# Ossifying fibroma and juvenile ossifying fibroma: A systematic review on clinical and radiological parameters, treatment modalities and recurrence

Blandine Gautier, Sophie Dugast, Pierre Guyonvarc'H, Julie Longis, Pierre

Corre, Hélios Bertin

► To cite this version:

Blandine Gautier, Sophie Dugast, Pierre Guyonvarc'H, Julie Longis, Pierre Corre, et al.. Ossifying fibroma and juvenile ossifying fibroma: A systematic review on clinical and radiological parameters, treatment modalities and recurrence. Journal of Stomatology, Oral and Maxillofacial Surgery, 2024, 126 (4), pp.102185. 10.1016/j.jormas.2024.102185. hal-05328084

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Review

# Ossifying fibroma and juvenile ossifying fibroma: A systematic review on clinical and radiological parameters, treatment modalities and recurrence

<figure><img src="image_4.png" /></figure>

CrossMark

Blandine Gautier<sup>a</sup>, Sophie Dugast<sup>a</sup>, Pierre Guyonvarc'h<sup>a</sup>, Julie Longis<sup>a</sup>, Pierre Corre<sup>a,b</sup>, Hélios Bertin<sup>a,c, 1,*</sup>

## ARTICLE INFO

**Article History:**

Received 1 December 2024

Accepted 2 December 2024

Available online 3 December 2024

**Keywords:**

Ossifying fibroma

Mandible

Jaws

Fibro-osseous

Treatment

Recurrence

## ABSTRACT

Ossifying fibroma (OF) is a rare benign fibro-osseous neoplasm developing mostly in maxillo-facial bones. OF is divided in cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF) and psammomatoid ossifying fibroma (PSOF). The aim of this systematic review was to synthetize the existing literature on OF, investigating the clinical and radiological parameters related to the different forms of the disease, and to compare the treatment modalities according to their associated recurrence rate. Three databases were searched in March 2024, with an update in September 2024. Eligibility criteria included studies reporting on patients with OF, surgical treatment and follow-up data. Of the 2016 studies identified, 22 were retained after eligibility assessment. A total of 492 patients were included. Most OF presented with painless swelling. COF affected 61.1 % of women with a mean age of 29.5, JTOF presented in 55.7 % of male children, and PSOF had no predilection for sex with a mean age of 19.5 years. Enucleation and curettage were associated with an elevated recurrence rate in JTOF (12/30) and PSOF (10/16). PSOF (6 cases) and JTOF (15 cases) showed no recurrence with radical surgery. Same recurrence rates in COF were seen for conservative and radical surgery. Although radical surgery seemed to avoid recurrence in JTOF and PSOF, conservative surgery such as enucleation and curettage with additional peripheral ostectomy should be considered primarily to lessen the morbidity induced by radical resection. Close clinical and radiological follow-up should be undertaken to diagnose early recurrence.

© 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

## 1. Introduction

Ossifying fibroma (OF) is a rare benign fibro-osseous neoplasm developing mostly in maxillo-facial bones. The term ossifying fibroma was first used to define a slow growing tumor, a firm mass unencapsulated and well demarcated from the normal bone located around. There has been many uncertainties as where to classify these lesions; in its 5th edition (2022) the world health organization (WHO) finally classified OF in odontogenic or non-odontogenic fibro-

osseous lesions [1]. Cemento-ossifying fibroma (COF) is considered as a benign odontogenic fibro-osseous neoplasm originating from the periodontal ligament. The juvenile trabecular ossifying fibroma (JTOF) and the psammomatoid ossifying fibroma (PSOF) are both classified under benign fibro-osseous tumors group of non-odontogenic origin, and as two separate entities [1,2]. The diagnosis of OF can then be made difficult due to the ever-changing classifications. The diagnosis is generally established based on concordant clinical, radiographic and pathologic features. In some cases, it may be difficult to separate OF from other fibro-osseous lesions such as fibrous dysplasia and odontogenic cysts.

OF is described as a painless swelling occurring mostly in the jaws. Studies have shown a women predilection reaching a ratio of 5:1 for COF, the mean age of presentation is 2nd to 4th decades [3]. However, according to histology younger patients can develop OF with a mean age of 11.5 years for JTOF [4]. The symptoms vary according to the site of development of the tumor; ranging from jaw swelling and face deformity when occurring in the mandible, to epistaxis and nasal obstruction at early stage in maxillary localizations and may induce

<footnote><sup>a</sup> Nantes Université, CHU Nantes, Service de Chirurgie Maxillo-Faciale et Stomatologie, F-44000, Nantes, France</footnote>

<footnote><sup>b</sup> Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France</footnote>

<footnote><sup>c</sup> Nantes Université, Univ Angers, CHU Nantes, INSERM, CNRS, CRCI2NA, F-44000, Nantes, France</footnote>

<footnote>* Corresponding author at: Nantes Université, CHU Nantes, Service de Chirurgie Maxillo-Faciale et Stomatologie, F-44000, Nantes, France.</footnote>

<footnote>E-mail addresses: blandine.gautier@chu-nantes.fr (B. Gautier), sophie.dugast@chu-nantes.fr (S. Dugast), pierre.guyonvarch@chu-nantes.fr (P. Guyonvarc'h), julie.longis@chu-nantes.fr (J. Longis), pierre.corre@chu-nantes.fr (P. Corre), helios.bertin@chu-nantes.fr (H. Bertin).</footnote>

<footnote n="1">¹ Given his role as Editor, Hélios Bertin had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to the Editor-in-Chief Narcisse Zwetyenga.</footnote>
proptosis and visual disturbance when the tumor extends to the orbital region. The main site for occurrence is the mandible for COF, whereas a predilection in paranasal sinuses has been demonstrated for the PSOF [5,6]. Most of the OF expose a well-defined radiolucency or a mixed lesion with central opacities at early stage and increasing with time. In few cases tooth displacement can be seen, rarely associated to tooth resorption [7]. The growth is slowly increasing in COF with the period between first symptoms and diagnosis reaching years whereas the lesion is more aggressive in the juvenile type with rapid growth motivating consultation within month due to functional and esthetic disturbances [4,8]. The microscopic examination shows fibrous and mineralized tissue, encapsulated and well demarcated from the normal bone. Variation of mineralization can be seen, similar to the degree of cellularity where hypercellularity is mostly seen in JTOF and PSOF [1]. Clinically, the pathology is polymorphous, and the symptoms are not specific with regards to the other bone tumors of the facial skeleton.

