. The PTCH gene which is a tumor suppressor gene is an important molecule in the SHH signaling pathway as it normally forms a receptor complex with the oncogene SMO [28–32]. The binding of SHH to PTCH releases the inhibition of growth signal transduction seen in PTCH binding to SMO. Mutation in PTCH gene mapped to chromosome 9 q22.3–q31 ultimately results in its inactivity and an eventual exaggeration of the proliferating–stimulating effect of SMO . Despite the fact that loss of heterozygosity (LOH) in the 9q22.3 region, a presumed tumorigenic feature, has been documented in most cases of OKCs studied, these changes are non-specific because some other odontogenic cysts also have been reported to exhibit LOH in this region [34–38]. Furthermore, reports that OKC has been successfully treated by marsupialization with reduction in rate of recurrences has also augmented the argument for its reinstatement as a cyst [39, 40].
OKC is generally more common in males than females. The mandible is by far the more frequently affected site, with the angle-ramus region being the predominant site. The cyst has a wide age of distribution spanning the first to ninth decades of life but with a peak in the second and third decades .
OKC characteristically grows rapidly within the medullary cavity in an anteroposterior direction such that clinically obvious swelling of the jaw bones appears late . Thus, patients are usually not symptomatic until the lesion grows to a large size to cause an obvious swelling. Other features of OKC include; pain (usually when infected), cystic content discharge and pathological fracture. Otherwise, early cases of this condition are discovered fortuitously with routine dental radiographs [1, 41].
It is paramount to outline the preoperative diagnostic differences between OKC and other odontogenic cysts or the cystic subset of ameloblastoma as this definitely has an impact on subsequent treatment planning and definitive management. In other words, working around the effective differential diagnoses of cystic jaw conditions can help surgeons better plan their final treatment, which tends to differ according to lesion.
Radiographically, OKC may present with displacement of the roots of adjacent teeth but root resorption is not common. Some cases may be associated with an unerupted tooth, thus mimicking a dentigerous cyst [1, 41].
With the use of conventional radiograph and computerized tomography (CT), it is not possible to differentiate between ordinary odontogenic cysts and ameloblastoma. Besides this, radiographic presentation of OKC (unilocular or multilocular radiolucency) is often similar to those of other odontogenic lesions such as; dentigerous cysts, calcifying odontogenic cysts, calcifying epithelial odontogenic tumors and cystic ameloblastomas [3–5, 7]. However, CT and magnetic resonance image (MRI) have been reported to aid accurate localization of OKCs particularly in the maxillary sinus and small crevices at the rim of the lesion [6–10]. In particular, conventional magnetic resonance imaging sequences (T1 and T2-weighted images) with or without fat suppressed or contrast enhanced (i.e. Gadolinium chelate) and MRI have the potential to differentiate these lesions [6–10]. OKCs present as heterogeneous signals intensity of cystic contents (non-enhancing lesions) with intermediate or high signal intensity on T1-weighted images, intermediate signal intensity on T2-weighted images and thin rim enhancement on contrast enhanced T1-weighted images lesion [6, 8–10]. Ameloblastoma on the other hand appears as low signals intensity on T1-wieghted images, high signals intensity on T2-wieghted images and relatively thick rim enhancement on contrast enhanced T1-weighted images. While odontogenic cysts present as homogeneous low signal intensity on T1-weighted images and homogeneous high signal intensity on T2-weighted images [9–10]. In addition, it has recently been reported that diffusion-weighted MRI may help to differentiate odontogenic cysts from odontogenic tumors using the measurement of Brownian motion of molecules technique in the attempt of tissue characterization [8, 11, 42–43]. Thus, estimation of apparent diffusion coefficient for non-enhancing lesions (cystic contents) can help to differentiate between OKCs and other odontogenic cysts. OKCs have been reported to have lower values of apparent diffusion coefficient of non-enhancing lesions when compared to ameloblastomas [11, 42–43].
