Abstract
Purpose
Odontogenic keratocysts (OKCs) have high recurrence rates. We aimed to identify recurrence patterns in OKCs and the onset of second primary OKCs in non-syndromic and syndromic patients.
Material and Methods
Patients with OKCs reporting to our department from 1998 to 2021 (23 years) were retrospectively evaluated using demographic, clinical (age, sex, location, and size), histopathological, radiographic, and treatment data. All patients were followed-up for > 3 years and evaluated for OKC recurrence. Patients with naevoid basal cell carcinoma syndrome (NBCCS) were evaluated separately.
Results
We included 38 and 13 patients in the non-syndromic and syndromic OKC groups, respectively. The recurrence rates were 15.8 and 21.4% in the non-syndromic and syndromic groups, respectively; 8.9% of patients exhibited a second recurrence and 1.8% a third recurrence. No second primary OKCs were observed in the non-syndromic group; 76.9% of patients in the syndromic group developed at least one.
Conclusion
We found a higher recurrence rate in patients with NBCCS compared with patients with non-syndromic OKCs (21.4 versus 15.8%). The probability of developing a second primary OKC in patients with NBCCS was higher compared with that in patients with non-syndromic OKCs (76.9 versus 0%). No statistically significant risk factors for OKC recurrence were identified.
Keywords: Odontogenic keratocyst, Naevoid basal cell carcinoma syndrome, Gorlin-Goltz syndrome, Keratocystic odontogenic tumour
Introduction
Odontogenic keratocysts (OKCs) were first described by Philipsen in 1956 [1] and renamed keratocystic odontogenic tumours by the World Health Organization (WHO) in 2005 because of their local aggressiveness and high recurrence rates [2].
In 2017, the WHO reconsidered the criteria and reclassified these tumours as OKCs [3]. The dental lamina epithelial remnants play key roles in OKC aetiology [4, 5]. Further, patched 1 (PTCH1) gene mutations are associated with syndromic and non-syndromic OKCs [6]. Naevoid basal cell carcinoma syndrome (NBCCS) is characterised by multiple OKCs in both the maxilla and mandible, although both syndromic and non-syndromic OKCs are predisposed to the mandibular third molar region [4, 7, 8]. The diagnosis of OKC can be challenging due to the lack of pathognomonic clinical or radiographic features and the resemblance of OKCs to dentigerous cysts, especially in association with teeth [4, 9]. Definitive diagnosis is possible only after histopathological examination, which demonstrates the presence of typical parakeratinised stratified squamous epithelium [7]. Different treatment modalities for OKCs have been described, including marsupialisation with or without secondary enucleation, enucleation with or without removal of the overlying mucosa, and radical resections. Additional modalities such as cryotherapy, Carnoy’s solution, and coagulation may eliminate epithelial islands and micro-keratocysts in the peripheral bone [4, 5, 7, 10]. Since there is no consensus on the ideal treatment, we aimed to identify the recurrence patterns and onset of second primary OKC, which can present even after radical resection.
Material and Methods
Study Design/Sample
We collected available data on patients with OKCs who presented to our department from January 1998 to December 2021. We included patients with parakeratinising OKCs with a minimum follow-up period of 36 months. The exclusion criteria were as follows: the presence of an orthokeratinising variant (considered a separate entity), a follow-up period of < 36 months, and insufficient data regarding radiology or surgery.
Variables
Data pertaining to the following clinical factors were collected: age at diagnosis, sex, presence of NBCCS, OKC location, treatment choice, presence of cortical perforation, pathological report, follow-up duration, and presence of recurrence. Radiographs were systematically evaluated to assess OKC size and location. The mandible was divided into three areas: symphysis (canine to canine), mandibular body (premolar to third molar), and posterior mandible (mandibular angle or ascending ramus). The maxilla was divided into two areas: anterior maxilla (canine to canine) and posterior maxilla (posterior to premolar region). In cases of doubt or in cases where the OKC extended over more than one area, the most distal region of involvement was considered. A second primary OKC was defined as a newly diagnosed OKC at a location where no OKC was previously diagnosed.