The treatment modality is adapted to each patient. It is commonly admitted that conservative surgery should be proposed for small lesions. However, for giant, recurrent or aggressive lesions, radical surgery removing the entire lesion with appropriate margins and reconstruction using bone graft or free flap is commonly proposed after multiple recurrence [9,10]. Nevertheless, there is no official recommendation for the treatment of OF. Also, there is no currently known predictive factor for recurrence. Prognosis is usually good if surgery is complete with a recurrence rate in published literature that varies from 0 % to 56 % in the juvenile types [4], recurrence rate varies mostly depending on the surgical strategy. There has been only two published cases of malignant transformation into sarcoma [11,12].

To our knowledge, there is no comparative study of the different subtypes of OF regarding the clinic-radiological parameters and treatment modalities. The current literature on OF is mainly based on case reports and case series with a low number of patients. The aim of this systematic review was to synthetize the existing literature on OF, specifically investigating the clinical and radiological parameters related to the different forms of the disease, and to compare the treatment modalities and the associated recurrence rate after surgery.

## 2. Methods

This study was compliant with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement and was registered on PROSPERO (CRD42024500518).

### 2.1. Literature search strategy, inclusion criteria

An advanced search was conducted through Pubmed, Scopus and Web of science databases on the 1st of March 2024, with an update in September 2024. The search used the combination of terms for OF with precision on location (mandible and maxilla), using the Boolean operators OR and AND (Supplementary Materials). There was no restriction on the year of publication or language. Articles were exported to Rayyan software for first review. The selection of studies was conducted by two researchers (B.G. and H.B.) starting with title and abstract screening, followed by full-text reading of the selected articles; discrepancies were resolved by discussion. Authors were contacted when full text was not available to obtain full article, and when data were mixed with other fibro-osseous lesions or extra-gnathic lesions. Articles in other language than English were translated (deepl.com). A manual search was also performed by consulting references cited in included articles, those articles were reviewed with the same inclusion and exclusion criteria.

Articles were included based on the following criteria: patients diagnosed with OF based on clinico-radiological criteria eventually

confirmed by histopathologic examination (P), having received a surgical treatment (I), comparing the three entities of the disease (COF, JTOF and PSOF) (C), and reporting the efficacy of the treatment and recurrence rates (O). Exclusion criteria were: articles reporting on extra-gnathic localization, mixed lesions, syndromic OF or reports on recurrent cases. Case reports reporting <2 patients were also excluded.

### 2.2. Data extraction

The following data were extracted by one reviewer (B.G.): author's last name, year of publication, country of publication, number of included patients, clinical and radiological data, histologic characteristics, location (maxilla vs mandible, anterior vs posterior), size of the lesion, treatment (conservative vs radical), follow-up (duration), and recurrence and time to recurrence.

### 2.3. Quality assessment

Risk of bias was assessed by two independent reviewers using the JBI critical appraisal tool for case series in ten questions, for all included articles [13]. The answers were either yes, no, unclear or not applicable. Overall judgement of bias on each study was defined by high, medium, and low risks. The case-control study was also assessed using the same tool, as the data of interest were observational (clinical and therapeutic data).

## 3. Results

### 3.1. Study selection

The PRISMA flow diagram is given in Fig. 1. After removing the duplicates, a total of 2016 articles were screened, and 1915 articles were excluded based on titles and abstracts. The manual search allowed to identify 10 supplementary articles. After screening, 22 articles were eligible for inclusion in the study.

### 3.2. Included studies, quality of studies

All the included articles were observational studies (case reports or case series) except the study from Nikitakis et al. that compared JTOF with conventional OF [14]. Most of the studies were monocentric [8,15–31], three authors reported multicentric case series [32–34]. Five articles reported on children [14,15,19,21,29], 2 on adults [27,31] and 15 on both adult and children [8,16–18,20,22–26,28,30,32–34]. The number of included patients per series ranged from 3 [20,29] to 79 [18], with a total of 492 patients (275 females and 217 males). Study characteristics are reported in Table 1.

Risk of bias was assessed for each included study. Six studies were considered of having high risk of bias, 8 of medium risk of bias, and 8 of low risk of bias (Supplementary materials).

### 3.3. Patients' characteristics

The mean age at diagnosis was 11.9 years for JTOF (ranging from 4 to 14 years) [16,29], 19.5 years for PSOF (ranging from 7.5 to 23 years) [25,29], and 29.5 years for COF (ranging from 24.9 to 41 years) [23,32]. There was a female predilection for COF with a M:F ratio of 1:1.6. There were a male predilection in JTOF, especially in studies concerning children [14,21,30,34]. PSOF showed no sex predilection.

