Central Odontogenic Fibroma: characteristics and management

-- Introduction: Central Odontogenic Fibroma (COF) is a rare benign odontogenic tumour of the jaws. Until its recent change in classi ﬁ cation by the WHO in 2017, this entity has gone without an agreed upon de ﬁ nition for many years. For this reason, COF would remain largely unknown to practitioners. Corpus: The pedagogical objectives of this article are, through a systematic review of the literature using the PRISMA methodology, to list the epidemiological, aetiological, clinical, radiological, histological, therapeutic and prognostic characteristics of COF. All the data collected made it possible to establish a COF management summary for practitioners in order to optimize it. Conclusion: Based on the 135 cases listed, it appears that surgical enucleation is the treatment of choice for COF. The recurrence rate is low and malignant transformation has never been reported. However, regular clinical and radiological follow-up of patients over several years seems to be a justi ﬁ ed precaution.


Introduction
According to the World Health Organization (WHO), Central Odontogenic Fibroma (COF) is a rare benign odontogenic tumour of mesenchymal origin [1]. This tumour consists of mature connective tissue in which islands or strands of inactive-looking odontogenic epithelium can be found with or without evidence of calcification. Described for the first time by the WHO in 1971, COF has not had a consensual definition for years and its classification has recently undergone changes. Since 2017, the WHO now distinguishes the lesion according to its location (central or peripheral) and no longer on the basis of histological criteria [1]. Simple and complex histological subtypes (poor and rich in inactive-looking odontogenic epithelium, respectively) have thus been removed from this classification, without any justification.
Very few studies have been published on COF, and those that have consist mainly of case reports or small series from which it is difficult to draw conclusions. In more, only one systematic review without histological variant has been carried out, but it does not specify the articles used for their statistical analysis [2]. Given its rarity, the evolving nature of its definition and classification, COF is relatively unknown to practitioners. Based on a systematic review of the literature using the PRISMA methodology, we collected and analysed the various cases of COF in order to optimize its management. The educational objectives are: -To update the epidemiological data on COF -To clarify its aetiology -To describe its clinical, radiological and histological characteristics -To discuss its possible differential diagnoses -To determine its treatment of choice -To assess its prognosis and to estimate the follow-up duration required after treatment.

Corpus
Materials and method of the systematic review A systematic review of the literature was performed according to the PRISMA methodology. An electronic search was conducted up until April 15, 2019 in the Scopus and PubMed databases. The keywords MeSH ("fibroma" and "odontogenic tumors") were used. The search equation was on Scopus: "KEY ("fibroma") OR KEY ("Odontogenic tumors") AND ALL ("central odontogenic fibroma") AND (LIMIT-TO (DOCTYPE, "ar") OR LIMIT-TO (DOCTYPE,"re"))", and on PubMed: "("Fibroma" The article selection process is described in the PRISMA flow chart (Fig. 1). 81 articles (7 retrospective studies and 74 case reports) were included bringing the total number of COF cases listed to 135. Data from these cases were extracted using a dedicated grid. This data concerned (1) age and sex, (2) clinical features, (3) radiological features, (4) histological features, (5) treatments performed, (6) follow-up duration, (7) possible recurrence and malignant transformation. Where the histological or radiological characteristics of COF were not fully described, two authors independently evaluated the figures to remedy it. The included publications had a low level of scientific evidence (level 4) according to the evaluation criteria of the National Agency for Accreditation and Evaluation in Health (ANAES). Based on the data from the included articles, the COF recurrence rate was calculated as follows: Total number of recurrences Total number of lesions included in the study Â 100 Responses to the educational objectives Epidemiology COF is considered by the WHO to be a rare tumour but no epidemiological data are shown [1]. It represented 1.5% of central odontogenic tumours (16 cases out of 1088 biopsied tumours) [3]. This was probably an overestimate since histological variants of COF (such as ossifying odontogenic fibroma) that are no longer recognized by the WHO have been accounted for. Our systematic literature review identified 135 cases of COF. This was 41 cases less than the 176 cases listed by Correa Pontes et al. in their systematic review but comparison with our data was impossible since these authors did not reference all the cases included [2]. Based on the 135 cases we identified, COF occurred in a wide age range, from 3 to 80 years, with an average age of 30 years (Fig. 2). A predominance was observed between the second and third decade of life regardless of gender. The male/female sex ratio was 0.8.

