Systematic Review Ameloblastomas vs recurrent ameloblastomas: a systematic review

-- Introduction: Ameloblastoma is an odontogenic tumour with high recurrence rate. The objective of the present study was to evaluate existing literature regarding clinical, radiographic, histopathologic features, treatment, and recurrence rate of ameloblastomas and compare it with features of recurrent ameloblastomas. Materials and methods: A systematic review was done based on the PRISMA statement. Search was performed in “ Pubmed ” database with search terminology “ recurrent ameloblastoma ” , “ ameloblastoma recurrence ” for articles published between 2010 and 2020. Data were extracted from full-text articles and discussed. Results: Out of 515 articles, 16 articles ful ﬁ lled the inclusion and exclusion criteria. Data was analysed in two sections. The ﬁ rst with 10 publications assessed features of ameloblastoma in general and their recurrence rate while the second section evaluated features of only recurrent ameloblastomas in 6 publications. There were 234 recurrences in 936 cases with recurrence rate of 23.50%. Male predominance was noted and mandible was commonly affected. Solid/multicystic ameloblastomas formed 74.5% of the tumours and unicystic formed 23.3%. The recurrence rate after conservative treatment was 64.9% and after radical treatment was 12%. Conclusions: The main factors for recurrence were multilocular ameloblastomas, follicular histopathology and conservative treatment.


Introduction
Ameloblastoma is a benign, locally aggressive, odontogenic tumor of epithelial origin [1]. Among the odontogenic tumours it accounts for the second most common tumour [2]. The incidence of ameloblastoma per year is 0.5 cases per million persons globally [3]. According to the proposed WHO (2017) classification, ameloblastoma is classified as conventional, unicystic, peripheral and metastasising types [2]. Ameloblastoma has high recurrence rate due to which opinions regarding the management of ameloblastoma have always been controversial [1,4].
Existing literature suggest recurrences of 55-90% with conservative treatment and 15-25% following a radical approach [4]. Patients present with serious aesthetic and functional impairment and need to undergo reconstructive surgeries with radical approach [4]. The reasons for recurrence can be multifactorial such as local invasiveness of the tumour, histological type, tissue components and the treatment approach [1,3]. The objective of the present study was to evaluate the literature regarding clinical, radiographic, histopathologic features; treatment and recurrence rate of ameloblastomas and compare it to features of recurrent ameloblastomas.

Materials and methods
The present systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement which was shown in Figure 1. Literature search was carried out in "Pubmed" database with search terminology "recurrent ameloblastoma", "ameloblastoma recurrence". Data available from 2010 to 2020 was selected. English-language articles and human studies were chosen for the study. In addition to this, manual searches were performed of the reference lists of the articles and similar articles shown in the Pubmed database. This manual search was done in order to find other eligible articles for the review which was not available in the electronic database. Reviews, systematic reviews, meta-analysis, original research articles were selected for the present review. Case reports were excluded. Our search criteria resulted in 59 articles. As a first step (screening) studies which did not report on clinicopathological details of the ameloblastomas, management and recurrence of ameloblastoma were excluded by screening the titles and abstracts from the search results. The article selection for the present review was done by two independent reviewers. Any disagreements regarding the inclusion of articles between the reviewers were resolved by discussion. Studies included in other review articles or meta-analyses which were already selected for our review were excluded to avoid doubling of data. In the second step, authors evaluated 16 full-text articles meeting the inclusion and exclusion criteria. The following data were extracted from full-text articles: author, publication year, number of cases reported, age, gender, location, radiographic features, tumour type, treatment type, recurrence rate, time period of recurrence after treatment and contributing factors for recurrence. The data was tabulated and the results recorded.
Data obtained was discussed under two different sections. The first section includes clinical, radiographic, histopathological, management details and recurrence rate of the ameloblastomas in general. In the second section authors specifically analysed recurrent ameloblastomas.

Results
Our search resulted in a total of 515 articles, out of which only 479 articles were available with full text. After exclusion of case reports, a total of 59 articles were identified. Of these, 43 articles were excluded from the present review due to missing information regarding clinical features, radiographic features, histological type, treatment and recurrence. We further categorised selected 16 articles into two sections. First section assessed features of ameloblastoma in general with their recurrence rate and included 10 publications with a total of 1206 cases of ameloblastoma while the second section evaluated features of only recurrent ameloblastomas and consisted of six publications with 1115 ameloblastoma cases.

Section 2: Clinicopathological features of recurrent ameloblastoma
Six publications with 1115 ameloblastoma cases were identified reporting a total of 180 cases of recurrence. Summary