Swelling was the main symptom, occurring in 95.7 % of the patients, with no variation according to the pathologic entity (94.9, 96.3 and 96.0 % in JTOF, PSOF and COF respectively). Pain was more observed in patients with PSOF (40 % of the patients), compared to 20.7 % and 17.8 % in JTOF and COF respectively. The mean size at diagnosis was comprised between 2 and 3 cm. Painful lesions often had a
<figure><img src="image_5.png" /><figcaption>Fig. 1. Prisma flow diagram.</figcaption></figure>

**Table 1**

Characteristics of the included studies. F, female; M, male; JTOF, juvenile trabecular ossifying fibroma; PSOF, psammomatoid ossifying fibroma; COF, cemento-ossifying fibroma.

<table><thead><tr><th>Authors (date)</th><th>Country</th><th>Number of patients</th><th>Sex ratio F(%)/M(%)</th><th>Age (mean)</th><th>Population</th><th>Type of OF</th><th>Article type</th></tr></thead><tbody><tr><td>Slootweg et al. (1994)</td><td>Netherlands</td><td>33</td><td>42.44%/57.56%</td><td>19.33</td><td>Adults and children</td><td>JTOF, PSOF</td><td>Multicentric case series</td></tr><tr><td>El-mofty (2002)</td><td>USA</td><td>4</td><td>25.00%/75.00%</td><td>13.75</td><td>Adults and children</td><td>JTOF, PSOF</td><td>Monocentric case report</td></tr><tr><td>Park et al. (2007)</td><td>South Korea</td><td>3</td><td>66.67%/33.33%</td><td>8.33</td><td>Adults and children</td><td>JTOF, PSOF</td><td>Monocentric case series</td></tr><tr><td>Bustamante et al. (2008)</td><td>Spain</td><td>7</td><td>57.14%/42.86%</td><td>35.00</td><td>Adults</td><td>COF</td><td>Monocentric case series</td></tr><tr><td>Imanimoghaddam (2009)</td><td>Iran</td><td>5</td><td>100.00%/0.00%</td><td>31.40</td><td>Adults</td><td>COF</td><td>Monocentric case report</td></tr><tr><td>Abuzinada and Alyamani (2009)</td><td>Saudi Arabia</td><td>3</td><td>33.33%/66.67%</td><td>6.33</td><td>Children</td><td>JTOF, PSOF</td><td>Monocentric case report</td></tr><tr><td>Liu Y. et al. (2010)</td><td>Japan</td><td>20</td><td>55.00%/45.00%</td><td>27.80</td><td>Adults and children</td><td>COF</td><td>Monocentric case series</td></tr><tr><td>Triantafillidou et al. (2012)</td><td>Greece</td><td>14</td><td>64.29%/35.71%</td><td>33.86</td><td>Adults and children</td><td>COF</td><td>Monocentric case series</td></tr><tr><td>De Noronha Santos Netto et al. (2013)</td><td>Brazil</td><td>22</td><td>91.00%/9.00%</td><td>35.20</td><td>Adults and children</td><td>PSOF, COF</td><td>Monocentric case series</td></tr><tr><td>Gopinath et al. (2013)</td><td>India</td><td>8</td><td>62.5%/37.50%</td><td>13.13</td><td>Children</td><td>JTOF, PSOF</td><td>Monocentric case series</td></tr><tr><td>Prabhu et al. (2013)</td><td>India</td><td>60</td><td>55.00%/45.00%</td><td>25.60</td><td>Adults and children</td><td>PSOF, COF</td><td>Monocentric case series</td></tr><tr><td>Urs et al. (2013)</td><td>India</td><td>22</td><td>54.55%/45.45%</td><td>23.77</td><td>Adults and children</td><td>JTOF, PSOF, COF</td><td>Monocentric case series</td></tr><tr><td>Mohanty et al. (2013)</td><td>India</td><td>24</td><td>45.83%/54.17%</td><td>24.71</td><td>Adults and children</td><td>PSOF, COF</td><td>Monocentric case series</td></tr><tr><td>Phattarataratip et al. (2014)</td><td>Thailand</td><td>79</td><td>65.00%/35.00%</td><td>28.75</td><td>Adults and children</td><td>JTOF, PSOF, COF</td><td>Monocentric case series</td></tr><tr><td>Han et al. (2016)</td><td>China</td><td>15</td><td>66.67%/33.33%</td><td>13.73</td><td>Children</td><td>JTOF, PSOF</td><td>Monocentric case series</td></tr><tr><td>Liu J. et al. (2017)</td><td>USA</td><td>4</td><td>75.00%/25.00%</td><td>33.25</td><td>Adults and children</td><td>PSOF, COF</td><td>Multicentric case series</td></tr><tr><td>Liu Y. et al. (2017)</td><td>China</td><td>50</td><td>32.00%/68.00%</td><td>10.37</td><td>Children</td><td>JTOF, PSOF, COF</td><td>Monocentric case series</td></tr><tr><td>Kaur et al. (2019)</td><td>India</td><td>16</td><td>62.50%/37.50%</td><td>26.56</td><td>Adults and children</td><td>COF</td><td>Monocentric case series</td></tr><tr><td>Titinchi (2021)</td><td>South Africa</td><td>17</td><td>35.3%/64.70%</td><td>13.00</td><td>Adults and children</td><td>JTOF, PSOF</td><td>Multicentric case series</td></tr><tr><td>Nagar et al. (2021)</td><td>India</td><td>24</td><td>62.50%/37.50%</td><td>23.21</td><td>Adults and children</td><td>JTOF, PSOF</td><td>Monocentric case series</td></tr><tr><td>Nikitakis et al. (2022)</td><td>Greece</td><td>5</td><td>40.00%/60.00%</td><td>11.80</td><td>Children</td><td>JTOF</td><td>Monocentric case control study</td></tr><tr><td>Okwuosa et al. (2022)</td><td>Nigeria</td><td>57</td><td>63.2%/36.80%</td><td>24.05</td><td>Adult and children</td><td>PSOF, COF</td><td>Monocentric case series</td></tr></tbody></table>
<table><caption>**Table 2**
Clinical and radiological characteristics of the patients. n, number of patients; JTOF, juvenile trabecular ossifying fibroma; PSOF, psam-momatoid ossifying fibroma; COF, cemento-ossifying fibroma.</caption><thead><tr><th></th><th>JTOF<br>(n = 75)</th><th>PSOF<br>(n = 73)</th><th>COF<br>(n = 344)</th><th>Total</th></tr></thead><tbody><tr><td><strong>Clinical characteristics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Age, years (mean)</td><td>11.9</td><td>19.5</td><td>29.5</td><td>23.3</td></tr><tr><td>Male / female ratio, n (%)</td><td>34 (55.7) / 27 (44.3)</td><td>28 (50.0) / 28 (50.0)</td><td>71 (38.9) / 113 (61.1)</td><td>216 (44.0) / 276 (56.0)</td></tr><tr><td>Swelling, n (%)</td><td>37/39 (94.9)</td><td>26/27 (96.3)</td><td>145/151 (96.0)</td><td>286/299 (95.7)</td></tr><tr><td>Pain (%)</td><td>6/29 (20.7)</td><td>8/20 (40.0)</td><td>27/152 (17.8)</td><td>47/282 (16.6)</td></tr><tr><td><strong>Localization</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Mandibular anterior</td><td>5/29 (17.2)</td><td>1/25 (4.0)</td><td>14/171 (8.2)</td><td>35/364 (9.6)</td></tr><tr><td>Mandibular posterior</td><td>9/29 (31.0)</td><td>10/25 (40.0)</td><td>108/171 (63.2)</td><td>202/364 (55.5)</td></tr><tr><td>Maxillary anterior</td><td>5/29 (17.2)</td><td>5/25 (20.0)</td><td>15/171 (8.8)</td><td>26/364 (7.1)</td></tr><tr><td>Maxillary posterior</td><td>10/29 (34.5)</td><td>9/25 (36.0)</td><td>34/171 (19.9)</td><td>101/364 (27.8)</td></tr><tr><td><strong>Radiologic features</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Size at diagnosis, cm (mean)</td><td>2.4</td><td>3.0</td><td>2.9</td><td>2.4</td></tr><tr><td>Well-circumscribed</td><td>41/52 (78.9)</td><td>22/28 (78.6)</td><td>103/137 (75.2)</td><td>345/408 (84.6)</td></tr><tr><td>Mixed lesion</td><td>24/41 (58.5)</td><td>16/28 (57.1)</td><td>66/129 (51.2)</td><td>175/385 (45.4)</td></tr><tr><td>Radiopaque lesion</td><td>5/41 (12.2)</td><td>2/28 (7.1)</td><td>28/129 (21.7)</td><td>97/385 (25.2)</td></tr><tr><td>Radiolucent lesion</td><td>12/41 (29.3)</td><td>10/28 (35.7)</td><td>35/129 (27.1)</td><td>113/385 (29.4)</td></tr><tr><td>Cystic-like</td><td>9/11 (81.8)</td><td>—</td><td>8/20 (40.0)</td><td>17/44 (38.6)</td></tr><tr><td>Root displacement</td><td>9/23 (39.1)</td><td>6/20 (30.0)</td><td>41/121 (33.9)</td><td>130/347 (37.5)</td></tr></tbody></table>

