Primary ameloblastic carcinoma: literature review with case series

Introduction

Ameloblastic carcinoma (AC) is considered a rare malignant epithelial odontogenic neoplasm, which shows the histological features of ameloblastoma (AB) with cytological atypia, regardless of the presence or absence of metastasis [1]. AC was classified into primary type and secondary type. The primary type (de novo carcinoma) is not preceded by simple AB, while the secondary type (carcinoma ex AB) is a malignant transformation of a pre-existing benign AB [2].
Casaroto et al. in 2012 correlated the demographic and phenotypic aspects of primary AC and secondary AC and found that secondary AC correlated with recurrence and mortality, suggesting it to be more aggressive than primary AC. They explained that result by the too short reported follow-up time of primary AC cases, which associated this tumour with more favourable prognosis when compared with cases of secondary AC [2]. Therefore, the aims of the present work were: to report the clinical, histopathological, immunohistochemical, and ploidy status and the therapeutic details of four cases of primary AC, and to review the literature with regard to clinical, follow-up, prognosis, histopathological, and immunohistochemical information of primary AC.

Case reports

Case I

A 25-year-old African male presented to our unit with paraesthesia of the lower lip and non-painful chin swelling. Incisional biopsy showed islands of odontogenic epithelium with ameloblastomatous character. The tumour cells showed frequent mitosis, pleomorphism, and loss of reverse polarity of ameloblast-like cells. Areas of necrosis and others with loss of follicular architecture were evident. Diagnosis of AC was reached (Fig. 1).
The surgical decision was marginal resection with placement of the reconstruction plate through an extra oral apron approach; level I and II neck lymph nodes were removed. Histological evaluation of the excised part confirmed the diagnosis of AC, with free margins and free lymph nodes. Upon flow cytometric (FCM) analysis of formalin-fixed paraffin-embedded (FFPE) sections, the tumour was diploid with an S-phase fraction (SPF) of 19.16%. Immunohistochemical staining with α-smooth muscle actin (α-SMA) revealed positivity of few stromal cells in close proximity to tumour islands and negative epithelial cells (Fig. 1). Follow-up of the patient for six months revealed no recurrence. The patient then travelled to South Africa.

Case II

A 29-year-old female presented with a non-healing socket after extraction of her lower left third molar three months previously. There was evident swelling both extra- and intraorally. CT scans revealed a multilocular radiolucency extending from the lower left second premolar up to the ipsilateral condyle with perforations medially and laterally.
Incisional biopsy revealed histopathological features of AB. The surgical decision was resection of the left hemimandible with a safety margin of 1 cm; the deep part of masseter and lateral part of medial pterygoid muscle were included in the safety margin as a second anatomical barrier.
Histopathological examination of the excisional biopsy demonstrated dysplastic features, loss of nuclear polarisation and stellate reticulum like cells, nuclear pleomorphism, and increased mitosis. Moreover, sheets of spindle cells, areas of acanthomatous differentiation, and areas of necrosis were observed. Thus, a correction of the diagnosis to AC was performed. Tumour invasion was also observed in the masseter muscle, medial pterygoid, and the medial bony margin. The tumour was diploid with SPF of 23.98%. α-SMA immunohistochemical staining revealed negativity of tumour cells and positivity of stromal cells in close proximity to tumour islands (Fig. 2). The patient died two weeks after surgery.

Case III

A 25-year-old Nigerian male presented with a pain-ful massive left mandibular swelling. Radiographic examination revealed a well-defined multilocular radiolucency related to an impacted third molar (Fig. 3). An incisional biopsy was performed, and it was diagnosed as AB. A hemi-mandibulectomy was planned, and the excisional biopsy revealed features of malignancy: increased mitosis, hyperchromatism, pleomorphism, and areas of necrosis, rendering a diagnosis of AC. FMC revealed diploid tumour with SPF of 23.31%. α-SMA staining showed strong nuclear positivity of epithelial cells (Fig. 3). Upon follow-up for six months, the patient was alive with no recurrence; the patient then travelled.

