What is Ameloblastoma?

Ameloblastoma, a rare human disease, is a benign tumor originating in the odontogenic epithelium. It is commonly found in the jaw bone. The tumor develops from the tooth germ's epithelium, odontogenic cyst epithelium, stratified squamous epithelium, and enamel organ epithelium. Ameloblastoma is the most frequent odontogenic tumor of epithelial origin with significant clinical implications, despite being categorized as a benign tumor.

Image Credit: Rames Khusakul/Shutterstock.com

Causes and symptoms

Because of the tumor's rarity, the cause of ameloblastoma is mainly unknown. According to new research, a link has been discovered between the development of ameloblastoma and the mutation of specific genes involved in cell growth, division, and survival risk factors like poor dental hygiene, ignoring any swelling in the jaw, and ethnicity (more common in African and Asian communities) are known to increase a person's chances of having this form of tumor.

Most commonly reported symptoms include – abnormal growth in the jaw, swelling (painless) in the jaw, a loose movement of multiple teeth, bone pain (maybe continuous), ulcerations in the mouth, and delayed tooth eruption.

Classification

In 2017, the World Health Organization (WHO) revised its ameloblastoma classification. The new version categorizes patients into three categories: conventional, unicystic, and peripheral. The most prevalent kind of ameloblastoma is conventional ameloblastoma, which accounts for 85 percent of all ameloblastomas and arises primarily in the third and fourth decades of life. Because of its increased recurrence rate, its biological behavior is thought to be more aggressive.

Unicystic ameloblastomas (AU) are neoplasms with cystic morphology. It is an ameloblastic epithelium that can cause tumor growth in the lumen and fibrous connective tissue. Peripheral ameloblastoma is the rarest type of ameloblastoma, accounting for approximately 1% of occurrences. It is most common in the gingiva of the mandible and affects individuals with an average age of 52 years. Even when treated conservatively, recurrences are uncommon.

Genetics of ameloblastoma

Several genetic mutations in ameloblastoma have been discovered in recent genetic investigations employing tumor tissue, cell lines, and transgenic mice. Recurrent somatic and activating mutations in the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) signaling pathways were discovered in the research.

The BRAF, RAS, and fibroblast growth factor receptor 2 (FGFR2) genes have all been found to have mutations in the MAPK pathway in ameloblastoma. BRAF, RAS, and FGFR2 mutations are found in about 79% of ameloblastoma cases.

Epidemiology

Ameloblastoma is an uncommon disease, with an annual incidence of 0.5 new cases per 1,000,000 individuals. There are, however, geographical distinctions: In comparison to the Western World, Africa, China, and India have higher incidences. Ameloblastomas are most commonly found between the ages of 30 and 60 (average of 36 years) with a peak around the fifth decade.

The ratio of males to females is 1.2:1. Ameloblastomas make up 1% of all tumors in the head and neck. Ameloblastomas are the most prevalent kind of odontogenic tumor, accounting for about 18% of all cases.

Diagnosis and treatment

A combination of both clinical examination and an X-ray is commonly used to diagnose suspected ameloblastoma. Referral to an Oral and Maxillofacial Surgeon for a second opinion and confirmation of the diagnosis is fairly usual. Many ameloblastomas are discovered by chance at the dentist during ordinary dental operations or X-rays.

When a tumor seems to be an infection, causing discomfort and swelling in the jaw, it is usually treated with antibiotics. When antibiotics fail to ease the symptoms, a regular X-ray is taken to further check the symptoms, and the probable ameloblastoma is discovered. Further tests including CT scans, MRI scans, and a biopsy of the bone are used to confirm the presence of the tumor.

Ameloblastomas are treated surgically or non-surgically for both initial and recurring cases. A cautious (type I) or extreme (type II) surgical technique could be used. Radial resection with 1-cm resection margins is now the standard treatment for ameloblastoma. The recurrence rate ranges from 0% to 15%.

Wider resection margins (such as the granular cell type) may be required for more aggressive kinds of ameloblastoma. Conservative surgery, such as enucleation and curettage, has a recurrence rate of up to 55% and is only recommended for unicystic ameloblastoma with a luminal development pattern.

Aside from the potentially more aggressive growth pattern, recurrent ameloblastoma is associated with two other major problems: the development of metastasis, referred to as malignant ameloblastoma, and the transformation into an ameloblastic carcinoma, both of which have rates of 2% in recurrent ameloblastoma.

Ameloblastomas having metastases primarily in the lungs (but with the same cytological markers as the initial ameloblastoma) are referred to as malignant ameloblastoma. An ameloblastic carcinoma, on the other hand, has all of the cytological characteristics of a malignant tumor.

Molecular targeted and drug-based therapies for ameloblastoma

The identification and elucidation of active molecular pathways have emphasized the possibility for innovative molecular targeted therapeutics in the treatment of ameloblastoma with genetic alterations. The main advantage of molecular targeted therapy is that it can reduce surgical morbidity in resection surgery, recurrent ameloblastoma, and metastasizing ameloblastoma.

Drugs that suppress the actions of mutant BRAF and MEK have the potential to be used in molecular targeted therapy for ameloblastoma. The mutated BRAF genes are inhibited by vemurafenib and dabrafenib; the mutation MEK gene is inhibited by trametinib, and the mutated FGFR2 genes are inhibited by ponatinib and regorafenib.

Three molecular targeted therapy for BRAF V600E mutation have been approved by the US Food and Drug Administration: vemurafenib, dabrafenib, and trametinib for BRAF mutations and trametinib for MEK mutations. Vemurafenib and dabrafenib have also been utilized to treat melanomas with BRAF V600E mutations using molecular targeted therapy.

In the future, clinical-pathological correlation studies will be required to develop novel medicines that are both effective and conservative, thereby increasing the quality of life of these patients.

References:

• Shi, H. A., Ng, C., Kwa, C. T., & Sim, Q. (2021). Ameloblastoma: A succinct review of the classification, genetic understanding, and novel molecular targeted therapies. The surgeon: journal of the Royal Colleges of Surgeons of Edinburgh and Ireland, 19(4), 238–243. https://doi.org/10.1016/j.surge.2020.06.009
• Cadavid, A.M.H., Araujo, J.P., Coutinho-Camillo, C.M. et al. (2019). Ameloblastomas: current aspects of the new WHO classification in an analysis of 136 cases. Surg Exp Pathol 2, 17. https://doi.org/10.1186/s42047-019-0041-z
• Kreppel, M., & Zöller, J. (2018). Ameloblastoma-Clinical, radiological, and therapeutic findings. Oral diseases, 24(1-2), 63–66. https://doi.org/10.1111/odi.12702
• Effiom, O. A., Ogundana, O. M., Akinshipo, A. O., & Akintoye, S. O. (2018). Ameloblastoma: current etiopathological concepts and management. Oral diseases, 24(3), 307–316. https://doi.org/10.1111/odi.12646
• (2016). Ameloblastoma. [online] Bone Cancer Research Trust. Available at: https://www.bcrt.org.uk/information/information-by-type/ameloblastoma/
• Masthan, K. M., Anitha, N., Krupaa, J., & Manikkam, S. (2015). Ameloblastoma. Journal of pharmacy & bioallied sciences, 7(Suppl 1), S167–S170. https://doi.org/10.4103/0975-7406.155891

Further Reading

• All Rare Disease Content
• Teaching old drugs new tricks – drug repurposing for rare diseases
• What is Agnosia?
• What is Apert Syndrome?
• What is Asherson’s Syndrome?