Ameloblastic carcinoma: a clinicopathologic analysis of cases seen in a Nigerian Teaching Hospital and review of literature

Introduction Ameloblastic carcinoma is a rare malignant odontogenic neoplasm that exhibits histological features of ameloblastoma in combination with cytological atypia. It may arise de novo or secondarily through malignant de-differentiation of pre-existing ameloblastoma or odontogenic cyst. Secondary ameloblastic carcinomas often results from repeated surgical intervention, which is a mainstay of odontogenic tumor management in resource limited settings. To date, relatively few cases of ameloblastic carcinomas have been reported and many cases have been misdiagnosed as ameloblastoma. This is due to its wide range of clinicopathological feature which range from indolent to aggressive. It may present as an aggressive ulcerated mass or as a simple cystic lesion; hence, it often challenging to delineate from its benign counterpart, ameloblastoma. Methods this study reviewed the clinicopathological data on 157 cases of odontogenic tumors diagnosed over a 10 years period from the pathology archive of the Oral Pathology Unit of Obafemi Awolowo University Teaching Hospital Complex (OAUTHC), Ile-Ife, Nigeria. Results of all these cases, we identified that 64.9% were Ameloblastomas, while 8.3% were ameloblastic carcinomas. Primary subtypes of ameloblastic carcinoma constituted 23.08%, while 69.23% of the cases were of the secondary subtype. We also found that the secondary subtype of ameloblastic carcinomas showed a higher mean duration value of 7.7 years. Most lesions were found in posterior mandible and presented with ulceration, perforation and ill-defined borders radiographically. Conclusion this study is among the few that have documented higher frequency of secondary ameloblastic carcinoma in the scientific literature.


Introduction
Ameloblastoma is a slowly-growing, locally-invasive epithelial odontogenic tumour and has been regarded as the most common odontogenic tumour in many studies [1][2][3]. However, other studies have documented it as the second most prevalent odontogenic tumor after the odontomas [4,5]. It has a reported prevalence of about 1-3% of all jaw tumors and cysts, with varied geographical prevalence ranging from 11-24% of all odontogenic tumors in North America to an estimated global incidence of 0.5 cases per million personyears [6,7]. Ameloblastoma constituted between 66%-99% of odontogenic tumors in sub-Saharan Africa, with the mandible being more commonly affected (in about 80% of cases) [6,8].
Ameloblastoma rarely exhibit malignant transformation, as evidenced by the low frequency of occurrence of Ameloblastic carcinoma (AC).
More than 100 cases of AC have been reported in the scientific literature, many of which are case reports; hence, there is currently a paucity of information on AC [9][10][11]. Controversy and lack of consensus still trails AC with regards to its nomenclature and prognosis, due to the relative rarity of this lesion; however, updated classification of Head and Neck tumors by World Health Organization in 2005 seem to have resolved this issue [12]. In this classification, AC was included as one of the odontogenic malignancies. Epithelial malignant odontogenic tumors in this category were: metastasizing were classified based on the histological evidence of origin thereby describing AC as tumors having the characteristics of ameloblastomas and squamous cell carcinomas [13]. Malignant (metastasizing) ameloblastoma and ameloblastic carcinoma are two distinct malignant variants of ameloblastoma. While AC arises either de novo, from ex-ameloblastoma or from odontogenic cyst [14]; malignant ameloblastoma is entirely an ameloblastoma with probable capacity to metastasis [10,15]. AC as an odontogenic malignancy, combines the histological features of ameloblastoma with cytological atypia, even in the absence of metastases [13]. It can be further subdivided into the primary and secondary subtypes [8]. The primary subtype, otherwise known as de novo, presents malignant neoplasm ab initio; whereas, the secondary subtype demonstrates a malignant transformation observed in a previously existing ameloblastoma, independent of the presence or absence of metastasis [8,16]. There is further division of the secondary type of AC into two subtypes namely the intraosseous type arising within a preexisting benign intraosseous ameloblastoma, and the peripheral type, arising within a benign peripheral ameloblastoma [12]. Metastasizing (malignant) ameloblastoma, is known as a tumour that retains its benign histological features regardless of the site of metastasis [9].
Ameloblastic carcinoma (AC) is very rare, nevertheless it is the most common malignancy of odontogenic tumours (OTs) and presents a higher incidence compared to that of malignant ameloblastoma by a ratio of 2:1 [7,17]. The clinical features and biologic behavior of AC are seemingly identical to ameloblastoma in terms of associated bony swelling, tooth mobility and multilocular radiographic presentation, nevertheless they can be distinguishable on the basis of thorough clinical examination and associated features such as attendant pain, ulceration, rapid rate of growth and cortical bone perforation with or without soft tissue invasion, which are often suggestive of malignancy [9,17]. Meticulous microscopic evidence of cytological atypia with presence of mitosis confirms the diagnosis of AC, despite the observation of classical histopathological features of benign ameloblastoma. AC is characterized by diverse histopathological features which presents a diagnostic dilemma, hence proper evaluation of the patients and extensive analysis of the surgical sections of specimen is advocated. The relative frequency of AC is less than 1% of all malignant neoplasms in the Head and neck region (H&N) [18]; and despite its low occurrence, its diagnostic dilemma necessitates highlighting of its essential clinical behavior and microscopic presentation. This is very important in oral pathology practices in sub-saharan regions of Africa, where human and financial resources are limited. Furthermore, advanced studies in immunohistochemistry and genetics can also facilitate precise diagnosis of AC [10]. Currently, there is dearth of report on AC from Africa, and majority of available studies in the scientific literature are cases reports from Asia and America [9][10][11]19]. Hence, the present study aims to highlight the clinical features and histopathologic behavior of AC in a tertiary health centre in Nigeria.

