Differential profile of primary and recurrent ameloblastomas among Afro-descendants and non-Afro-descendants – a systematic review

Abstract

Ameloblastoma is an aggressively growing jaw tumor with high recurrent properties. Reports on global and racial distribution of ameloblastoma are variable and inconclusive. The role of race and ethnicity on ameloblastoma growth characteristics, genetic mutational profile and recurrence are also still unclear. The primary aim of this systematic review was to assess genetic, racial and ethnic distribution of primary and recurrent ameloblastoma from published literature. The secondary aim was to assess potential correlations between ethnicity, genetic mutation and disparities in ameloblastoma treatment outcomes in Afro-descendants and non-Afro-descendants. Twenty three eligible articles were selected based on Preferred reporting items for systematic review and meta-analysis (PRISMA), and a total of 169 ameloblastoma cases were evaluated. Data on patient demographics, ameloblastoma growth characteristics and genetic status were collected for quantitative analysis. Among a total of 169 ameloblastoma cases, Afro-descendant patients had higher primary and recurrent ameloblastomas at 15.5% and 4.7% respectively compared to non-Afro-descendant at 10.7% and 1.8% respectively. Additionally, BRAF V600E was positively associated with 48.8% of all ameloblastomas and strong predilection for Afro-descendants. Despite the paucity of information on genetic profile of ameloblastomas in the Afro-descendant patient cohort, this ethnic group still accounted for 2.95% of all BRAF V600E positive tumors. These suggest that Afro-descendants are understudied regarding ameloblastoma characteristics, genetic profile and recurrence profile. Mutational analysis of ameloblastoma tumors in Afro-descendants should be promoted.

Introduction:

Ameloblastoma is a locally-aggressive benign odontogenic tumor of epithelial origin [1] Ameloblastomas display a locally-destructive painless growth pattern that may remain for a long time until it becomes large and expansile tumor[2] In sub-Saharan Africa among the Black racial population/Afro-descendants, it is not uncommon for patients to present with massive large facially-deforming tumors[1]. Ameloblastoma accounts for 1% of all the jaw tumors and 18% of all odontogenic tumors [3].The classification of ameloblastomas by the World Health Organization (WHO) has recently been simplified to 3 major types that include conventional, unicystic and peripheral ameloblastomas[4]. Up to 10% of ameloblastomas recur despite radical surgery [5] even though patients treated with radical surgery have a reduced chance of developing recurrence compared to those treated conservatively [6]. Recurrence is often dictated by the size of the tumor, treatment approach and histological type [1; 7]. Histologically, conventional ameloblastoma could display either plexiform or follicular cellular pattern. About 50% of ameloblastoma recurrences occur in follicular ameloblastomas (Fig. 1).

Fig. 1.

Histology of follicular ameloblastoma

Photomicrograph of follicular ameloblastoma (H and E staining x100). The black arrow shows individual islands of odontogenic epithelium comprised of peripheral palisading cells showing reverse polarization and central loose stellate reticulum- like cells. The black arrow head shows delicate fibrous connective tissue stroma.

Oncogenic mutations in ameloblastoma play a role in activating signal transduction pathways like mitogen-activated protein kinase (MAPK) and Sonic Hedgehog (SHH) pathways [4; 8; 9]. BRAF is the most commonly mutated gene that causes activation of MAPK pathways in mandibular ameloblastoma of generally younger patients, while mutations of smoothened gene (SMO), a G-protein-coupled receptor and signalling effector component of SHH pathway are associated with the activation of SHH pathways in maxillary ameloblastoma of generally older patients [10]. The higher association of BRAF mutation with majority of ameloblastic lesions suggests a biologic rationale for potential gene targeted therapies for ameloblastoma. An earlier report evaluating presence of BRAF V600E mutation in ameloblastoma reported that 62.5% of the ameloblastoma cases are BRAF V600E positive [10]. A more recent report indicate that 80–90% of ameloblastomas are associated with BRAF V600E mutation [11]. However, the interplay of genetic mutations, race and recurrence of ameloblastoma are still unclear.

Currently, there are no established correlations between ameloblastoma gene mutational profile and geographical or racial distribution. In North and South Americans, the African-American racial group is five times more likely to be affected by ameloblastoma than Caucasians [12]. The annual incidence of ameloblastoma standardized against the standard world population for Blacks are 1.96 and 1.20 for males and females respectively, and similarly, 0.18 and 0.44 for White males females respectively [13] These suggest that the Black racial group may be more susceptible to ameloblastoma, however, it is still unclear whether race and ethnicity play any role in ameloblastoma growth characteristics, genetic profile or recurrence. There is insufficient data to compare rates of ameloblastoma among different countries and different racial or ethnic groups. Multiple case series on ameloblastoma described in the literature are geographical and country dependent without any correlations with race or ethnicity. The objective of this study was to review published literature to assess whether genetic and recurrent patterns of ameloblastoma among Afro-descendant and non-Afro-descendant patients are ethnicity-dependent.

