Clinicopathologic Profile, Management and Outcome of Sinonasal Ameloblastoma—A Systematic Review

Sinonasal ameloblastoma (SNA) is considered to be a subtype of ameloblastoma. It differs from gnathic ameloblastoma in terms of clinicopathologic features, management and prognosis. Thus, the objective of the present review was to study the complications, survival, recurrence rate and outcomes following the management of SNA. The electronic search process was conducted on PubMed-Medline, Embase, and Scopus. Google Scholar was used to search grey literature. Quality assessment of the case reports (CR) and case series (CS) was done based on CARE guidelines. The initial search resulted in 2111 articles. 15 studies (13 CR and 2 CS) were found to meet the eligibility criteria. The majority of the studies described histological features of SNA, which were consistent with ameloblastomas of gnathic origin. There were no SNA-related deaths reported in the included studies. Five studies described endoscopic surgeries to remove SNAs, and three SNAs were treated with post-surgery radiotherapy. Data from included studies suggest that sinonasal ameloblastomas are histologically similar to gnathic ameloblastomas, but their clinical presentation is different. They may cause complete or partial obstruction of the nasal cavity and the sinus. They appear to affect an older demographic, and their resection may be accompanied by the excision of a large portion of the maxilla, necessitating maxillofacial prosthetic rehabilitation.


Introduction
Ameloblastomas are rare tumors derived from the odontogenic epithelium [1]. More affecting the mandible than the maxilla, they are rarely malignant or metastatic and grow slowly, they can be locally invasive. Sinonasal ameloblastomas are rare tumors of the sinonasal tract that arise from sinonasal epithelium [2]. If untreated, they may lead to several complications, including tooth mobility, resorption of roots of the teeth, malocclusion and soft tissue involvement. Hence, the invasive nature of these tumors necessitates surgical resection and prosthetic rehabilitation [3]. Post-surgical rehabilitation also requires reconstructive surgery and bone grafting in addition to the construction of complex prostheses. Although less common than their mandibular counterparts, maxillary ameloblastoma are more dangerous as they may lead to the brain via the sinonasal passages and pterygomaxillary fossa [4]. The ameloblastoma originates from the remnants of dental lamina, the developing enamel organ, the epithelial lining of odontogenic cysts, or the basilar epithelial lining of epithelial cells of the gingival surface epithelium.
Histopathology of the ameloblastomas has revealed both neoplastic and cystic features [5]. They exhibit two main histological patterns: follicular or plexiform. The follicular pattern is characterized by an outer layer of columnar ameloblast-like cells surrounding an inner region of the stellate reticulum, similar to those observed in the bell stage of development of the tooth. On the other hand, a plexiform pattern is indicated by anastomosing strands ('cord-shaped' pattern) of epithelium with an inconspicuous stellate reticulum. Other histopathologic variants are acanthomatous, basal cell-like, granular cell and desmoplastic.
More recently, a sub-set of ameloblastomas has been described in the sinonasal tract which are so-called 'sinonasal ameloblastomas' (SNA) [2]. A study by Schafer et al. (1998) that surveyed 19,658 tumors associated or present in the sinonasal tract estimated that 0.11% of those tumors were ameloblastomas, making them exceedingly rare [6]. Recent literature has attempted to describe their diagnosis, treatment, and prognosis [7,8]. Untreated SNAs can lead to various complications, including rhinorrhea, nasal obstruction, and facial disfigurement due to swelling [7,8]. Progressive enlargement of SNAs can also lead to loosening and eventual loss of teeth [9]. Therefore, it is imperative to synthesize evidence regarding the clinical, radiographic and histological features, along with the treatment and diagnosis. This review aims to summarize and critically appraise the literature regarding SNAs published to date. Furthermore, we hope that the review will aid in establishing clinical guidelines for managing SNAs.

Focused Question
Using a modified version of the Participants, Intervention, Control and Outcomes (PICO) protocol (the Participants, Intervention and Outcomes (PIO) protocol), recommended in the Preferred Reporting Items in Systematic Reviews and Meta-Analysis (PRISMA) [10], the following focused question version was constructed: 'What are the complication/death rates, recurrence rates, prognosis and quality of life (outcomes) reported following management (intervention) of patients with Sinonasal Ameloblastomas (participants)?' The following types of literature were deemed eligible for inclusion: case reports (CR) and case series (CS).

Inclusion Criteria
• CR and CS reporting sinonasal ameloblastoma.

•
Pre-clinical studies, letters to the editor, commentaries and reviews were excluded.

Literature Search
The entire search process was conducted independently by two investigators. An electronic search was conducted on the following research databases: PubMed-Medline, Embase, and Scopus. Furthermore, Google Scholar was used to search grey literature (newsletters, technology assessment reports, patients and speeches) focusing on SNAs. The medical subject headings (MeSH) were: [((sinonasal ameloblastoma) OR (((sinus) OR (nasal)) AND (ameloblastoma))) AND ((treatment) OR (diagnosis) OR (prognosis) OR (recurrence) OR (oral cancer) OR (jaw lesions))]. The following journals were handsearched: Journal of Dental Research, Oral Oncology, Journal of Cranio-Maxillo-Facial Surgery and Journal of Oral Rehabilitation. The reference lists of the included articles were scanned to find additional studies meeting our inclusion criteria. Any disagreements were solved by discussion. An inter-examiner reliability score (Kappa score) was calculated to gauge the agreeability between the examiners. Any disagreements were solved by discussion. Google Translate was used to attempt the translation of studies not in English.