Methods
This study reviewed the clinicopathological data on AC in relation to other odontogenic tumors (OTs) over a 10-year period (2007-2016 Histopathology features obtained are summarized in Table 2. The histopathology parameters were graded by dividing each of the two slides into four quadrants using a slide pen, this is done for each lesion at the centre of the mounted specimen (at X10 Magnification).
Quality assurance: two independent certified pathologists carried out all slide examination and the average score was taken as the final score for each lesion as summarized above (Table 2).

Results
A total of 790 cases of Oral and jaw lesions were seen within the 10-year study period. Of these, 157 (19.9%) cases of OTs were found out of which 102 (64.9%) cases were Ameloblastomas. ACs constituted 13 (1.64%) cases of the total biopsy and 8.3% of OTs. Table 1 summarizes the demography of ACs in this study. Three cases were primary subtypes of AC, constituting 23.08%, while 9 (69.23%) cases where of the secondary subtype. It was observed that the secondary subtypes had a higher frequency of occurrence.
One case could not be sufficiently accounted for; hence, it was not categorized either as primary or secondary AC subtype.  Cytological atypia including pleomorphism, abnormal chromaticity and reverse nuclear/cytoplasmic ratio were frequently observed.
Overview of histological finding is provided in Figure 4 and Figure 5.