Method and materials

Protocol and registration.

This systematic review was conducted according to the guidelines for preferred reporting items for systematic review and meta-analysis (PRISMA)[14; 15]. The study protocol was not eligible for inclusion in PROSPERO [15; 16] because it had progressed beyond the point of data extraction at the time of initial registration.

Information sources and search strategy.

A literature search of English language articles was performed in PubMed, Embase and Google Scholar electronic databases. To capture all relevant articles related to the research objective, there was no limit set for the time frame. All the three databases were searched using the following key terms: Caucasian AND ameloblastoma, African American AND ameloblastoma, race AND recurrent ameloblastoma, (race AND BRAF AND recurrent ameloblastoma), (mutation AND race AND ameloblastoma), Black AND ameloblastoma, SMO AND ameloblastoma, BRAF AND ameloblastoma, gene mutation AND ameloblastoma, African American AND recurrent ameloblastoma, (mutation AND race AND recurrent ameloblastoma), gene mutation AND recurrent ameloblastoma, Black AND recurrent ameloblastoma, race AND SMO AND recurrent ameloblastoma, SMO AND recurrent ameloblastoma, BRAF AND recurrent ameloblastoma and Caucasian AND recurrent ameloblastoma. MESH terms were: Ameloblastoma, recurrence, genes, mutations, racial groups, Whites, Blacks, African American. Duplicate references were identified and removed using Endnote^™ 20.4 (Clarivate Analytics) reference manager.

Study selection and data extraction.

Two independent reviewers screened the search results based on PRISMA guidelines[14; 15]. If there was any uncertainty or disagreement in selection or deletion of a particular record, both authors critically evaluated that article and came to an agreement. An article was included if it contains individual patient information regarding race/ethnicity, gender, sex, type of ameloblastoma whether primary or recurrent with or without gene mutation information. An article that did not meet these criteria was excluded. The articles were evaluated and information extracted based on a modified PECO scheme [17] to answer the question: Are Black individuals more affected by ameloblastoma than non-Black? The PECO question was developed based on Patients/Population: Ameloblastoma patients; Exposure: Black race; Comparison: Non-black race and Outcomes: Primary outcome was type of the ameloblastoma (whether primary or recurrent) and secondary outcome was the gene mutation profile of the ameloblastoma.

Risk of bias assessment.

Risk of bias across studies was evaluated by comparing characteristics and variability among ameloblastoma cases, methodological heterogeneity, and risk of bias in individual studies.

GRADE Assessment.

Assessment of Grading of Recommendations Assessment Development and Evaluation (GRADE) outcomes[18] was not applicable in this systematic review since the purpose was to only summarize the evidence base without making any clinical recommendations.

Data analysis.

Patient demographic information and ameloblastoma characteristics from all eligible articles were collected and analysed based on percentages of primary and recurrent ameloblastoma, gene mutation and race to assess correlations between these variables. Statistical analysis was performed using SAS statistical package v 9.4 (Cary NC).

Results

A total of 654 articles were identified from PubMed (n=244), Embase (n=354) and Google Scholar (n=56). After duplicate articles were removed, the titles and abstracts of n= 433 were reviewed for full text articles. A total of n=101 full text articles were eligible for screening and only n= 23 articles were eligible for qualitative synthesis (Fig. 2, Table 1).

Fig. 2.

Search Strategy

Search strategy based on Preferred Reporting Items for Systematic Reviews

and Meta-Analyses (PRISMA) guidelines

Table 1.