Aspiration and analysis of cystic content to identify amount of total protein (which is usually less than 4g/100 mL), albumin, pre-albumin, and detection of epithelial squames may be used as a reliable preoperative diagnosis of OKC [44–46]. However, for non-expansile lesions where aspiration is relatively difficult to perform, incisional biopsy through an open technique will provide adequate tissue sample to obtain a definitive histologic diagnosis prior to undertaking treatment.
Pindborg and Hansen in 1962 were the first to propose necessary histological criteria for the diagnosis of OKC as; uniformly thin lining of stratified squamous epithelium devoid of rete ridges, above which is an equally thin parakeratinized surface layer, intracellular oedema present within a 4–8 celled spinous layer and a relatively thin fibrous connective tissue capsule that lacks inflammatory cells but may contain daughter cysts . The friable and thin lining coupled with absence of rete ridges usually makes it easy for the epithelial cells to detach from the connective tissue capsule during treatment, leaving remnants of cyst epithelium behind and forming foci for recurrence . In previously inflamed OKC, the epithelial lining appears thicker and becomes orthokeratinized; masking the actual pathology [48–51]. In such instances, it is advisable to obtain multiple incisional biopsy specimens from sites adjudged to be uninflamed for histologic assessment . Hopefully, a small area of these several cuts should give the diagnosis.
Recent reports have supported the intraoperative use of frozen section in the diagnosis and management of OKC. This technique can either be employed without a prior incisional biopsy in “the one stage method” or it is used intraoperatively to determine if the entire cystic lining has been removed from the surgical site . Later use of frozen section biopsy will help decide which further adjunctive treatment option is appropriate [52–54].
Immuno-staining with p53 has been reported to reveal significantly higher levels of abnormal p53 in OKC than other epithelial cysts and oral mucosa. Thus, the locally invasive behavior and high recurrence rate of OKC can be attributed to the presence of mutant or otherwise inactive p53 protein . Higher Ki-67 positive cells with increased proliferation rates have been reported in epithelium of OKC as compared to other developmental cysts. In addition, when compared with non-recurrent type, the recurrent OKC had a higher median LI for Ki-67. These findings have been proposed to contribute to the clinical aggressiveness of OKC . Immune-staining with α-SMA has been found to be significantly highest in OKC than other destructive jaw lesions, indicating the presence of a higher mean number of myofibroblasts in OKC compared with other tumours that behave aggressively .
In view of the peculiar nature of OKC especially its high recurrence potential (placed at 20–60%) [ ] which can be ascribed to the nature of its cystic lining, it has become necessary to proffer a unified treatment modality that will help attain the least chance of recurrence in its management.
We recommend that treatment for confirmed cases of OKCs presenting as small unilocular radiolucencies be careful enucleation without as much as possible violating the cyst integrity (although this is almost impossible given the friable nature of the lining). Extraction of adjacent involved teeth is then done. This treatment should be followed by selective management of the bone walls by use of either Carnoy’s solution (with or without chloroform) or liquid nitrogen or 5-FU. In areas where cortical perforation has occurred, the overlying attached oral mucosa should also be excised. Studies on recurrence of OKCs have reported secondary lesions in close proximity to retained adjacent teeth . This is the rationale for extraction of adjacent involved teeth in dentate patients.
A long-term follow-up period of up to twenty-five years is advised as such variants have been reported to recur several years later .
When large unilocular radiolucent lesions located in the posterior mandible or maxilla is encountered, the OKCs might often have perforated the thin cortex of the maxilla with possible invasion into the pterygopalatine space. The recommended and best treatment for such cases, aside enucleation followed by peripheral ostectomy is the excision of the overlying attached soft tissue. In large posterior maxillary cysts in particular, where the invasion of ptrygomaxillary space is imminent but undesirable, decompression prior to definitive treatment is recommended. Additionally, selective cauterization using Carnoy’s solution (with or without chloroform) or liquid nitrogen or 5-FU can be applied [17, 26, 41, 50, 60–64].
