Ameloblastic Carcinoma of the Jaws: A Comprehensive Review of its Current Perspectives and Emerging Trends

INTRODUCTION

Ameloblastoma (AB) has been recognized and studied for over a century. Despite being the most common lesion within the odontogenic category, it continues to raise significant differences of perspective among pathologists and surgeons regarding its classification within the neoplastic continuum, its biological conduct, and its treatment approach.^[1] AB is described as a benign odontogenic but locally invasive tumor of the jaw, which may arise from a developing enamel organ, the epithelial lining of an odontogenic cyst, the rests of the dental lamina, or basal cells of the oral mucosa. Different varieties of this tumor are solid/multicystic, unicystic, and peripheral.^[2] It is one of the most common oral lesions, accounting for 1% of all oral cysts and tumors.^[3] Despite being benign, AB has a high recurrence rate, can cause local destruction, and requires complex surgical management for optimal cure.^[4] It has a strong potential to recur and, if left untreated, may transform into a malignancy, which is known as malignant AB. Malignancy deriving from AB has been given varied nomenclature, including ameloblastic carcinoma (AC),^[5] malignant AB,^[6,7] metastatic AB,^[8] and primary intra-alveolar epidermoid carcinoma.^[9]

Malignant AB has been divided into four distinct types, which are (1) metastasizing AB, (2) AC–primary type, (3) AC–secondary type (dedifferentiated), intraosseous, and (4) AC (dedifferentiated), peripheral. Although rare, it is of great importance because of its aggressiveness.^[10]

Of all tumors and cysts, the worldwide prevalence of AC has been reported to be 1–3%, which is relatively low compared to other lesions of the jaw.^[11] It usually arises from the remnants of epithelial tissue that remain after the development of teeth and related structures.^[12]

Elzayet first introduced the term AC in 1982.^[13] AC is a rare malignant odontogenic tumor. It is more aggressive than the other types of malignant AB. It may metastasize to the lungs and distant organs, though many cases do not metastasize.^[14] The peripheral location of some pulmonary secondaries suggests hematogenous and lymphatic routes of metastatic spread besides aspiration. Common symptoms include pain and rapid growth, which are absent in benign AB.^[7] The treatment of choice for AC is considered to be surgical resection with wide margins.^[12]

The mean overall survival is reported to be 17.6 years from the time of diagnosis, and a poorer survival rate is associated with increasing age. A 50% death rate has been reported in cases with metastasis and long-term follow-up.^[12]

There is a lack of collective studies on this tumor because of its low prevalence, although important studies regarding this tumor have been published. This study is a comprehensive report on the epidemiology, features, diagnosis, treatment, and prognosis, which may be valuable in knowing the disease better.

SEARCH STRATEGY

A comprehensive search was conducted in electronic databases, including PubMed, Scopus, and Web of Science from database inception to July 2025, with additional key older studies manually included for context. The following keywords and medical subject headings terms were used in various combinations: “Ameloblastic carcinoma,” “jaw tumors,” “odontogenic carcinoma,” “oral malignancies,” and “maxillofacial neoplasms.” Articles were included if they were in English, peer-reviewed, and focused on clinical features, diagnosis, management, or prognosis of AC. Case reports, reviews, and original research were considered.

EPIDEMIOLOGY

AC is a rare odontogenic malignancy, representing approximately 1–3% of all odontogenic tumors^[11] and accounts for about 30% of malignant odontogenic tumors,^[15] with a global incidence estimated to be 0.5 per million person-years.^[16]

Benlyazid et al. have reported 66 cases between 1927 and 2006.^[17] Akrish et al. analyzed 37 patients with AC who were reported between 1984 and 2007. In these patients, the male-to-female ratio was 2:1, the mean age was 52 years, and the maxillary-to-mandibular tumor ratio was 13:25.^[18] It may occur at any age and is more common in males, accounting for two-thirds of the cases.^[19]

It involves the mandible in two-thirds of the cases, according to Braimah et al.,^[19] and the ratio of this tumor occurring in the mandible is higher in other studies as well.^[18,20] The mandible to maxilla ratio was found to be 1.80:1, and a male-to-female ratio of 2.58:1 has been reported by Deng et al.^[21] The age range mentioned in the literature is 51–84 years, with a mean of 53.5 years.^[22] The prevalence of AC is 11–24% of all odontogenic tumors in North America.^[16]

In a New Zealand study, biopsies done on 34,225 cases resulted in 1.4% consisting of AC and malignant odontogenic tumor.^[23] According to a Chinese study by Li et al., primary AC occurred in 12 patients among 538 AB patients at West China Hospital of Stomatology, Sichuan University.^[24] Niu et al. diagnosed 15 cases of AC over a period of 6 years and found that the mean age was 53, according to a Japanese study. The mandible was the most common site with 86.7% of the cases, and 13.3% found in the maxilla.^[25] There is a lack of a standardized reporting system, which poses a problem in determining the exact epidemiological scenario, the incidence, and mortality of this cancer. The epidemiological variations are shown in Table 1.