Discussion
The term ameloblastic carcinoma (AC) was introduced by Shafer et al., (1974) to describe a tumor arising from malignant transformation of epithelial cells of an ameloblastoma [20]. Despite the rarity of AC compared to ameloblastoma, AC is the most common malignant OT.
The pathophysiological mechanism of its evolution is still poorly understood, and this has resulted in a lot of controversy about its biology [11,19]. Sequential carcinogenesis in ameloblastoma has been suggested to involve long term accumulation of multiple genetic defects. This could also be due to a spontaneous mechanism following repeated therapies which may eventually lead to aggressive clinical manifestation [9,21]. Primary types of AC have been widely reported to be more common than the secondary type [8,9], however finding from this study contradicts this observation. We found the secondary type being more frequent with a remarkable ratio of 3:1.
Furthermore, the overall mean duration at the time of presentation was 5.9 years for primary AC, as compared with the secondary type which was 7.7 years. The range of occurrence of secondary AC in our study was 4 months to 16 years. This alludes to the fact that most of our cases arose from carcinomatous dedifferentiation of a pre-existing intraosseous ameloblastoma (as evident from the initial documented histologic diagnosis of ameloblastoma). To the best of our knowledge, this is one of the few studies of AC from the sub-Saharan African region where secondary AC is more frequent than the primary type.
A possible factor attributable to this is patients' attitude. Most patients tend to delay in seeking orthodox medical treatment (as indicated in the mean year of duration) and there are limited resources for timely surgical intervention. Zarbo et al. (2003), submitted that malignant transformation may take up to 10yrs to occur [22], and this is consistent with what we found in our study. Repeated surgical trauma with induction of chronic inflammation was also noted in this study as some of our patients were exposed to multiple biopsies prior to  [6,24]. The general consensus from most studies is higher frequency of occurrence in males [9,11,26]. Findings from our study of male to female ratio of 1.6:1 concur with general observation from previous studies. This higher male predilection of AC follows the distribution pattern of its benign counterpart, ameloblastoma [6].
Although mandible is the preferred site for AC as seen in our study, however, a systematic review has shown equal predilection for both jaws [9]. In addition, 69.2% of our cases involved the posterior region of either jaw which is in accordance with other studies [9,11]. AC presents more aggressive biologic behavior and the most commonly observed characteristics are swelling often with pain, rapid growth and cortical perforation [11,27]. Trismus, gingival bleeding, paresthesia, epistaxis and dysphonia have also been mentioned [24]. In another study, Abdelhamed et al. [38] investigated the expression of midkine and Ki67 immunomarkers in ameloblastoma and AC. The study established that midKine and Ki-67 expression were significantly higher in AC than in ameloblastoma. Furthermore, use of Ki67 and AgNOR to differentiate AC from ameloblastoma showed that these markers were highly expressed in AC [29]. In addition, Lei et al. [39] also attempted to differentiate AC from ameloblastoma and atypical ameloblastoma with the use of SOX2 marker (sex determining region-Y-related high mobility group box 2), which is a protein that is involved in ameloblastic epithelial lineage.  [41]. Furthermore, advanced imaging technique using positron emission tomography (PET) and magnetic resonance imaging (MRI) have been used to distinguishing AC from benign Ameloblastoma [42]. In this study, preoperative 18Fα-methyl tyrosine positron emission tomography and magnetic resonance imaging was utilized in the identification of malignant region in AC, although the result was inconclusive.
Because of the rarity of large clinical series and long-term follow-up, treatment protocol for AC is debatable. Some clinicians prefer radiotherapy [28], while others advocate for surgical treatment [13,24]. Ramadas et al., [43] also considered chemotherapy such as use of cisplatin, adriamycin, and cyclophosphamide to be beneficial in cases of unresectable lesion and as post-surgical adjuvant treatment. AC is considered to be radioresistant by some authors and its use is therefore restricted to pre/post-surgical management, cases not suitable for surgical management, as well as in those that exhibit advanced local or metastatic disease [31]. Wide local excision with about 2cm safety margin (with or without adjuvant radiotherapy and or chemotherapy) has been considered as the mainstay of treatment of AC. Although variable successes have been recorded with radiotherapy or surgery either in combination or alone. Role of chemotherapy in the management of AC is still debatable hence it has not been indicated as a primary treatment mode [9]. The benefit of neck dissection is controversial in the absence of evidence of metastasis [30].

Conclusion
AC is a rare malignant lesion that demonstrates a spectrum of demography, clinicopathologic features and biologic behavior that ranges from indolent/benign to aggressive/malignant, as observed in this study. Due to the rare nature of AC, it often presents diagnostic dilemma to many oral pathologists in resource limited settings. Due to lack of consensus on parameters for the diagnosis of AC, cases should thus be carefully analyzed and evaluated both clinically and histopathologically to detect subtle changes that may predict its aggressive behavior and diagnosis. This study is among the few in the scientific literature that documented higher frequency of secondary AC. In addition, little is known till date of its pathogenesis, although delay in seeking orthodox treatment by patients in low and middle income world setting may be an important contributory factor.
Although scientific literatures has overwhelmingly favored the surgical management as the treatment of choice, novel emerging molecular therapies may soon overtake conventional therapies in an era of precision medicine.

What is known about this topic
• Ameloblastic carcinoma is a rare malignant odontogenic neoplasm; • Ameloblastoma rarely exhibit malignant transformation to ameloblastic carcinoma; • Due to its rarity, ameloblastic carcinomas is often misdiagnosed as ameloblastoma.

What this study adds
• This study reviews a large cohort of odontogenic tumors in sub-saharan Africa; • We have examine variations in presentation of ameloblastic carcinoma and provided tips on how to delineate it from other odontogenic tumors; • This study documents higher frequency of secondary ameloblastic carcinoma in our study population

Competing interests
The authors declare no competing interests.