size over 3 cm [16,18,19,23]. The mandible and maxilla were divided into four areas: anterior area was defined as the incisor-canine block and posterior area corresponded to the area behind the first premolars for both mandible and maxilla. Overall, OF mostly occurred in the posterior area of the mandible with 55.5 % of all the OF. COF was mostly observed in the posterior areas (83.1 %), especially in the mandible (63.2 %). PSOF also showed a predilection for posterior areas with 40 % of lesions occurring in the posterior area of the mandible and 35 % in the posterior area of the maxilla. JTOF were also seen in posterior areas but with a slight predilection in the maxillary posterior area with 34.5 %, and 31 % in the posterior mandible.

The radiological aspect mostly consisted in a well-circumscribed lesion in 75.2 % of COF, 78.6 % of PSOF and 78.9 % of JTOF. In almost half of cases, OF presented as a mixed radio-lucent and radio-opaque lesion (in 51.2 % of COF, 57.1 % of PSOF and 58.5 % of JTOF). Radiolucency was mostly observed in JTOF and PSOF in opposition to COF in which radiolucency was observed in only 27.1 % of cases. A cystic lesion was reported in 38.6 % of the patients, ranging from 40 % in COF to 81.8 % in JTOF. Root displacement was documented in 37.5 % of the patients with no differences between the different types of OF, however it was mostly seen in patients with bigger lesions (mostly over 4 cm) [18,22]. Patient characteristics are reported in Table 2.

### 3.4. Treatment

Data on treatment was available for 398 patients. Biopsy was reported before surgical treatment in 11 studies [17,19,23–25,27,29–31,33,34], some performed complete excisional biopsy when the lesion was small [19,29,31], the others authors did not provide data on biopsy before therapeutic consideration. Conservative surgery was defined as enucleation, curettage or excision of the lesion, whereas the radical surgery included large resection (mandiblectomy or maxillectomy) with or without reconstruction. Overall, the conservative surgery was the most performed procedure in 80.1 % of patients, with no difference regarding the subtype of lesion JTOF (80.4 %), PSOF (83.3 %) and COF (87.1 %). Table 3 reports the repartition of the type surgery performed according to the type of OF.

Gopinath et al. only performed conservative surgery and reported on small lesions with a mean of 1.9 cm. Mohanty et al. also reported conservative surgery for bigger lesions of almost 4 cm.