Recurrence was defined as a newly diagnosed OKC at a location of a previously treated OKC. A second recurrence was defined as a newly diagnosed OKC at a previously treated recurrence location. A third recurrence was defined as a newly diagnosed OKC at a previously treated second recurrence location.
Data Collection Methods
We searched our hospital’s oral and maxillofacial surgery database; clinical, radiological, and surgical notes were evaluated.
Data Analyses
Statistical analyses were performed by an external statistical bureau. The data was analysed using S-Plus 8.0 for Linux (TIBCO Software Inc., Palo Alto, CA, USA). Chi-square tests were used to compare variables between syndromic and non-syndromic OKCs. Recurrence risk factors were identified with time-to-event analyses using Cox proportional hazards models and Kaplan–Meier curves. P-values < 0.05 were considered significant.
Figures were made using MS Office 365.
Results
All cases were individually screened and classified into two groups: the non-syndromic OKC and NBCCS OKC groups.
Non-Syndromic Lesions
Thirty-eight patients with non-syndromic OKCs were included in this study: 23 men (60.5%) and 15 women (39.5%) (male to female ratio, 3:2). The mean diagnosis age was 43 (range 9–87) years. Most OKCs occurred in the mandible (25 patients, 65.8%), although some occurred in the maxilla (13 patients, 34.2%). The mandible and maxilla were divided into sections (Table 1).
Table 1.
Location of OKCs
| Non-syndromic OKC | NBCSS OKC | ||
|---|---|---|---|
| Maxilla | Anterior | 2 (5.3%) | 1 (1.8%) |
| Posterior | 11 (28.9%) | 24 (42.9%) | |
| Mandible | Symphysis | 0 (0%) | 5 (8.9%) |
| Body | 8 (21.1%) | 15 (26.8%) | |
| Posterior | 17 (44.7%) | 11 (19.6%) |
Data are presented as n (%)
NBCSS naevoid basal cell carcinoma syndrome; OKC odontogenic keratocyst
The mean OKC area on orthopantomograms was 5.68 (1.00–17.5) cm2. OKC-related cortical perforation occurred in 26 patients (68.4%). In one case, some data was missing on the surgery report, and the radiographs were unclear. Most perforations were located in the buccal cortex (12 cases, 46.2%), though eight cases (30.7%) demonstrated perforation through the lingual cortex and six cases (23.1%) reported bi-cortical perforation. Cortical perforation of the maxilla and mandible were calculated separately (Table 2). Six OKCs (15.8%) were polycystic and 32 (84.2%) were uni-cystic. Twenty-five OKCs were identified near the inferior alveolar; in 17 cases (68.0%) the inferior alveolar nerve was displaced by the OKC, and the mean OKC area on orthopantomograms was 6.15 (1.00–17.5) cm2. Only one case (2.6%) with root resorption was identified. Satellite lesions were identified in two cases (5.2%).
Table 2.
Perforation of the primary OKC
| Non-syndromic OKC | NBCSS OKC | ||
|---|---|---|---|
| Maxilla and Mandible | Buccal | 12 (46.2%) | 33 (63.5%) |
| Lingual | 8 (30.7%) | 13 (25%) | |
| Bi-cortical | 6 (23.1%) | 6 (11.5%) | |
| Maxilla | Buccal | 7 (87.5%) | 23 (100%) |
| Lingual | 0 (0%) | 0 (0%) | |
| Bi-cortical | 1 (12.5%) | 0 (0%) | |
| Mandible | Buccal | 5 (27.8%) | 10 (34.5%) |
| Lingual | 8 (44.4%) | 13 (44.8%) | |
| Bi-cortical | 5 (27.8%) | 6 (20.7%) |
Data are presented as n (%)
NBCSS naevoid basal cell carcinoma syndrome; OKC odontogenic keratocyst
The treatments comprised marsupialisation alone (one case, 2.6%), marsupialisation and enucleation (6 cases, 15.8%), or enucleation alone (31 cases, 81.6%). Adjuvant treatment (rinsing with Carnoy’s solution) after enucleation was performed in 21 patients (55.2%).