For multilocular lesions, aspiration and incisional biopsies are usually easily performed because of bone expansion. While tissue biopsy remains the gold standard in diagnosis of OKC, MRI sequencing images is able to help in differenting between tumors and others cystic lesions [3, 5–11, 42–43] and, in localizing perforations, fenestrations and daughter’s cysts specifically in maxillary lesions . The treatment of choice for multilocular OKCs smaller than 3 cm is cyst enucleation and the bony defect are managed using Carnoy’s solutions (with or without chloroform) or liquid nitrogen or 5-FU. Extraction of any adjacent involved teeth for dentate patients is carried out.
Where the lesion has perforated the bony confines, excision of the overlying attached gingiva should be performed. In addition, for those lesions located in suspected areas (posterior mandible and maxilla), more attention is required because of the presence of bony fenestration in the ascending ramus and thin perforated buccal cortex in the posterior maxilla respectively. Thus, excision of the overlying attached mucosa should be performed with cyst enucleation, followed by treatment of bone defect to destroy and fix any remnant of epithelial cells and daughter cyst using Carnoy’s solution (with or without chloroform), or Liquid nitrogen or 5-FU. Selective cauterization of the bony defect should be performed in the maxilla to avoid injury to the sinus lining. Peripheral ostectomy of the surrounding bone defect should be done before chemical cauterization of alveolar process and tuberosity [17, 26, 41, 50, 60–64]. In cases where multilocular lucent lesions less than 3 cm radiographically are situated in close proximity to vital structures, either enucleation or marsupialization followed by residual cystectomy is recommended .
Multilocular lesion larger than 3 cm
Initial OKCs greater than 3 cm that are located in the tooth bearing areas should be treated using a conservative approach, specifically for pediatric, elderly and compromised patients or lesions that are approximate to vital structures. A recent meta-analysis showed 12% recurrence of KCOTs (now OKCs) after decompression followed by residual cystectomy . Consequently, the recommended treatment is marsupialization, simultaneously with incisional biopsy of the cyst lining. The overlying attached oral mucosa should be examined closely to identify aspects with fenestrations or bone perforation. To decompress the cyst, excision of the overlying oral mucosa that has attached cyst lining (through fenestration or perforation) is strongly recommended. By so doing, possible presence of epithelial islands clusters and microcysts that could contribute to the development of new cysts if left behind (recurrence) would be eliminated. Twice daily cystic cavity irrigations (with 0.12% chlorhexidine gluconate and saline) through the inserted secured tube should be performed. Clinical and radiographic follow up for 1 year (every 2 months) should be carried out or until further treatment is engaged. After radiographic confirmation of considerable decrease in size of the lesion and obvious bone formation, the tube is remove and residual cystectomy performed with emphasis on excising overlying mucosa to completely eliminate remnant clusters of epithelial islands and microcysts that might be present between mucosa and cystic lining. This should be followed by peripheral ostectomy and treatment of bone defect using Carnoy’s solution (with or without chloroform) or liquid nitrogen or 5-FU.
In unresponsive cases (when size of lesion does not regress after 6 months of decompression) of multilocular OKCs with resorption of inferior and or posterior mandibular borders; these signs should be considered as indicators of aggressiveness. Thus, such lesions should be treated by radical resection with excision of affected/involved overlying attached mucosa.
For all cases of recurrent OKCs (primary or secondary recurrence) we recommend aggressive treatment; due to the likely contamination of the surrounding environment (bone and mucosa/soft tissue) with offshoots from the cyst lining or epithelial islands and microcysts. Thus, such lesions should be resected with or without continuity defect. In addition, dissection of supra periosteal area of overlying attached mucosa or adjacent soft tissue are highly recommended [13, 54, 63–65].
The management of teeth related with / associated with OKC has received some appreciable attention in literature. Interventions offered ranged from extraction, to endodontic treatment and no treatment at all. Findings from these interventions suggest no statistically significant association between recurrence rate and treatment method applied to related teeth (p = 0.579) . Others imply that preservation of teeth involved in the lesion appears to increase the risk of recurrence [66, 67]