Two studies did not report detailed data according to the tumor entity [21,26]. Liu Y. et al. reported 26 patients with radical resection, 9 with local resection and 7 with curettage [21]. Prabhu et al.

reported 49 patients with excision, 5 with curettage, 3 with partial mandiblectomy and 3 with partial maxillectomy [26]. Finally, Urs et al. reported to perform curettage, “en-bloc” resection and segmental resection with no further details [25].

Only two authors reported peripheral ostectomy in normal surrounding bone after conservative treatment [29,34]. Although radical surgery imply macroscopically margins of resection, Slootweg et al. was the only author to have reported large resection with margins [33]. Alternate treatments found in the studies were surveillance after biopsy (patient refusing surgery), and debulking for cosmetic consideration [22,30,33].

No adjuvant treatment was reported in any of the included studies.

### 3.5. Follow-up and recurrence

Data on recurrence was reported for 366 patients, with a mean follow-up duration of 47 months (ranging from 3 months to 17 years [24,27]). The mean recurrence rate was 17 %, ranging from 0 % to 100 % regardless of the OF subtype (Table 4). However, a higher recurrence rate was observed for PSOF involving 20 patients (38 %) among the 44 patients with available data, especially when conservative surgery was performed. The mean time to recurrence in this group ranged from 15 to 42 months. A recurrence rate of 30 % was noted for JTOF (on 56 patients analyzed), with a mean of 12 months after the resection procedure. Disparities between surgical procedures were observed for PSOF and JTOF, the recurrence rate for conservative surgery was 40 % (on 30 patients) for JTOF and 63 % (on 16 patients) for PSOF, when the radical surgery had a recurrence rate of 0 % (10 patients for JTOF and 6 patients for PSOF). The recurrence rate was low in the COF, affecting 15 patients (9 % on the 168 analyzed in this group), with no difference regarding the treatment strategy (5 % after radical surgery and 7 % after conservative treatment). The mean time to recurrence in COF was available in only one study, and was estimated at 30 months [24]. There were no case of malignant transformation reported in the included studies.