Discussion
Management of ameloblastoma has always been a difficult decision for the surgeon with both conservative and radical methods having their advantages and disadvantages [3,20]. Conservative surgery preserves tissues and decreases morbidity and is preferred in younger individuals but is associated with higher recurrence rate. Radical surgery involves tumor resection with wide bone margin and is associated with decreased recurrence but higher morbidity and need for surgical grafts and prosthetic rehabilitation [3].
In the analysis of recurrent ameloblastomas, we found that multilocular radiographic appearance, follicular histopathology and conservative treatment were risk factors for recurrent ameloblastoma. Among the analysed cases of ameloblastoma, conservative management was associated with significantly increased recurrence. Multilocular lesions were associated with higher recurrence rate although majority (62%) of analysed cases were unilocular ameloblastomas.
The mean age of subjects in the study was 43.34 ± 8.5 years. This is higher than that reported in previous studies. Krishnapilllai et al. [15] reported a mean of 30 years with highest cases in 3rd decade while More et al. reported a similar mean age of 43.5 years. Hasegawa et al. [21] reported a mean age of 28.2 years. Almeida et al. [4] reported a mean age of 38 years which is similar to the present study. The mean age is reported as different in different parts of the world where the fifth and sixth decades have higher incidence in Europe and North America while the peak incidence in Asia is between third and sixth decades [22]. Overall prevalence worldwide is in the third decade [22]. One reason for the higher reported age of the present study could be because we excluded those manuscripts which only included subjects below 20 years of age. Slight male predilection was noted in the current study which is similar to that reported by Krishnapillai et al. [15] and Hendra et al. [23].
In the analysis of recurrent cases, the average age was 36.18 ± 5.47 years. This is similar to the average age of occurrence of ameloblastomas and implies that recurrences occur within a few years of treatment. Arotiba et al. [17] and Milman et al. [12] reported highest recurrence in the third and fourth decade. Recurrent cases showed male predilection with male female ratio similar to that of ameloblastomas. Mandibular predominance has been noted in most studies similar to ours where the mandible was involved eight times as often as the maxilla. This is similar to the results by Fregnani et al. [14] and Hong et al. [24].
Among the recurrent ameloblastomas, cases were 6 times higher in the mandible. This is probably because ameloblastomas occur mainly in the mandible.
In the present analysis, we found higher proportion of unilocular ameloblastomas when compared to multilocular. This is in contrast to Cadavid et al. [25] and More et al. [26] who reported higher incidence of multilocularity. This difference might be due to the fact that not all included manuscripts mentioned the radiographic features.
Among recurrent ameloblastomas, 70% had multilocular appearance while unilocular appearance was seen in 30%. Thus, recurrences appear to be higher in multilocular lesions. This may be due to incomplete surgical removal of microcysts and daughter cysts.
Approximately three fourth cases were of the solid/ multicystic variant with the follicular type being the commonest followed by plexiform variant. Fregnani et al. [14] reported that solid ameloblastomas were more prevalent than unicystic. Cadavid et al. [25] mention that the plexiform and follicular variants are the most common while Arotiba et al. [17] reported that the follicular type was commonest.
Among the recurrent ameloblastomas, solid/ multicystic ameloblastomas predominated with 82% and the follicular variant was the most common histopathologic type followed by unicystic ameloblastomas. This suggests that multicystic ameloblastomas are more aggressive than unicystic. Similar   [22,23]. Hong et al. [24] mention that follicular, granular cell and acanthomatous ameloblastomas are associated with the highest recurrence and need more radical treatment while plexiform and desmoplastic types have low recurrence. This is similar to the present results. Follicular types are more often multilocular ameloblastomas while unicystic ameloblastomas tend to be unilocular [24]. Conservative treatment includes enucleation, marsupialization followed by enucleation, enucleation with bone curettage without a safety margin while radical treatment includes resection with a bone margin, en bloc resection, marginal mandibulectomy and segmental resection or maxillectomy [21].
Conservative management was done in 64.4% cases in the present study. The recurrence rate after conservative treatment was 64.9% and after radical treatment was 12%. Thus, recurrence after conservative treatment was markedly higher than after radical treatment. This is similar to the study by Laborde et al. [13] where conservative treatment was associated with a recurrence rate of 90.9%. Other studies have also reported similar results [5,24]. Thus our results support the hypothesis that radical treatment is associated with lower risk of recurrence. Fregnani et al. [14] reported than a ruptured basal cortical bone was associated with three times increased risk of recurrence. A systematic review of treatment of unicystic ameloblastomas found that resection was associated with the lowest risk for recurrence followed by enucleation and Carnoy's solution and simple enucleation [27].
The average period of follow up was 6.2 years. Recurrences in ameloblastoma can occur as long as 10-15 years after treatment [16]. Our results showed that most recurrences occurred within 5 years. The reported recurrence rates in the studies ranged from 9.78% [6] to 29% [18]. Among the evaluated studies, we found a recurrence rate of 23.5%.
Hong et al. [24] suggest that resection with safety margin is the best management for ameloblastomas with conservative management reserved for patients below 10 years and unicystic or plexiform ameloblastomas. Hendra et al. [22] and Bansal et al. [10] recommended conservative management only to avoid functional psychological and esthetic side effects in children. Antonoglou et al. [8] in an analysis of conservative versus radical treatment found that radical surgery was associated with decreased recurrence in a 5-year follow up. Almeida et al. [4] recommend bone resection for all cases diagnosed with multicystic ameloblastoma.
There were a few limitations in the present study. Data was extracted from a single database only. This could have led to selection bias. Further, all articles did not report all clinical and radiographic features thereby limiting the data availability.
Prospects: In the present study, ameloblastoma recurrence was associated with multilocular ameloblastomas, follicular histopathology and conservative treatment. Future research should concentrate on management strategies for these specific types of ameloblastoma in order to reduce the incidence of tumour recurrence and its associated morbidities.

Conclusion
Highlight of present review is features of ameloblastomas in general and recurrent ameloblastomas being analysed and presented separately. Our study concluded that the clinicopathologic features of ameloblastomas in general were similar to recurrent ameloblastomas. The main contributing factors identified for recurrence were multilocular ameloblastomas, follicular histopathology and conservative treatment methods. Based on the present systematic review, radical management is recommended for solid/multicystic ameloblastomas in order to decrease the recurrences. However, various factors such as age of the patient, size of lesion, soft tissue involvement and histological parameters have to be taken into consideration when deciding management of ameloblastomas. In such cases, regular follow up is mandatory.