Aetiology
The aetiology of COF remains unknown. According to one hypothesis that was taken up by the WHO in 2005, COF would derive from the dental follicle for simple histological types and from the periodontal ligament for complex types [4]. These 2 potential origins are no longer listed in the current WHO classification (2017) [1]. In addition, one case of COF associated with tuberous sclerosis complex [5] and one case associated with Gorlin syndrome [6] have been described without a proven causal link.
Clinical features COF was located more frequently in the mandible (53.3% of cases) than in the maxilla (46.7% of cases) (Fig. 3A). In the mandible, the most affected area was the posterior molar sector (58.3% of cases), followed by the premolar sector (38.9% of cases) and the ramus (26.4% of cases) (Fig. 3B). In the maxilla, the premolar region was most frequently affected (63.4% of cases), followed by the incisor À canine sector (49.2% of cases) and finally the posterior molar sector (19% of cases).
COF is considered by the WHO to be a non-aggressive and non-recurrent tumour [1]. While it was difficult to determine the aggressiveness of COF based on literature data, recurrence was quantifiable. Four cases of recurrent COF were reported [9,19,43,73]. The recurrence rate of COF was 6% and its annual recurrence rate was 1.4%. For these calculations, only data from 67 patients with a minimum follow-up of 12-months after surgical treatment was considered (estimated duration of effective mucosal and bone healing) [6,7,9,10,12,14,[16][17][18][19]22,[27][28][29][32][33][34]36,38,[42][43][44]46,[48][49][50][51][52][55][56][57][58][59]62,65,66,69,70,72,73,78,81,83,85]. This recurrence rate of 6% was lower than the rate of 10% suggested by Correa Pontes et al. [2]. This last rate was calculated based on 5 cases of recurrent COF out of a total of 50 cases that indicated the presence (or absence) of recurrence. The authors did not impose a minimum duration of follow-up after treatment for the selection of these 50 cases, which would have allowed to distinguish a delay in healing from a recurrence of the lesion. Moreover, the cases selected to establish this rate were not referenced. No prognostic factors could be identified from the literature because the number of recurrent cases seems too limited to allow a reliable calculation of the recurrence rate of COF for each suspected risk factor.
Recurrences were diagnosed between 16 and 108 months after treatment (mean = 52 months, SD = 42). It should be noted that although the longest recurrence was diagnosed at 108 months (i.e. 9 years) after the procedure, a radiological examination at 48 months had already detected a radiolucent lesion at the same site as the COF. Earlier diagnosis would have been possible if additional investigations had been undertaken at this time. To estimate the minimum duration of follow-up for a COF after treatment, we took into account the longest time between treatment and the onset of signs of recurrence of the lesion, which was 60 months [19].
Nonetheless, given the lack of regular follow-up of the patient concerned, this is probably a high estimate. Regular long-term clinical and radiological follow-up seems to be necessary to detect signs of potential recurrence. Surgical management of COF recurrences has not been specified for 3 of the 4 cases listed [9,19,43]. In one case an interruptive hemimandibulectomy was performed [73]. Finally, malignant transformation of COF has never been reported in the literature.
An illustrated pedagogical summary of the management of COF, based on the results of this systematic literature review, is proposed to guide practitioners (Fig. 5).

Conclusion
COF is a rare benign tumour that predominantly affects 20-30-year-olds and the mandible. The lesion most often manifests as a firm and painless vestibular swelling. The radiological signs are not pathognomonic. The lesion is mostly radiolucent, unilobular with well-defined limits. It tends to push the surrounding structures without invading them. It is frequently associated with an impacted tooth. In rare cases, it can lead to external root resorptions and cortical bone perforations. Diagnosis is based on the convergence of clinical, radiological and histological data. Surgical enucleation is the treatment of choice for COF with a low recurrence rate. Malignant transformation has never been reported in the literature. However, regular clinical and radiological follow-up of the patient over several years seems to be a justified precaution.

Conflicts of interests:
Prof. Philippe Lesclous is editorin-chief of JOMOS review.