CAUSES

Most cases of AC arise without a previous history, and the specific cause is unknown.^[26] However, it has been conjectured by researchers that several factors may be responsible for the formation of this tumor, such as immunological, genetic, diet, stress, and environmental factors such as chemical and radiation. The genetic changes may occur without any predisposing factors or may also be inherited in some rare cases.^[14]

AC may even arise from pre-existing AB or a benign odontogenic cyst if left untreated.^[16] It has been reported in a study that only 15% of AC arise from pre-existing tumors, while most of the cases, 85%, arise without any history, de novo.^[11]

Mutation of tumor suppressor genes or oncogenes may also be responsible for this tumor. Researchers have suggested that the disorientation of deoxyribonucleic acid may be the reason behind this malignant transformation. The reason for this transformation is mostly unknown, or in some cases, may be inherited.^[14] Immunosuppression may also be an important risk factor for the formation of this oral cancer.^[27]

PATHOPHYSIOLOGY

AC is believed to arise either de novo from odontogenic epithelium or through malignant transformation of a preexisting AB.^[15,22,28] The exact mechanisms behind this transformation remain unclear because of the tumor’s rarity and the limited number of molecular studies available.^[20,29]

Histopathologically, AC displays a combination of benign AB-like features – such as peripheral palisading and reverse nuclear polarization – along with malignant characteristics including cellular pleomorphism, hyperchromatic nuclei, frequent mitoses, necrosis, and perivascular invasion.^[28,29] Immunohistochemical (IHC) markers such as Ki-67, cytokeratin 18 (CK18), and p53 have shown strong expression in AC, suggesting a higher proliferative index and malignant potential than AB.^[20,25,30]

Some recent studies state that SOX2 is often found in AC and not as much in other similar tumors.^[31] This might help in telling it apart from other types when the diagnosis is tricky. Another marker that has been reported is glypican 3 (GPC-3), which rarely shows up in regular AB. Finding it in AC might help confirm a diagnosis.^[20] In terms of gene changes, mutations in B-Raf proto-oncogene, serine/threonine kinase (BRAF V600E) and rat sarcoma (RAS) pathways have been seen in AC, similar to that found in AB.^[32,33] There are a few other genes such as smoothened (SMO), fibroblast growth factor receptor 2 (FGFR2), and catenin beta-1 (CTNNB1). These have been connected to tumor growth, maybe through mitogen-activated protein kinase (MAPK) or wingless and Int-1 (Wnt) pathways, though not every study agrees.^[32,34]

Furthermore, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are enzymes that break down the tissue around the tumor. Some studies found that MMP-2 and MMP-9 seem to turn up more in AC than in the usual benign ones.^[35] These enzymes might be helping the tumor break through surrounding tissue, but it is yet not completely certain.

Several changes happening slowly in the cells that build up over time result in AC instead of a single cause, which pushes the tumor to act more aggressively later on. The pathophysiology is shown in Figure 1.

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Figure 1:

Illustration showing the proposed pathophysiology of ameloblastic carcinoma. The diagram highlights its potential origins from AB or odontogenic epithelium, the involvement of molecular pathways such as MAPK and signaling, and the role of genetic mutations (e.g., BRAF, RAS, SMO) and immunohistochemical markers (e.g., Ki-67, p53, SOX2) in malignant transformation.

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CLINICAL FEATURES

AC may be asymptomatic in some individuals^.[14] Common clinical features are pain and swelling, which can be either localized in the jaw or may spread throughout the entire face.^[20,36]

Rapidly progressing painful swelling, bone resorption, and significant mobility of the tooth with extensive local destruction have been reported.^[12] Gingival bleeding, paresthesia, trismus, dysphonia, and epistaxis have also been reported. An ulceroproliferative growth with everted margins can be seen clinically.^[37]

Ulceration of soft tissue has been found in 61.7% of cases, with some cases of painless swelling as well.^[16] Robinson et al. showed that most patients presented with either painless (41.2%) or painful (40.7%) swellings.^[20] Facial asymmetry and loss of function were reported by Makiguchi et al.^[38]

Tooth mobility, periodontal disease, and ill-fitting dentures have also been reported.^[39] Other clinical features include exophytic ulcerated mass, focal calcification, and numbness.^[40] Table 1 shows the common clinical features.