OKC recurrence was observed in six cases (15.8%) (Table 3).
Table 3.
Differences in outcomes between non-NBCSS and NBCSS groups
| Non-syndromic OKC | NBCSS OKC | |
|---|---|---|
| Recurrence | 15.8% | 21.4% |
| Time of recurrence, months | 32.3 | 58.8 |
| Second primary | 0% | 76.9% |
| Perforation preference | ||
| Maxilla | Buccal | Buccal |
| Mandible | Lingual | Lingual |
| Nerve displacement | 68.0% | 22.2% |
| Root resorption | 2.6% | 0% |
NBCSS naevoid basal cell carcinoma syndrome; OKC odontogenic keratocyst
The mean recurrence was 32.3 (15–49) months after primary OKC treatment: marsupialisation (one case, 16.7%) or enucleation (five cases, 83.3%). Four patients with recurrence (66.7%) received adjuvant treatment with Carnoy’s solution. One patient experienced a second recurrence (2.6%) 13 months post-treatment of the primary recurrence. This patient was treated with enucleation followed by rinsing with Carnoy’s solution. The follow-up duration of each individual patient is presented in Fig. 1; the mean follow-up duration was 74.2 (36–187) months. Treatment types and clinical and radiographic variables were compared with the presence of recurrence. No variables were associated with a high recurrence rate (P > 0.05).
Fig. 1.
Follow-up period of each participant in the non-syndromic OKC group. Follow-up period for each non-syndromic patient. Note that that none of the non-syndromic patients developed a second primary OKC. OKC, odontogenic keratocyst
Naevoid Basal Cell Carcinoma Syndrome
NBCCS, or Gorlin-Goltz syndrome, is an autosomal dominant disease characterised by multiple primary OKCs and various tumours, including basal cell carcinoma [8].
Thirteen patients with NBCCS were included in this study: seven women (53.8%) and six men (46.2%). The mean age at the first visit was 32.7 (range 5–70) years. Ten patients (76.9%) with NBCCS had > one primary OKC, one patient suffered from ten primary OKCs. The number and follow-up period of every primary OKC per patient are shown in Fig. 2. We identified 56 primary OKCs: 29 occurred in men and 27 in women. Most OKCs occurred in the mandible (31, 55.4%), although 25 (44.6%) occurred in the maxilla (Table 1).
Fig. 2.
Number and follow-up period of each primary OKC in the NBCSS group. All primary OKCs with their individual follow-up period are shown per NBCSS patient. Note that 10 patients have more than one primary OKC. Patient 11 developed ten primary OKCs. NBCSS, naevoid basal cell carcinoma syndrome; OKC, odontogenic keratocyst
The mean primary OKC area on orthopantomography was 4.58 (0.10–22.75) cm2.
In 52 cases (92.9%), the cortical bone was perforated by the OKC, and most perforations were located in the buccal cortex (33 cases, 63.5%); lingual cortex perforation was reported in 13 cases (25%) and bi-cortical perforation in six cases (11.5%). Cortical perforation of the maxilla and mandible were calculated separately (Table 2). Uni-cystic lesions were observed in 47 cases (87.1%) and polycystic lesions in 7 cases (12.9%); however, uni-cystic or polycystic lesions could not be differentiated owing to poor radiograph quality in 3 cases. Twenty-seven OKCs were identified near the inferior alveolar nerve site. In six cases (22.2%), the inferior alveolar nerve was displaced by the OKC, and the mean OKC area on orthopantomography was 4.28 (0.10–22.75) cm2. No root resorption was identified. Satellite lesions were not observed. The treatment modalities included: marsupialisation alone (5 cases, 8.9%), marsupialisation followed by enucleation (4 cases, 7.2%), or enucleation alone (47 cases, 83.9%). Adjuvant treatment (rinsing with Carnoy’s solution) after enucleation was performed in 31 patients (55.3%). OKCs recurred in 12 cases (21.4%) (Table 3). The mean time to recurrence was 58.8 (13–156) months post-treatment for the primary OKC. Treatments for recurrence included marsupialisation (2 cases, 16.7%) or enucleation (10 cases, 83.3%), and an additional rinse with Carnoy’s solution was performed in 6 cases (66.7%). Five patients experienced a second recurrence (8.9%), which occurred at a mean of 66 (range, 33–95) months post-treatment of the primary recurrence. The second recurrence was treated with enucleation in four cases, combined marsupialisation and enucleation in one case, and additional rinsing with Carnoy’s solution in three cases. One patient experienced a tertiary recurrence (1.8%) 74 months post-treatment of the primary recurrence; the tertiary recurrence was treated with enucleation. The mean follow-up of all thirteen patients was 126 (range 36–235) months. The individual follow-up period for each primary OKC in the syndromic group is shown in Fig. 2. All clinical and radiographic factors in addition to different treatment types were compared to assess the rate of recurrence. Polycystic OKCs tended to have higher recurrence rates (28.6%) compared with uni-cystic OKCs (20.4%; p = 0.0822). Further, syndromic patients treated with enucleation showed a greater recurrence tendency compared with patients treated with marsupialisation (p = 0.0677).