Case IV

A 62-year-old male patient presented with an exophytic mass appearing from a non-healing socket of an extracted upper 8. The lesion appeared as a maxillary well-defined multilocular radiolucency. Incisional biopsy revealed hypercellular strands of odontogenic epithelium with increased mitosis and loss of polarisation (Fig. 4). Areas of necrosis and areas of acanthomatous metaplasia were evident. A diagnosis of AC was reached. The tumour was diploid upon FMC analysis, with an SPF of 23.15%. α-SMA staining revealed negative epithelial cells and positive stromal cells in close proximity to tumoural cells (Fig. 4). The patient refused to undergo the surgery.

Material and methods

The Medline database was searched using the term ameloblastic carcinoma and primary type, and all cases of primary AC published in English between 2012 and 2017 were reviewed, including our cases. Data analysis including patient age, gender, location, radiograph, management, follow-up, and histopathological features of tumours have been recorded in Tables I and II.

Results

The review of English literature from 2012 to 2017 revealed 40 reported cases of primary AC, including our cases. The age ranged from (8-70 years) with a mean of 37.5 years. The male : female ratio was 4 : 1 and the ratio of occurrence of AC in mandible : maxilla was 3 : 1. The cases with reported radiographic picture were 27; 14 cases were unilocular radiolucency (53.8%), 12 cases were multilocular lesion (46.15%), two of them were mixed radiolucent radiopaque lesions, and one case was peripheral AC showing saucerisation of the cortical bone. Cortical bone erosion was demonstrated in 13 cases (50%) and soft tissue invasion was detected in four cases (15.38%).
Metastatic status was reported in 34 cases: 29 cases with no metastasis (85%), four cases with lymph node metastasis (11.76%), and only one with metastasis in lung, pleura, and bone marrow. The management was reported in 38 cases; all of them treated with resection or hemi-mandibulectomy/hemi-maxillectomy with or without neck dissection, except one case which was treated with chemotherapy. Five cases were subjected to postoperative radiotherapy with two of them subjected to helical tomotherapy.
Follow-up was reported in 26 cases with a period of wide range (half-108 months) and with a mean of 34.5 months. Three cases were lost in follow-up. The outcome was non-specified in 11 cases. Twenty-five cases were alive with no recurrence (86.2%) and two cases showed recurrence (6.9%). Death was reported in three cases (10.34%).
The histopathological analysis revealed that 18 cases were follicular in pattern (75%), one of them with cribriform pattern. Six cases were plexiform (25%), and 16 cases were non-specified. Twenty-five cases showed peripheral palisading and increased mitosis; the remaining 15 cases were non-specified. Reverse polarity was seen in seven cases (46.66%), and 25 cases were non-specified. Twenty cases showed stellate reticulum-like cells (86.95%) and 17 cases were non-specified. Necrosis was detected in 18 cases (85.7%), but 19 cases were non-specified. Acanthomatous metaplasia were detected in 16 cases (61.5%), and 14 cases were non-specified. Clear cells were detected in three cases, spindle cells were detected in five cases, and one case showed ghost cells.