RADIOGRAPHIC FEATURES

AC often presents various radiographic features, some of which may be identical to different cysts and benign or malignant tumors.^[41]

AC and AB can have identical radiological features, although specific imaging features help in diagnosis.^[40] AC presents focal opacities, which are rarely found in AB. Dystrophic calcification with necrosis is also evident in AC.^[17]

Decorticated border and thinning of both buccal and lingual cortices have been reported in various studies.^[28,42] Hence, as this tumor presents various radiological findings, advanced diagnostic procedures such as computed tomography (CT) scans and magnetic resonance imaging (MRI) can be used to provide more precise results.

Common radiological features of AC include unilocular or multilocular radiolucency. According to a study by Akrish et al., 67% of the cases were found to have multilocular lesions, and 33% of the cases had unilocular lesions.^[18]

DIAGNOSIS

Detailed patient history, clinical presentations, clinical examinations, radiographic evaluation, histopathological examination, and differential diagnosis play a vital role in the diagnosis of AC.

TREATMENT

Surgical resection is the treatment of choice. Surgical resection is done with a 2–3 cm margin. For positive margins or perineural invasion, chemoradiotherapy can be applied.^[43] En bloc resection with 1–2 mm of healthy bone margins is the safest treatment protocol to ensure the absence of recurrence.^[12]

Practitioners usually follow the most current treatment strategies, which include neck dissection, chemotherapy, and radiotherapy.^[44] Radiotherapy is reserved for adjuvant treatment of high-risk cases with positive margins, perineural invasion, or extracapsular spread, as well as for unresectable or recurrent lesions. Contemporary management follows head-and-neck oncology protocols, in which microscopic disease or elective regions are typically treated to approximately 50–60 Gy, while gross or residual disease receives about 60–70 Gy in 1.8–2 Gy fractions using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) techniques.^[45] Particle therapy, including proton beam or carbon-ion therapy, has shown encouraging local control in selected recurrent or unresectable cases at doses around 60–70 Gy (GyE).^[46,47] In contrast, lower palliative doses (20–30 Gy in 5–10 fractions) may be employed for symptomatic relief but are not curative.^[48] Modern data support dose escalation above the previously cited 3000–5000 cGy range, which is now considered subtherapeutic for adjuvant intent.^[49] Neck dissection has been noted to be controversial in cases with no metastasis.^[42]

Targeted therapies have become popular now as they reduce morbidity associated with major surgeries. Dabrafenib has been mentioned as the most utilized drug for targeted therapy of AC.^[50] The IHC markers and treatment modalities of different studies are summarized in Table 3.

Recent studies have identified key molecular alterations in AC that may inform targeted therapeutic strategies, particularly in advanced, recurrent, or unresectable cases. Integrating these molecular insights with clinical, histopathologic, and IHC findings allows for a structured management approach. Table 4 summarizes the most relevant molecular markers alongside a stepwise management algorithm, including diagnostic pathway, treatment modalities, and prognostic determinants, to guide evidence-based care for patients with AC.

PROGNOSIS

AC is known to have a poor prognosis. Patient prognosis is difficult to determine as there is a rarity of well-documented follow-up reports. Metastasis has been identified to be the prime factor related to prognosis.

While overall 5-year survival is typically reported to be between 60% and 70%, the prognosis varies depending on the stage of the disease. The 5-year survival rate of patients with distal metastases was reported to be 21.4%. Giridhar et al. have mentioned in their study that the survival rate of patients younger than 45 years old is higher than that of elderly patients.^[51]

The location of this tumor also contributes to prognosis, as the prognosis of maxillary tumors is more unfavorable in comparison to that of mandibular tumors.^[52] Primary AC has been shown to have a better prognosis than secondary AC. The primary predictor of prognosis is the clinical course of the disease, which includes aggressiveness, local destruction, and distant metastasis.^[17] Metastatic AC shows a worse prognosis than metastasizing AB.^[53]