Eligible Articles

Author Information	Year of publication	Individual patient information provided	Age data provided	Race data provided	Genetic mutation provided (test used)	Tumor characteristics provided
Adebayo et al.	2011	✓	✓	✓	N/A	✓
Altini et al.	1976	✓	✓	✓	N/A	✓
Altini and Slabbert et al.	1991	✓	✓	✓	N/A	N/A
Broudic et al.	2019	✓	✓	✓	✓ (N/A)	✓
Castro S. et al.	2012	✓	✓	✓	N/A	✓
Cavalcante et al.	2009	✓	✓	✓	N/A	✓
Daramola et al.	1975	✓	✓	✓	N/A	✓
Derakhshan et al.	2020	✓	✓	✓	✓ (IHC, SS)	✓
Kokubun et al.	2022	✓	✓	✓	✓ (IHC, SS)	✓
Kurppa et al.	2014	✓	✓	✓	✓ (IHC, SS)	✓
Lee et al.	2019	✓	✓	✓	N/A	✓
Menditti et al.	2011	✓	✓	✓	N/A	✓
Nascimento et al.	2009	✓	✓	✓	N/A	N/A
Nastro et al.	2012	✓	✓	✓	N/A	✓
Oh K. Y. et al.	2019	✓	✓	✓	✓	✓
Ord et al.	2002	✓	✓	✓	N/A	✓
Rais et al.	2019	✓	✓	✓	N/A	✓
Reid-Nicholson et al.	2009	✓	✓	✓	N/A	N/A
Said- al-Naief et al.	1997	✓	✓	✓	N/A	✓
Schaberg et al.	1983	✓	✓	✓	N/A	✓
Suomalainen et al.	2006	✓	✓	✓	N/A	N/A
Yoshioka et al.	2013	✓	✓	✓	N/A	N/A
Zabro et al.	2003	✓	✓	✓	N/A	✓

✓ = information provided

IHC = Immunohistochemistry

SS = Sanger sequencing

N/A = information not provided

The global distribution of ameloblastoma patients in the included studies is spread across 10 different countries and 5 continents (Fig 3). Males accounted for 58.6% and females were 41.4 of all the 169 ameloblastoma cases at a male: female ratio of 1.4:1 (Table 2). Along racial lines, there were 21.9% Black, 13.6% Caucasian, 29.6% Middle Eastern and 33.7 % Asian (includes 14.8% Japanese, 17.7% Korean) patients. Also, there were 1.2% patients whose race or ethnic information was not listed. Based on age, 7.1% were grouped into ages 0 – 12 years (children), 18.9% were within ages 13 – 17 years (adolescent), 62.1% were within ages 18 – 64 years (adults) and lastly, 11.9 % were 65 years and above (older adults)[19; 20]

Fig. 3.

Global distribution of ameloblastoma cases included in qualitative analysis.

Table 2.

Distribution of all ameloblastoma cases

Summary of all ameloblastoma patients
Gender	Females		Males
(Cases)	70 patients		99 patients
(%)	41.4		58.6
Age distribution (%)	0–12 years (Child)	13–17 years (Adolescent)	18–64 years (Adult)	≥ 65 or more (older adults)
	7.1	18.9	62.1	11.9
Race/Ethnicity (%)	Black	Caucasian	Asian	Middle-Eastern	Unknown
	21.9	13.6	33.7	29.6	1.2
Genetic profile (%)	BRAF V600E	SMO+	BRAF or SMO WT	Unknown
	48.8	0	25	26.2

Primary ameloblastomas were 43.8%, while recurrent ameloblastomas were 22.5% (Fig. 4). Furthermore, there was one case of metastatic ameloblastoma [21] and 56 cases (33.1%) that information on the type of ameloblastoma was not provided. BRAF V600E was the most commonly reported gene mutation (48.8%). There were 26.2% patients whose gene mutation status was unavailable. Black patients with primary and recurrent ameloblastomas were 15.5% and 4.7% respectively compared to Caucasians with 10.7% and 1.8% respectively (Fig. 5).

Fig. 4.

Ameloblastoma types

Bar graph shows that primary ameloblastoma was the most reported. Diagnostic information of a significant number of ameloblastomas was not available

Fig. 5.

Ethnic distribution of ameloblastoma cases

Bar graph shows that both primary and recurrent types of ameloblastomas were higher in Afro-descendants relative to non-Afro-descendants but association of tumor type with ethnicity was not significant (p < 0.005). There were more cases on unclassified ameloblastoma types among Afro-descendant patients

The remaining ameloblastoma cases were classified into a non-homogeneous racial group of patients. To further assess relationships between Black vs. Caucasian ameloblastomas, two binary variables assessed: whether ameloblastoma type was recurrent or primary and whether the patient race is Afro-descendant or non-Afro-descendant. Chi square test was used to assess association between race and tumor type but this was not statistically significant (p>0.05). Outcomes of BRAF genetic testing for ameloblastoma whether mutated or not did not indicate any significant differences between Afro-descendant or non-Afro-descendant patients. However, a significant number of ameloblastomas in Afro-descendants were not genetically-tested or mutational information was not reported (Fig. 6).

Fig. 6.