Comparison Between Non-Syndromic and Syndromic OKCs
Clinical factors were compared between the non-syndromic and syndromic OKC groups using chi-square tests. A significant age difference between the two groups was observed (P = 0.0002). The primary OKC location differed significantly between groups (P = 0.014). The chi-square test showed a significantly greater chance of cortical perforation in the syndromic group (92.9 versus 68.4%) (P = 0.0186). A similar perforation pattern was identified in both groups. The perforations in the mandible were mostly through the lingual cortex (44.4% of non-syndromic OKCs and 44.8% of syndromic OKCs). Nerve displacement was observed in 68% of non-syndromic OKCs and 22.2% of syndromic OKCs situated in the mandibular body or posterior mandible. In both non-syndromic and syndromic OKCs, treatment of recurrence with enucleation was associated with a significantly lower chance of second recurrence compared with marsupialisation alone (P = 0.0044). More second and third recurrences were seen in the NBCCS group, although this difference was not statistically significant (P > 0.05) (Table 3).
Discussion
Demographic and Clinical Data
Syndromic OKCs were diagnosed earlier than non-syndromic OKCs. The mean age at diagnosis for non-syndromic and syndromic OKCs was 43 and 32.7 years, respectively (p = 0.0002). This may be attributed to the genetic predisposition for OKC occurrence and shorter gaps in follow-up visits since most patients had a familial history of NBCCS.
According to Stoelinga, most OKCs occur in the third molar region [4]. In our study, up to 44.7% of non-syndromic OKCs occurred in the posterior mandibular region, whereas the posterior maxilla (42.9%) was the preferred location among syndromic OKCs; however, most OKCs in both groups occurred in the mandible (65.8%, non-syndromic OKCs; 55.3%, syndromic OKCs; Table 1).
Root resorption is not usually associated with OKCs, as confirmed in our study; only one case with associated root resorption was identified among the non-syndromic OKCs.
The preference for lingual perforation by OKCs [7] was confirmed in the mandible, although a preference for buccal perforation in the maxilla was observed (Table 2). A higher rate of nerve displacement was observed among non-syndromic OKCs (68.0 vs 22.2%), possibly owing to the large area of OKC involvement in the mandibular body and posterior mandible at the time of diagnosis among non-syndromic OKCs (6.15 cm2 vs 4.28 cm2).