CRITICAL ANALYSIS

Across the reviewed series, several consistent themes emerge, but with important quantitative and methodological differences. Most cohorts report a predominance of mandibular lesions and a middle-to-older adult age distribution (mean ages ~41–53 years).^[18,21,24] However, sample sizes vary widely (12–37 cases), and the reported male: female ratios are inconsistent, suggesting either regional/selection variation or small-sample noise. Clinically, swelling and pain are commonly reported, but studies differ in how they categorize symptoms: Robinson et al. reports near-equal proportions of painless and painful presentations (≈41% vs. 40%),^[20] whereas Soyele et al. emphasize ulceration present in 61.7% of cases^[16] – a difference likely driven by study case mix (advanced vs early lesions) and reporting definitions. On diagnostic testing, several groups report increased proliferative indices and p53/GPC-3 overexpression in AC^[25,30] while more recent work has highlighted SOX2 as a promising, relatively specific marker.^[31] Treatment series consistently endorse surgery as the mainstay;^[12] reported outcomes vary Giridhar et al. report 5-year survival 60– 70%,^[51] and Niu et al. have suggested that site (mandible vs. maxilla) influences prognosis.^[25]

AREAS OF DISAGREEMENT AND PLAUSIBLE EXPLANATIONS

LIMITATIONS OF THE CURRENT EVIDENCE BASE

• Small retrospective case series and case reports dominate the literature, limiting statistical power and introducing publication bias toward unusual or severe cases.

• Heterogeneous case definitions and reporting (e.g., variable definitions of “recurrence,” inconsistent symptom categorization, and missing follow-up durations) prevent meaningful pooled estimates.

• IHC and molecular methods are not standardized: Differing antibody clones, scoring methods and panels, mean marker prevalence and diagnostic performance are not directly comparable across studies.

• Short or poorly documented follow-up in many reports undermines reliable assessment of long-term outcomes such as late recurrence or metastasis.

• Selection and referral bias – tertiary centers and case reports preferentially represent complex or advanced disease, skewing apparent severity and outcomes.

• Limited molecular profiling data: only a minority of cases undergo comprehensive NGS panels, so the true frequency and prognostic value of actionable mutations (BRAF, Kirsten rat sarcoma virus (KRAS)/neuroblastoma RAS viral oncogene homolog (NRAS), estimated glomerular filtration rate (EGFR), phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT), tumor protein 53 (TP53)) remain uncertain.

RECOMMENDATIONS FOR FUTURE RESEARCH

FUTURE DIRECTIONS

Most of the information available on AC comes from individual case reports or short series, so it is tough to draw solid conclusions. The condition is rare, which makes larger studies difficult to conduct. Because of this, comparing treatments or long-term outcomes across studies is not very reliable.

Furthermore, not every study uses the same way to diagnose or report cases, which adds confusion. Some researchers have tested markers such as Ki-67 and p53, but how useful they are is still debatable because not everyone uses them the same way. In the future, more hospitals working together could help create stronger evidence. It might also be worth looking into newer methods of diagnosis that could make things clearer earlier on.

Research into molecular and genetic profiling may also help in identifying more specific biomarkers or treatment targets. Standardized reporting guidelines and multi-center registries could improve the quality and comparability of future studies. Exploring the effectiveness of newer treatment approaches like targeted therapies or immunotherapy might also open new possibilities for managing this rare malignancy.

This review consolidates and critically analyzes the current evidence on AC, highlighting updates in clinicopathologic features, IHC and molecular markers, and treatment strategies. Markers such as Ki-67, p53, SOX2, BRAF, and KRAS/NRAS show increasing utility in distinguishing AC from benign AB and identifying potential therapeutic targets.

The rarity of AC, heterogeneity in diagnostic criteria, and inconsistent follow-up limit the strength of available evidence despite these advances. Multicenter collaborations are essential to establishing standardized diagnostic protocols and comprehensive registries. These efforts will facilitate prognostic modeling, enable robust comparisons of outcomes across populations, and support the design of targeted therapy trials.

This review contributes by synthesizing data into an analytical framework, highlighting key gaps in current knowledge, and outlining actionable avenues for future research that may improve the diagnosis, prognostication, management, and help us to have a clearer knowledge of AC.

CONCLUSION

AC is still a mystery to pathologists and clinicians, as its exact cause is still unclear. Histologically, it demonstrates malignant features in both the primary and metastasis. This study on AC provides more comprehensive, updated, and elaborated data and information, helping pathologists and clinicians know this odontogenic tumor better and providing knowledge to aid surgeons in proper diagnosis and management of cases.

AC needs to be surgically excised with wide margins to prevent recurrence, which commonly occurs due to the minimal extent of excision. Prognosis is considered favorable if early diagnosis followed by proper surgical intervention is performed, but neglecting and delaying the process may worsen the prognosis in cases with distant metastasis. More studies related to this relatively rare tumor are needed to understand its pattern and nature.