Ameloblastic carcinoma (AC) is a very rare malignant odontogenic tumor, with features of both ameloblastoma and carcinoma. An approximate male-to-female ratio of AC is 2:1 and a mandible-to-maxilla ratio is 1.7:1(1). The common symptoms of AC are pain, swelling, and rapid growth. Clinically, AC is a typically aggressive tumor with extensive local destruction. Lymph node involvement and distant metastasis have also been reported (2-6). AC, first introduced as a distinct entity by Elzay in 1982 (1,2), is defined as a rare odontogenic malignancy that combines the histological features of ameloblastoma with cytological atypia regardless of metastasis, after considerable debate, by the World Health Organization classification of odontogenic tumors in 2005. It is classified into primary- (de novo) and secondary-type (malignant transformation of pre-existing ameloblastoma). Secondary-type AC is further divided into two subtypes: Intraosseous and peripheral. This classification was preserved with the 2017 update of the classification.

No standard treatment has been established for this rare tumor. Previous reports indicate complete surgical resection with wide local excision and cervical lymph node dissection as a commonly used approach (1-4,7); however, aesthetic failure and dysfunction after surgery, such as dysphagia, dysarthria, and nasopharyngeal closure dysfunction, are severe. The treatment efficacy of systemic chemotherapy and/or radiotherapy seemed poor and limited; local control rate is low and physical strength may decline due to decreased bone marrow function or difficulty in oral intake. These conservative therapies have been used as an adjunctive therapy (1). Strojan et al reported that cumulative dose of cisplatin in concurrent chemoradiation protocols for head and neck squamous cell carcinoma (SCC) has a significant positive correlation with survival (8). Among these non-surgical approaches, intra-arterial infusion chemotherapy (IAIC) combined with radiotherapy has been increasingly performed in recent years for locally advanced head and neck cancers to avoid surgery. Several studies using IAIC reported that the outcomes of this organ-preserving approach were not inferior to those of surgery (9-11). Although AC is considered to be a radioresistant tumor, there are some reports of good treatment results with X-rays, gamma knife, and particle beam therapy, including proton beam therapy (PBT) and carbon ion therapy (CIT) (12-16). Particle beam therapy, which provides several advantages including a rapid dose fall-off at the distal end and the possibility to induce double strand DNA breaks leading to catastrophic damage to cancer cells (17), is an effective approach that provides high-dose irradiation to the tumor without increasing toxicity to the normal tissue (18). Although the therapeutic effect of particle beam therapy has been reported for non-SCC of the head and neck (19), few reports investigated its efficacy in AC (15,16). Here we report a case of recurrent secondary-type AC treated by PBT in combination with IAIC that resulted in a good long-term course.

A 71-year-old man was referred to the Southern Tohoku Proton Therapy Center in March 2009 with severe pain and swelling of the right palatal gingiva. In October 2007, he was diagnosed with ameloblastoma of the right maxilla based on the histopathology of biopsy and underwent partial resection several times owing to tumor recurrence. The patient was diagnosed with AC in March 2009 based on pathological assessment after the fourth surgery (Fig. 1).

At the time of admission, his hard palate on the right was swollen with bony expansion to the oral cavity, and the tumor had invaded the right alveolar ridge. He had paresthesia of the right face. Enhanced magnetic resonance imaging (MRI; Signa HDx, GE Healthcare) revealed a large, heterogeneously enhanced mass extending from the right maxillary sinus to the upper gingiva, measuring ~50x70 mm in dimensions. The medial extension reached the right nasal septum and the right ethmoid sinus. The tumor had destroyed the floor of the right maxillary sinus, perforated the anterior wall of the right maxillary sinus, and extended into the surrounding soft tissue. ¹⁸F-fluorodeoxyglucose (synthesized and used in our own facility) positron emission tomography computed tomography (FDG-PET/CT; Discovery ST Elite, GE Healthcare) showed high FDG concentration in the right maxillary sinus (maximum standardized uptake value, 21.6). There were no suspicious lymph nodes or remote metastases.