Recurrence of OKC
A meta-analysis of 6427 OKCs reported an overall recurrence rate of 21.1%, with a higher recurrence rate (35.4%) in the NBCCS group [10], similar to our findings; the recurrence rate in the NBCCS group was higher (21.4%) than that in the non-syndromic group (13.9%). The recurrence risk increases up to 7 years after treatment [7], and in this study, recurrence occurred at a mean duration of 32.3 (15–49) and 58.8 (13–156) months after treatment in the non-syndromic and NBCCS groups, respectively. Different theories regarding OKC recurrence have been proposed. In cases with incomplete removal, epithelial islands or micro-keratocysts may be left behind [11–14]. They can be situated in the bone or overlying mucosa of the OKC [11, 14]. Although epithelial islands or micro-keratocysts are not always present in the overlying mucosa, incidence rates between 32.5 and 52.2% have been reported [15]. Therefore, some studies emphasise the importance of removing the overlying mucosa where the cyst herniates through the cortex and cauterising the defect to reduce the OKC recurrence risk [4, 12, 14]. We could not evaluate the presence of micro-keratocysts and epithelial islands in this study because data on their presence or absence was missing from the anatomopathological reports. Some risk factors for higher OKC recurrence include cortical perforation [7], polycystic lesions (since they are more difficult to remove completely) [7, 8, 10], and posterior mandibular lesions [7]. We could not assess the association between these risk factors and recurrence rate in syndromic or non-syndromic OKCs. Here, most OKCs presented with cortical perforations (68.4% among non-syndromic and 92.9% among syndromic OKCs). However, neither syndromic nor non-syndromic OKCs exhibited higher recurrence rates with cortical perforation. In this study, most OKCs were uni-cystic (84.2% among non-syndromic OKCs and 87.1% among syndromic OKCs). In the NBCCS group, polycystic OKCs demonstrated a higher recurrence rate compared with non-syndromic OKCs (P = 0.0822).
Choice of Treatment
A systematic review and meta-analysis conducted in 2017 revealed radical resection as the optimal modality to prevent OKC recurrence. However, radical resection is associated with high morbidity and should be performed only for multiple recurrent lesions [11, 16] or if other structures, such as the internal pterygoid and masseter muscles, are involved [12]. Enucleation and adjuvant treatment with Carnoy’s solution or cryotherapy should be the first choice of treatment. In case of marsupialisation, cystectomy should be performed at the second stage. In our study, both non-syndromic and syndromic OKCs showed a lower chance of second recurrence when treated with enucleation compared with marsupialisation alone as the initial therapy for recurrence (P = 0.0044), confirming that the first treatment choice should be enucleation, not marsupialisation alone.
Syndromic OKCs were diagnosed earlier than non-syndromic OKCs. The mean age at diagnosis for non-syndromic and syndromic OKCs was 43 and 32.7 years, respectively (P = 0.0002). In our study, additional rinsing with Carnoy’s solution was only performed in 55.2% of the non-syndromic OKCs and 55.3% of the NBCSS OKCs. Furthermore, this additional rinsing was mostly performed in earlier cases since the use of Carnoy’s solution was banned in our hospital in 2015 owing to its carcinogenic effect. We did not observe any significant reduction in recurrence in cases where Carnoy’s solution was used. Slusarenko da Silva et al. [9] suggested yearly follow-ups for the first 5 years and every 2 years thereafter in cases of small cysts in areas with teeth [9].
Conclusions
Syndromic OKCs are diagnosed at a younger age (32.7 vs 43 years) and have higher cortical perforation (92.9 vs 68.4%) and recurrence rates (21.4 vs 13.9%), with recurrence occurring later when compared with that of non-syndromic OKCs (58.8 vs 32.3 months post-treatment). The preferred perforation location was the same for both groups, with more buccal perforations in the maxilla and more lingual perforations in the mandible. Regular follow-up should be advised in patients with OKCs, since a recurrence even after 156 months was observed in this study. Although recurrence rates are high, the biggest challenge for patients with NBCCS is the development of new OKCs in different locations of the jaws (76.9%), which was not observed in the non-syndromic population.
Author Contributions
All authors contributed to the study conception and design. Material preparation data collection and analysis were performed by TVC and XJ. The first draft of the manuscript was written by TVC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declarations
Conflict of interest
The authors have no relevant financial or non-financial interest to disclose.
Ethics Approval
This retrospective observational study was evaluated and approved by the appropriate ethics committee ([blinded for review]).
Patient Permission/Consent
The ethics committee waived the requirement for informed consent owing to the retrospective nature of the study and use of de-identified data.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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