Discussion

AC is an extremely rare odontogenic tumour arising from odontogenic epithelium and accounts for approximately 1% of all jaw tumours [18]. The pathogenesis of AC is controversial, with many genes being associated with malignant transformation. Khojasteh et al. in 2013 observed methylation of p16 in AC [19]. Mitochondrial apoptosis-inducing factors have been considered to play a role in malignant transformation in AB [1].
Malignant odontogenic tumours show up-regulation of coronin gene and downregulation of STK19 (Serine/Threonine Kinase) [20]. García-Mu¼oz et al. in 2015 found that PITX2 expression, which participates in cell proliferation, cell migration, cell invasion, and tumour growth, is highly augmented in AC [21].
Similar to AB, the most common site of AC is the posterior mandible [2]. Painful swelling, numbness of lower lip, rapid growth, cortical bone expansion with erosion, perineural invasion, and mucosal ulceration are the typical clinical manifestation of AC [5]. The most common radiographic picture of AC is an ill-defined radiolucency either unilocular or multilocular [11]. Mixed lesions seem to be related to maxilla. Bone erosion was seen in half of the lesions; however, soft tissue invasion is uncommon in primary AC. Maxillary lesions were more aggressive, with invasion to the nasal cavity, eyeball, or base of the skull. Peripheral AC is extremely rare, causing saucerisation of cortical bone [16]. Radiographic differential diagnosis of AC includes odontogenic keratocyst, odontogenic myxoma, AB, and calcifying epithelial odontogenic tumour [11].
Metastasis in AC is infrequent (15%), mainly to regional lymph nodes or lung, originally believed to be due to aspiration from the oral lesion rather than a true hematogenous or lymphatic spread. Few cases have reported metastasis to the brain, bone marrow, and liver [9]. Zwahlen et al. reported a case with histologically proven myocardial metastasis of a maxillary malignant AB [22].
AC shows the architectural features of AB with cellular dysplasia, such as: pleomorphism, hyperchromatism, bizarre mitosis, and altered nuclear/cytoplasmic ratio. Squamous metaplasia and keratin pearl formation could be detected in many cases (61.5%). In the second place, spindling of the cells was reported in five cases, including our case. Clear cells detected in three cases, and only one case showed ghost cells resembling ghost cell odontogenic carcinoma.
Histologically, AC should be differentiated from primary intraosseous carcinoma that lack the peripheral palisading and stellate reticulum. Furthermore, this lesion tends to resemble squamous odontogenic tumour, which also lacks stellate reticulum, peripheral palisading, and cytologic atypia [11]. Ameloblastic carcinoma mimics histologically high-grade mucoepidermoid carcinoma (mucicarmine positive) and metastatic carcinoma to the jaws [9]. Spindle cell variant of AC should be differentiated from odontogenic sarcoma and ameloblastic carcinosarcoma; spindle cell areas are negative for vimentin and positive for cytokeratin [1].
Flowcytometric analysis of our cases revealed diploidy of all tumours with a mean SPF of 22.4%, which indicates hyperactive proliferation. These results were in accordance with the previous work of Bello et al., who, in 2009, examined the ploidy of AC and found that all the cases were diploid. They explained that result by the presence of excessive cell debris in paraffin-embedded sections, which may have hidden small aneuploid peaks [18]. Furthermore, Mahmoud et al., in 2017 investigated the diagnostic accuracy of flow cytometric analysis in AC and found that all the examined tumours were diploid with a mean SPF value of 14.05%. They determined the cut off value of SPF as 11.5% [23].
Many proliferation markers had been used to diagnose AC, especially, Ki-67, PCNA, and MCM proteins. Bello et al., in 2009 found that Ki-67 labelling index in AC is three times that of AB [18]. Maya et al. in 2012 found that PCNA values of AC were almost five times the value of AB [24]. Casaroto et al. in 2012 found that the mean Ki-67 in AC was 42.45% [2]. Bologna-Molina et al. in 2013 studied PCNA and Ki-67 expression in AC and found that the mean proliferation index of AC using Ki-67 was 48.7%, and while using PCNA it was 93.3%, significantly higher than AB. Furthermore, they found that Ki-67 was a more specific marker for the proliferation of ameloblastic tumour cells [25]. Carreón-Burciaga et al. in 2015 found that Ki-67, MCM2, and MCM3 expression levels were higher in AC than in AB, which indicates aggressive, invasive, and metastatic neoplasm [26].