### 4. Discussion

OF is a rare fibro-osseous neoplasm, and its incidence is still not determined due to the regular changing in terminology and the lack of epidemiological studies. There is to date no recommendation on the therapeutic approach. The therapeutic strategy depends on the
<table><caption>**Table 3**
Type of surgery performed. JTOF, juvenile trabecular ossifying fibroma; PSOF, psammomatoid ossifying fibroma; COF, cemento-ossifying fibroma.</caption><thead><tr><th rowspan="2">Authors</th><th rowspan="2">Number of patients</th><th colspan="2">JTOF (n = 56)</th><th colspan="2">PSOF (n = 54)</th><th colspan="2">COF (n = 186)</th></tr><tr><th>Conservative surgery (n)</th><th>Radical surgery (n)</th><th>Conservative surgery (n)</th><th>Radical surgery (n)</th><th>Conservative surgery (n)</th><th>Radical surgery (n)</th></tr></thead><tbody><tr><td>Slootweg et al. (1994)</td><td>30</td><td>(7) curettage</td><td>(2) resection with margins</td><td>(20) curettage</td><td>(1) resection with margins<br>(1) resection</td><td>—</td><td>—</td></tr><tr><td>El-mofty (2002)</td><td>2</td><td>(1) incomplete resection</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Park et al. (2007)</td><td>3</td><td>(1) excision</td><td>—</td><td>(2) excision</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Bustamante et al. (2008)</td><td>7</td><td>—</td><td>—</td><td>—</td><td>—</td><td>(1) curettage</td><td>(6) resection</td></tr><tr><td>Imanimoghaddam (2009)</td><td>5</td><td>—</td><td>—</td><td>—</td><td>—</td><td>(2) enucleation<br>(3) excision</td><td>—</td></tr><tr><td>Abuzinada and Alyamani (2009)</td><td>3</td><td>—</td><td>(1) partial maxillectomy (Weber – Ferguson flap approach), reconstruction using calvarial cirtical blocks</td><td>(1) enucleation and curettage<br>(1) curettage and peripheral ostectomy</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Liu Y. et al. (2010)</td><td>9</td><td>—</td><td>—</td><td>—</td><td>—</td><td>(3) excision<br>(2) curettage</td><td>(2) resection of jawbone and reconstructive internal plate fixation<br>(1) resection of jawbone and rib graft<br>(1) resection of jawbone and ceramic prosthesis</td></tr><tr><td>Triantafillidou et al. (2012)</td><td>14</td><td>—</td><td>—</td><td>—</td><td>—</td><td>(9) curettage<br>(4) enucleation</td><td>(1) segmental mandibulectomy and first reconstruction with titanium plate. Six months later replaced by an iliac bone graft</td></tr><tr><td>De Noronha Santos Netto et al. (2013)</td><td>7</td><td>—</td><td>—</td><td>(1) conservative</td><td>—</td><td>(6) conservative</td><td>—</td></tr><tr><td>Authors</td><td>Number of patients</td><td>JTOF (n = 56)<br>Conservative surgery (n)</td><td>Radical surgery (n)</td><td>PSOF (n = 54)<br>Conservative surgery (n)</td><td>Radical surgery (n)</td><td>COF (n = 186)<br>Conservative surgery (n)</td><td>Radical surgery (n)</td></tr><tr><td>Gopinath et al. (2013)</td><td>8</td><td>(6) excision</td><td>—</td><td>(2) excision</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Prabhu et al. (2013)</td><td>60</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Mohanty et al. (2013)</td><td>24</td><td>—</td><td>—</td><td>(1) enucleation</td><td>—</td><td>(2) curettage<br>(17) enucleation</td><td>(3) resection and reconstruction<br>(1) resection and reconstruction with rib graft</td></tr><tr><td>Phattarataratip et al. (2014)</td><td>46</td><td>(1) enucleation</td><td>(1) resection</td><td>(5) enucleation</td><td>(3) resection</td><td>(29) enucleation</td><td>(7) resection</td></tr><tr><td>Han et al. (2016)</td><td>15</td><td>(6) curettage</td><td>(1) resection<br>(1) resection + costal<br>(2) resection + iliac crest</td><td>(1) enucleation<br>(2) curettage</td><td>(1) resection<br>(1) resection + fibula free flap</td><td>—</td><td>—</td></tr><tr><td>Liu J. et al. (2017)</td><td>4</td><td>—</td><td>—</td><td>(1) curettage</td><td>—</td><td>—</td><td>(1) maxillectomy<br>(1) partial resection of right maxilla bone<br>(1) resection</td></tr><tr><td>Liu Y. et al. (2017)</td><td>42</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Kaur (2019)</td><td>16</td><td>—</td><td>—</td><td>—</td><td>—</td><td>(15) excision</td><td>(1) en bloc resection and lingual corticotomy</td></tr><tr><td>Titinchi et al. (2021)</td><td>17</td><td>(1) enucleation<br>(5) curettage with peripheral ostectomy</td><td>(4) resection</td><td>(5) curettage with peripheral ostectomy</td><td>(2) resection</td><td>—</td><td>—</td></tr><tr><td>Nagar et al. (2021)</td><td>24</td><td>(11) excision</td><td>—</td><td>—</td><td>—</td><td>(13) excision</td><td>—</td></tr><tr><td>Nikitakis et al. (2022)</td><td>5</td><td>(5) enucleation</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Okwuosa et al. (2022)</td><td>57</td><td>—</td><td>—</td><td>(3) excision</td><td>—</td><td>(54) excision</td><td>—</td></tr></tbody></table>
<table><caption>**Table 4**
Recurrence rates. N, number of patients; JTOF, juvenile trabecular ossifying fibroma; PSOF, psammomatoid ossifying fibroma; COF, cemento-ossifying fibroma.</caption><thead><tr><th>Authors</th><th>Patients (n)</th><th>JTOF (%)</th><th>PSOF (%)</th><th>COF (%)</th><th>Total (%)</th></tr></thead><tbody><tr><td>Slootweg et al. (1994)</td><td>22</td><td>3/8 (38 %)</td><td>6/14 (40 %)</td><td>—</td><td>9/22 (39 %)</td></tr><tr><td>El-Mofty (2002)</td><td>2</td><td>1/1 (100 %)</td><td>0/1 (0 %)</td><td>—</td><td>1/2 (50 %)</td></tr><tr><td>Park et al. (2007)</td><td>3</td><td>1/1 (100 %)</td><td>1/2 (50 %)</td><td>—</td><td>2/3 (67 %)</td></tr><tr><td>Bustamante et al. (2008)</td><td>7</td><td>—</td><td>—</td><td>0/7 (0 %)</td><td>0/7 (0 %)</td></tr><tr><td>Imanimoghaddam (2009)</td><td>5</td><td>—</td><td>—</td><td>0/5 (0 %)</td><td>0/5 (0 %)</td></tr><tr><td>Abuzinada and Alyamani (2009)</td><td>3</td><td>0/1 (0 %)</td><td>2/2 (100 %)</td><td>—</td><td>2/3 (67 %)</td></tr><tr><td>Liu Y. et al. (2010)</td><td>9</td><td>—</td><td>—</td><td>3/9 (33 %)</td><td>3/9 (33 %)</td></tr><tr><td>Triantafillidou et al. (2012)</td><td>14</td><td>—</td><td>—</td><td>2/14 (14 %)</td><td>2/14 (14 %)</td></tr><tr><td>De Noronha Santos Netto et al. (2013)</td><td>7</td><td>—</td><td>—</td><td>—</td><td>0/7 (0 %)</td></tr><tr><td>Gopinath et al. (2013)</td><td>6</td><td>0/4 (0 %)</td><td>2/2 (100 %)</td><td>—</td><td>2/6 (33 %)</td></tr><tr><td>Prabhu et al. (2013)</td><td>60</td><td>—</td><td>1/4 (25 %)</td><td>8/56 (14 %)</td><td>9/60 (15 %)</td></tr><tr><td>Urs et al. (2013)</td><td>17</td><td>0/2 (0 %)</td><td>1/3 (33 %)</td><td>0/12 (0 %)</td><td>1/17 (6 %)</td></tr><tr><td>Mohanty et al. (2013)</td><td>24</td><td>—</td><td>0/1 (0 %)</td><td>0/23 (0 %)</td><td>0/24 (0 %)</td></tr><tr><td>Phattataratip et al. (2014)</td><td>8</td><td>1/1 (100 %)</td><td>2/2 (100 %)</td><td>5/5 (100 %)</td><td>8/8 (100 %)</td></tr><tr><td>Han et al. (2016)</td><td>15</td><td>6/10 (60 %)</td><td>3/5 (60 %)</td><td>—</td><td>9/15 (60 %)</td></tr><tr><td>Liu J. et al. (2017)</td><td>4</td><td>—</td><td>0/1 (0 %)</td><td>0/3 (0 %)</td><td>0/4 (0 %)</td></tr><tr><td>Liu Y. et al. (2017)</td><td>42</td><td>4/9 (44 %)</td><td>2/8 (25 %)</td><td>6/25 (24 %)</td><td>12/42 (29 %)</td></tr><tr><td>Kaur et al. (2019)</td><td>16</td><td>—</td><td>—</td><td>0/16 (0 %)</td><td>0/16 (0 %)</td></tr><tr><td>Titinchi et al. (2021)</td><td>17</td><td>2/10 (20 %)</td><td>0/7 (0 %)</td><td>—</td><td>2/17 (12 %)</td></tr><tr><td>Nagar et al. (2021)</td><td>23</td><td>1/11 (9 %)</td><td>—</td><td>0/12 (0 %)</td><td>9/23 (4 %)</td></tr><tr><td>Nikitakis et al. (2022)</td><td>5</td><td>2/5 (40 %)</td><td>—</td><td>—</td><td>2/5 (40 %)</td></tr><tr><td>Okwuosa et al. (2022)</td><td>57</td><td>—</td><td>0/3 (0 %)</td><td>0/54 (0 %)</td><td>0/57 (0 %)</td></tr><tr><td>Total</td><td>366</td><td>30 %</td><td>38 %</td><td>9 %</td><td>17 %</td></tr></tbody></table>