The growth speed of the tumor was extremely rapid, and further surgical resection was deemed not to be sufficient for possible tumor control. Therefore, the patient was treated using PBT in combination with IAIC to the artery supplying the tumor. Written informed consent was obtained from the patient. This treatment was approved by the Ethics Committee of Southern Tohoku Research Institute for Neuroscience (approval no. 338). This study was conducted according to the principles of the Declaration of Helsinki.

Surgical resection is generally performed as an approach for recurrent AC. Chemotherapy and radiotherapy are not efficient and considered as treatment options for inoperable cases, with poor prognostic outcomes (7). Yoon et al reported that 5-year overall survival of 72.9% for AC and recurrence rate after surgical resection was reported as 28.3%, which was 92.3% in patients treated with conservative therapy using chemotherapy and radiotherapy (1). There are over 150 reports of patients treated for AC, with radiotherapy utilized in approximately one-third of the cases, especially in recent years (25-29). In majority of the cases, the therapeutic effects of conventional radiotherapy were inadequate, and high-dose radiation led to severe chronic disorders such as osteoradionecrosis (2).

To date, a few studies have reported radical radiation therapy for AC (12-14). However, it may not be a desirable treatment from the view of therapeutic effect because AC is resistant to X-ray therapy. PBT is a type of particle therapy, similar to CIT. In comparison with conventional radiotherapy, particle beams are characterized by their unique Bragg peak and can deliver high-dose radiation to the tumor while sparing normal tissues (18). Additionally, compared with conventional X-ray therapy, a higher antitumor effect by direct impairment of cancer cell DNA is expected (17). Importantly, the therapeutic effect of PBT was reported in non-SCC (15,16,19). One difference between proton beams and carbon ion beams is their RBE; the RBE of protons is approximately 1.1, whereas that of carbon ions is approximately 3.0. However, no significant difference in the therapeutic effect between PBT and CIT was reported (30). To date, only two case reports of particle therapy for AC was published, including one patient treated by CIT (15) and one patient treated with PBT (16); however, AC appeared to have arisen de novo in both cases. Most ACs appear to be de novo; however, few cases of secondary-type AC arising from pre-existing ameloblastoma were reported. The current case was diagnosed with secondary-type peripheral AC, which recurred shortly after surgery, advanced extensively, and exhibited high malignancy.

Recent studies assessing IAIC for locally advanced head and neck cancers to avoid surgery reported excellent treatment outcomes. Fuwa et al reported good clinical outcomes of treatment with weekly IAIC and radiotherapy in a series of 92 patients with head and neck cancer, including 84 patients with oral SCC (20). Mitsudo et al assessed treatment results with daily IAIC and conventional radiotherapy in a series of 112 cases with stage III and IV oral SCC and reported that the 5-year local control rate and over-all survival rate were 79.3 and 71.3%, respectively (11). Our previous study in which we used PBT and IAIC in T4 SCC of the maxillary gingiva, the 3-year local control and overall survival rates were 69 and 59%, respectively (31). In the current case, treatment of aggressive AC with a combination of IAIC and PBT achieved a good therapeutic effect. To the best of our knowledge, this is the first report of a good long-term course of 94 months with radical treatment using chemoradiotherapy for postoperative recurrent secondary-type AC. During the follow-up period, the patient had skin atrophy and non-infectious fistula in the right cheek. The cheek fistula had no effect on food and conversation, and the patient did not wish for reconstructive surgery. Although the tumor was close to the right optic nerve, visual acuity was maintained for several years. However, the patient suffered from ischemic syndrome of the right eye and developed grade 2 optic nerve disorder four years after treatment. Blood flow disturbance after radiation therapy have been reported in the past (32,33), and are considered as adverse event of the treatment. It indicates that additional effort to avoid risk organ may be necessary to reduce adverse events with this therapeutic approach. In this study, a passive scattering method, which is difficult to apply for complicated cases, was used to deliver the proton beam. In the future, intensity-modulated proton beam therapy using a pencil bam scanning system can be used to reduce late adverse events.

Although case series studies with large samples are necessary for further elucidation of this treatment approach, the current case illustrates the good long-term outcome of recurrent secondary-type AC treated with PBT and IAIC. The beneficial therapeutic effect and organ preservation were achieved without any severe late adverse events, suggesting that PBT in combination with IAIC might be an effective treatment option for inoperable, locally advanced AC.