Among the apoptosis regulators, Bcl-2 expression in AC was investigated by Kallianpur et al. in 2014 and revealed strong positivity [1]. Furthermore, Casaroto et al. in 2012 investigated the expression of P53 and Bcl-2 in AC and revealed strong positivity [2]. Among the differentiation markers, Ansari et al. in 2015 found negative expression of CK19 in AC, while Uzawa et al. (2015) found positive expression of vimentin in AC epithelial cells, which indicates dedifferentiation of epithelial cells [13, 14].
Grewal and Sethi in 2014 found that AC showed a significantly higher nuclear expression of Autocrine Motility Factor Receptor in the neoplastic epithelial cells when compared to benign AB, which plays a role in cell motility [27].
Lei et al. in 2014 found that diffuse nuclear staining of sex determining region-Y-related high-mobility group box 2 (SOX2) is suggestive of malignant ameloblastic neoplasm [28]. Kamath et al. in 2010 found decreased expression of syndecan-1 in AC when compared to various ABs, which indicates aggressiveness [29].
In accordance with Roy and Garg (2013) and Ansari et al. (2015), α-SMA immunostaining in our patients revealed only one case with positivity in epithelial cells and stromal cells in close proximity to epithelial cells; the other three cases showed positivity in stromal cells only [7, 13]. The immunoreactivity of stroma is due to the emergence of myofibroblasts caused by the release of TGFβ1 and PDGF from neoplastic cells during the invasion process [7]. Myofibroblasts promote epithelial-mesenchymal transition, which is essential for tumour invasion and metastasis causing immunoreactivity of α-SMA in epithelial cells [6].
Bello et al. in 2009 found strong positivity of α-SMA within the tumour islands (in both peripheral and central cells) [18]. Furthermore, Kamath et al. in 2010 found definite positivity of α-SMA in stroma in close approximation with the epithelial islands and in the stellate reticulum like cells [29]. Safadi et al. in 2016 found that α-SMA expression in epithelial islands provided 100% specificity to favour a diagnosis of AC versus Ki-67 with a specificity of 95% [30].
Furthermore, histochemical staining using AgNOR was investigated in AC vs. AB by Kamath et al. (2010), Prasanna et al. (2014), Da Silva et al. (2016), and Mahmoud et al. (2017), who found that the mean ANOR count/cell in AC was more than 3 dots/cell, which is twice that of AB [29, 31, 32, 23].
The treatment of choice for AC includes wide surgical resection with 2-3 cm of bony margins with or without cervical lymph node dissection [2]. Various chemotherapeutic agents have been used, including cisplatin, cyclophosphamide, carboplatin, paclitaxel, doxorubicin, methotrexate, prednisone, bleomycin, 5-fluorouracil, and dacarbazine, with varying degrees of response [10]. Horvath et al. in 2012 lost an AC patient with pulmonary metastasis, who was treated with chemotherapy, but it may have been due to the advanced stage of disease [5].
In incomplete resection cases and advanced soft tissue invasion, adjuvant postoperative radiotherapy may be considered as a treatment option. This management has been reported in many cases with patients alive and free of disease [3, 4, 9]. Koca et al. (2014) used postoperative helical tomotherapy for a patient with incompletely resected maxillary AC and found reduction of remaining lesion size [10]. Furthermore, Takahashi et al. (2015) managed a patient with maxillary AC invading the base of the skull with surgical resection and postoperative single fraction helical tomotherapy, and the patient found alive and free of disease [15].
The survival rate of AC depends on medical background, local recurrence, and regional or distant metastasis. Maxillary AC has a worse prognosis than mandibular lesions due to rapid growth and extension into sinuses, orbit, base of the skull, and other vital areas nearby [1].

Conclusions

To sum up, primary AC is a rare malignant epithelial odontogenic tumour that favours the posterior mandible with profound male predilection and appears as an ill-defined radiolucency. Metastasis and invasion are more likely to occur in maxillary cases. The treatment of choice is wide surgical resection with 2-3 cm of bony margins with or without cervical lymph node dissection. Adjuvant postoperative radiotherapy is beneficial in incomplete resection cases and advanced soft tissue invasion. The most specific diagnostic method of AC, as concluded from review, is α-SMA in epithelial cells in conjunction with Ki-67 index value and SPF more than 11.5%.

The authors declare no conflict of interest.

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Address for correspondence

Sarah Ahmed Mohamed Mahmoud
Oral & Maxillofacial Pathology Department
Faculty of Dentistry
Cairo University
Egypt, Postal address: 11222
tel. 002 01119742598