Data Extraction
Two investigators tabulated data independently based on general criteria: ethnicity of the patients reported, country in which the study was conducted, number of participants/patients, number of SNAs reported in each study, age (mean/median or range) of the included patients, gender of the patients, features (histological, radiographic and clinical), any SNA-related deaths and follow-up. Treatment details, recurrence rate and time and any post-treatment complications were also extracted.

Quality Assessment
Quality assessment for CR and case series CS was done based on CARE guidelines, specifically the CARE guidelines and elaboration document [11]. Briefly, the following aspects of the studies were assessed to grade each report as 'low', 'moderate', or 'high': the title, keywords, quality of the abstract, introduction, reported patient information, findings of the physical/clinical examination, timeline, diagnostic assessment, reporting of interventions, follow-up details, quality of the discussion, patient perspective and informed consent/ethical approval reported.
The systematic review was registered with the International Prospective Register of Systematic Reviews on 10 November 2015, which was in accordance with the guidelines, and was last revised on 14 October 2022 (Registration Number CRD42022364686).

Literature Search
The initial search resulted in 2111 articles. After the exclusion of 1909 irrelevant articles, the abstracts and titles of 202 articles were read for potential inclusion, resulting in the further exclusion of 183 articles. Therefore, the full texts of 19 articles were downloaded for potential inclusion. After the exclusion of 4 articles (one review [12], two studies that described tumors that were not SNA [13,14] and one study which could not be translated due to the limitations of Google Translate [15]), 15 studies (13 case reports [7-9,16-25] and 2 [6,26] case series). No additional studies were found among the references of the included studies. The Kappa score was calculated as 0.83. The literature search process is illustrated as a PRISMA flow diagram ( Figure 1).

Management, Recurrence Rate and Post-Op Complications
Five studies described endoscopic surgeries to remove SNAs [7,8,19,23,26] and three SNAs were treated with post-surgery radiotherapy [6,16,17]. Five studies removed the same number of SNAs with maxillectomy [6,17,20,21]. Ethmoidectomy was described in two studies [9,20] and in one study, ethmoidectomy was also stated as one of the steps for surgical management of SNA [8]. In one study, the uncinate process (a portion of the medial wall of the maxillary sinus) was resected unilaterally to allow access for the removal of the SNA [24]. In two studies, the recurrence (or absence of recurrence) was not reported [9,26]. Three studies reported a post-surgical recurrence at 6 months, 10 months and 2 years [8,24,25]. One study reported a 5% recurrence rate within 1 to 13 years after surgery of 24 SNAs [6]. In one study, tooth 27 was extracted because it had developed numbness post-surgery [8]. In one study, the recurrent mass was not removed [25]. A detailed description is given in Table 2. Left uncinate process resected endoscopically and maxillary sinus was opened for access (two surgeries required due to recurrence) 1 (10 months) None
Several reports required maxillectomy to remove SNAs and the structures they had invaded [6,17,20,21]. To date, no guidelines have been established for the optimal surgical management of SNAs. Still, due to their locally invasive nature, prosthodontic or maxillofacial prostheses are very likely to be needed to effectively rehabilitate such patients. In none of the studies a comprehensive rehabilitation treatment plan was described. In one study, post-surgical paresthesia of the upper second molar was reported [8], which could be most likely due to trauma to a sensory nerve to the tooth.
Overall, the quality of the studies included in this review was low. The majority of the studies did not report the ethnicities of the affected patients. Similarly, to date, no study has established a racial predilection to ameloblastoma. Furthermore, most studies have described detailed surgical procedures for removing SNAs, which would be crucial for future guidelines.
Although no SNA-related deaths were reported, the included patients' sample size was insufficient to ascertain the survival statistics. The recurrence rate of ameloblastoma depends on many factors such as histological variant, site and the management. It is more frequent in mandible than maxilla. Follicular ameloblastoma has a higher recurrence rate compared to plexifom. Thus, the site and the histologic variant could be the reasons for the lower recurrence rate of SNAs compared to gnathic ones. Cases treated with a conservative approach show a significantly higher recurrence rate compared to the cases treated with a radical approach. Recurrence was reported only in four studies which included nine cases. Out of the total nine cases, five cases recurred in a span of 1 to 13 years, two after 2 years and two within 6 to 10 months. There are no complications reported in any of the studies, except one which mentioned numbness associated with a tooth.
This systematic review has some limitations. Firstly, due to the nature of the pathology studied, all the studies were either case reports or series-which may have several sources of bias. Furthermore, data from only 38 cases were included. In addition, the classification of SNAs based on the type, i.e., unicystic or solid multicystic could not be taken into consideration. Additionally, it was not feasible to carry out a meta-analysis due to the nature of the studies included.

Conclusions
Data from included studies suggest that SNAs are histologically similar to gnathic ameloblastomas, but their clinical presentation is different. They may cause complete or partial obstruction of the nasal cavity and the sinus. Additionally, they may also lead to rhinorrhea and nasal bleeding. Furthermore, they appear to affect an older demographic (mean age 59 years), and their resection may be accompanied by the excision of a large portion of the maxilla, necessitating maxillofacial prosthetic rehabilitation. SNAs have a better outcome in terms of recurrence and complications, however the histopathologic variant and management approach should be taken into consideration. Nevertheless, more cases should be reported adequately so that guidelines may be developed for diagnosing and managing SNAs to have a better outcome.