size, location and anatomical conditions of the lesion, as well as the surgical team's habits, and ranges from surveillance to radical surgery. Due to the benign nature of the tumor, most of surgeons tend to be more conservative; however some authors advocate for a more radical approach suggesting a large resection with margins to avoid residual disease and immediate reconstruction [9]. The 5th WHO classification of tumors separated OF in three distinct entities: COF of odontogenic origin, and JTOF and PSOF of non-odontogenic origin. We hypothesized that these three entities would behave differently clinically and radiologically, given their different histological origins. This could also influence therapeutic strategy, depending on the histological type of tumor and the recurrence rate. Through a systematic review of the literature, we aimed to synthesize the current knowledge on clinico-radiological presentation of the different subtypes of OF, as well as to clarify the indications for surgical treatment depending on disease recurrence.

With 492 patients analyzed, this systematic review is the most important series on OF, the largest observational study reporting data on 80 patients [18]. Sex distribution and mean age at presentation are in accordance with previous publications. PSOF showed no predilection for sex, and occurs in patients with a mean 19.5 years (ranging widely from 3 months to 72 years) [6]. JTOF occurs earlier with a mean 11.3 years of age and presents a slight male predilection, as suggested in the systematic review from Chrcanovic et al. performed on 131 cases [4]. Williams et al. also showed a higher male predilection in JTOF in children under the age of 15 in a series of 8 reported patients [35]. The pathophysiology of JTOF is little known, the disease appears as a rapidly growing lesion often located in the maxilla [30]. As evidenced in various bone tumors, OF is characterized by a dysregulation in the triad receptor activator of NFκB (RANK), its ligand (RANKL) and osteoprotegerin (OPG). The binding RANK/RANKL stimulates the formation of osteoclast leading to bone resorption while OPG acts as a decoy receptor to RANKL to inhibit osteoclastogenesis. In an immunohistochemical study on bone biopsies, Tater and Diazil showed a various of OPG and RANKL in OF subtypes with higher expression in COF compared to JTOF and PSOF [36]. The overstimulation of the RANK/RANKL/OPG complex in growing child could explain the difference in age occurrence between the OF subtypes. Also, bone formation depends on multiple hormonal factors with sex steroids being more important on trabecular bone, that

could explain some differences in clinical behavior of OF subtypes [37].

The clinical presentation was largely dominated by the apparition of a painless swelling of the jaws, while an incidentaloma discovered on a routine orthopantomogram was scarce. Pain remains rare, in 16 % of cases at the presentation as evidenced by Macdonald et al. [38]. However, an increased percentage of patients presented with pain at diagnosis for PSOF (40 % of patients). There is a difference in stromal fibroblast cell expression among the different types of lesions [1]. The histological aspect of PSOF is characterized by numerous small ossicles known as psammomatoid bodies within a high cellular stroma, which can coalesce into larger mineralized regions, sometimes with cystic degeneration, distinguishing it from other ossifying fibromas [6]. Mantyh et al. suggested that bone pain had two components: a nociceptive one and a neuropathic one [39]. The authors showed that associated stromal cells of malignant tumors release factors that 1/ sensitize and activate bone nociceptors, 2/ injure the sensory nerve fibers, and 3/ release growth factors that drive ectopic sprouting of nerve fibers and neuroma formation, all of which contributing to peripheral and central sensitization [39]. A similar pathophysiology could explain the pain on benign active or aggressive benign lesions. Aneurismal bone cyst (ABC) is commonly reported in PSOF, it induces a more severe prognosis as the tumor may be more aggressive and is associated with tumor recurrence [40]. The presence of such ABC in OF could also play a role in lesion associated pain.

The main radiological presentation was a well-circumscribed mixed opacity. The radio-opacity was mostly seen in COF (21.7 %) compared to JTOF (12.2 %) and PSOF (7.1 %). This difference could be explained by a slower development allowing time for bone regeneration to take place [38]. Also, the higher expression of OPG in COF could explain the predominance of radiopaque lesions secondary to the inhibition of bone resorption [36]. The three OF subtypes can be distinguished radiologically: PSOF presents as a ground glass lesion, JTOF as a radiolucent lesion with scattered and irregular calcifications and COF depending on the time of evolution, presenting from complete radiolucency to complete radio-opaque lesion [41]. At early stage, COF exposed a predominance to tooth bearing areas, unlike JTOF that develops in maxillary and mandibular bones [41]. MRI and CT scan also show difference between lesions as non-odontogenic lesions (JTOF and PSOF) show a bright enhancement after contrast
administration, and COF/odontogenic lesion show no enhancement [16].