Mutational profile of ameloblastomas

Bar graph shows that testing for BRAF V600E was the most common genetic mutational analysis of ameloblastomas from both Afro-descendants and non-Afro-descendants. However, a significant number of ameloblastomas in Afro-descendants were not genetically-tested

Discussion

The periodic updates on classification of odontogenic tumors and cysts of the orofacial region by the WHO is highly significant as it takes into account new scientific information that can be applied to improving management of head and neck tumors [4]. However, there is usually sparse information on the impact of race on pathogenesis and treatment outcomes of odontogenic tumors like ameloblastomas. This is a frequency systematic review from published literature focused on further analysis of racial disparities in ameloblastoma characteristics, genetic profile and treatment outcomes.

The details of clinicopathological features of ameloblastoma were not completely reported in some of the reviewed literature. However, information about the whether the ameloblastoma was either a primary or recurrent tumor was captured. We found the male to female ratio of 1.4:1 in this review to be consisted with similar 1.2:1 ratio previously reported. [22]. Similarly, the common age distribution of ameloblastomas between the 3^rd and 5^th decades of life previously reported[23] is consistent with our findings. Using the American Psychological association’s guidelines for age groups [19; 20], we also found that 62.1% of ameloblastoma cases were between ages 18 – 64 years.

Ameloblastoma recurrence can be as high as 13% [24; 25]. The higher incidence of ameloblastoma between the 3^rd and 5^th decades also correlates with higher recurrence is the same age bracket as it has been previously reported that the mean age for recurrent ameloblastoma is 36.18 ± 5.47 years[26]. Similarly, we found that 22.5% of ameloblastoma patients that had recurrent ameloblastoma corresponded to a mean age of 32.8 years, Taken together, these suggest that ameloblastoma is highly recurrent during the 3^rd decade of life. Unlike age, the impact of race and ethnicity on molecular and clinicopathologic characteristics of ameloblastomas as well as recurrent pattern is yet to be fully elucidated. In this review, Afro-descendants patients had higher percentage of recurrent ameloblastomas (4.7%) than non-Afro-descendants (1.8%). Since characteristics of several ameloblastomas were not provided in more Afro-descendant patients (1.8%) relative to non-Afro-descendants (0.6%), it is possible that disparity between these two racial groups would have been wider if these additional information was available. Most of the ameloblastoma cases with incomplete description were presented in articles that focused generally on different odontogenic tumors and not specifically ameloblastoma. More recently, BRAF V600E mutation is now associated with 80–90% of ameloblastomas[11] and there is a possible trend for more statistically significant association between BRAF V600E mutation and ameloblastoma recurrence[27]. Surprisingly, we found only one eligible study that reported genetic mutational profile of ameloblastoma in Afro-descendant individuals and this study retroactively assessed tissues obtained from formalin-fixed paraffin-embedded (FFPE) ameloblastoma specimens rather than fresh-frozen samples as previously reported [10].

In spite of paucity of genetic testing of ameloblastoma tissues obtained from Afro-descendants, 2.95% of ameloblastoma in Afro-descendant group compared with 3.6% in non-Afro-descendants were associated with BRAF V600E. Although Afro-descendants patients accounted for 4.5% of all the BRAF tested ameloblastoma compared to 6.5% in non-Afro-descendants, it does not indicate that non-Afro-descendants have higher BRAF-associated ameloblastoma but rather that ameloblastoma in Afro-descendants patients have not been equally subjected to mutational analysis. Interestingly, majority of the ameloblastoma genetic mutation data in non-Afro-descendants were reported in Asian and Middle Eastern ethnic groups[28; 29]but fewer reports were available for Afro-descendants and Caucasian sub-group of non-Afro-descendants (Table 2, Fig. 6). Additionally, no SMO-associated ameloblastoma was identified in either Afro-descendants or Caucasian sub-group, which might relate to the higher genetic testing of ameloblastomas obtained from both Asian and Middle Eastern individuals. There are targeted therapies to control several BRAF and SMO mutated tumors [9; 30], so full understanding of the relationships between race, genetic mutation and pathogenesis of ameloblastomas will provide more insights on ameloblastoma recurrence that could lead to improved predictive algorithms for recurrence [11; 31; 32].

Conclusion

In conclusion, this systematic review suggests that BRAF V600E mutation can potentially be associated with recurrent ameloblastoma and apparent ethnical predilection for Afro-descendants. There is also strong indication that Afro-descendants are understudied regarding ameloblastoma characteristics, genetic profile and recurrence profile. More genetic studies on the profile of ameloblastoma in Afro-descendants are needed. This will enhance our understanding of any racial or ethnic disparities associated with ameloblastoma aggressive growth properties and recurrence pattern as well as development of potential non-surgical therapeutic approaches to management.