Nevertheless, the differential diagnosis of OF with other fibro-osseous lesion can be difficult on the basis of clinical and radiological evidence alone. Bone biopsy is then necessary to distinguish between fibrous dysplasia (FF) and COF, and JTOF/PSOF from osteosarcoma or fibrosarcoma. There is currently no specific marker for OF. Differential diagnosis with FG is made possible by the identification of the mutation of GNAS1-gene in chromosome 20q13.3 of osteoprogenitor cells [42]. Nevertheless, the mutation is present in 74 % of the patients with FD and its absence does not allow the diagnosis to be ruled out. Amplification of murine double minute 2 (MDM2) protein which negatively regulates the transcriptional activity of p53, and RASAL1 (telomeric gene on chromosome 12) represents an early molecular signature of the risk of sarcoma transformation of JTOF [43]. Amplification of MDM2 and CDK4 (a cyclin-independent kinase involved in cell cycle transition) is usually not observed in benign fibro-osseous lesions, thus making it a valuable tool for differential diagnosis between low-grade OS and OF [44]. Those markers could help determine aggressivity or recurrence factors and then guide the therapeutic decision. This systematic review did not include the syndromic OF observed in hyperparathyroidism-jaw tumor syndrome (HPT-JT syndrome) with up to 30 % of COF. This syndrome exposes inactivating mutations in the tumor suppressor gene HRPT2 (CDC73), and those mutations were also seen in sporadic COF.

Regarding the surgical treatment, Eversole et al. showed a high recurrence rate (28 %) after enucleation and curettage performed alone [45]. Chrcanovic et al. reported a 12.5 % recurrence rate after curettage associated with peripheral ostectomy when recurrence reached 35 % after enucleation or curettage alone [4]. Radical resection should be avoided whenever possible as it provides high morbidity in young patients with all-time disfigurement [4,34]. In a descriptive series of 24 cases, Macdonald et al. showed a low recurrence rate (one patient) over a 5.3 years period [46]. This patient with recurrence did not show difference in histological or radiological characteristic [46]. Abuzinada and Alyamani reported a recurrence of JTOF with changing in the radiological appearance from radio-lucent lesion at diagnosis to mixed radiolucent and radiopaque features at recurrence, without changes in the histological diagnosis [29]. This systematic review adds to the current concepts for therapeutic decision-making regarding OF. It now seems reasonable to propose a conservative approach for COF considering that it is a non-aggressive slowly evolutive lesion exposing similar recurrence rate between radical and conservative surgery. The conservative treatment should associate peripheral ostectomy to reduce the risk of recurrence. The main question still lies on the psammomatoid and juvenile forms of OF that show a clear difference in recurrence rates according to the type of surgery performed. There could be an interest to operate radical surgery firstly for aggressive lesions in order to allow complete excision with no residual disease, and so minimise the morbidity induced by repeated surgeries. Also, radical surgery should be indicated when the lesion has atypical presentation. Koury et al. showed that osteosarcomas or fibrosarcomas could be mistaken as benign fibro-osseous lesions such as OF [47]. Close radiological and clinical follow-up should also be recommended. When necessary, bone graft reconstruction should be considered in order to rehabilitate and lessen the deformity. Lv et al. discussed reconstruction on giant ossifying fibroma (described as OF confined in the jaws with diameter over 6 cm and having repercussion on function) [10]. The authors suggested that bone defect over 6 cm should be replaced by vascularized graft, as opposed to non-vascularized graft with high failure rates when over 6 cm. They reconstructed patients with fibula or iliac osteomyocutaneous flap and with maximal preservation of soft tissue. Fibula should be preferred over iliac flap when the defect is over 10 to 12 cm. To restore the height of neomandible, the authors chose to use double barrel vascularized fibula graft [10]. Fauvel et al.

on the other hand, reported a case of free bone graft reconstruction using a costo-chondral transplant in a child [48]. The authors used an 8 cm costal transplant to replace the bone defect in the posterior area of the mandible with maximal preservation of periosteal layer. They showed spontaneous bone regeneration a year after surgery and suggested dental implants replacement once the height and width of neomandible is sufficient [48]. The dysregulation of the bone resorption/formation balance could suggest efficiency in the use of antiresorptive drugs as evidenced in fibrous dysplasia [49]. But this strategy has not been tested yet [36]. Radiotherapy should not be used for treatment of OF for its elevated risk of malignant transformation and secondary radio induced complications.

Although representing the largest OF series published to date, our study suffers from some limitations. The first lies in the low overall quality of included studies as the disease is rare and most of the publications are observational studies based on few cases. In case of rare diseases, the contribution of case series and case reports can have strong value for recognition, comprehensive description and development of treatment. Secondly, patients' samples were heterogeneous from one study to another. Furthermore, we regret the many missing data due to lost to follow up patients. We can assume that the recurrence rates could be overestimated as the patients did not report back to a health care center because they were free of the disease. In the same way, we can also assume that recurrence rates can be underestimated with a short time of follow-up in the case of recent lesion.

## 5. Conclusion

Although the level of evidence of existing literature is very low, this review still allowed us to differentiate the three forms of OF with different clinical and radiological behavior. However, for treatment and recurrence, the heterogeneity of the patients, follow-up and between studies should lead to treat our results with caution. Larger prospective multicentric studies could be interesting to describe better this lesion, its physiopathology and explore the therapeutic options.

## Declaration of competing interest

The authors declare to have no conflict of interest regarding this manuscript.

## CRediT authorship contribution statement

**Blandine Gautier:** Data curation, Formal analysis, Writing – original draft. **Sophie Dugast:** Conceptualization, Methodology, Validation, Writing – review & editing. **Pierre Guyonvarc'h:** Conceptualization, Validation, Writing – review & editing. **Julie Longis:** Supervision, Validation, Writing – review & editing. **Pierre Corre:** Supervision, Validation, Writing – review & editing. **Hélios Bertin:** Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing.

## Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jormas.2024.102185.

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