Journal of Hard Tissue Biology 26[4] (2017) 425-430 2017 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved. CODEN-JHTBFF, ISSN 1341-7649 Clinical Note Pathological and Clinical Study of Japanese Ameloblastic Fibro-

Shintaro Sukegawa1), Keisuke Nakano2), Takahiro Kanno3), Hotaka Kawai2), Kenichi Matsumoto1), Yuka Sukegawa-Takahashi1), Masanori Masui1) and Yoshihiko Furuki1)

1) Division of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Japan 2) Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 3) Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Shimane, Japan (Accepted for publication, August 31, 2017)

Abstract: Ameloblastic fi bro- (AFO) is defi ned as a tumor with general characteristics of an ameloblastic fi broma along with the presence of enamel and dentine. AFO is a well-encapsulated, painless, slow-growing, and expanding tumor in young patients. Histologically, it has been classifi ed as an ameloblastic fi broma or odontoma. In the 2017 new WHO classifi cation of , AFO is described that they in most cases represent developmental stages of either complex or compound odontoma and that retaining them as separate entities would therefore be illogical. However, there is still considerable confusion concerning the nature and of AFO and the surgical therapy for this lesion. Here we present a case of maxillary AFO and review the relevant literature regarding the clinical and surgical features of this lesion.

Key words: Ameloblastic fi bro-odontoma, Odontogenic tumor, Japanese patients, Review

Introduction In addition, there was a radiolucent area containing punctate calcifi ed Ameloblastic fibro-odontoma (AFO) is an uncommon mixed components (Fig. 2A). Computed tomography (CT) images revealed odontogenic tumor of the odontogenic epithelium with a mesenchyme a radiolucent lesion containing punctate calcifications scattered origin1,2). According to the World Health Organization (WHO) throughout the center of the lesion in the left maxillary area, with classification, AFO is a lesion resembling ameloblastic fibroma, constriction of the maxillary sinus (Fig. 2B). Buccopalatal expansion which also shows inductive alterations involving both enamel and and perforation of the involved cortices were not observed. Considering dentin3). Since the introduction of the WHO classification, AFO has the clinical and radiological fi ndings, the possible diff erential diagnoses been recognized as a histological and clinical entity, but it is still rare were calcifying epithelial odontogenic tumor, adenomatoid odontogenic among Japanese people. The purpose of this report was to describe a tumor, and AFO. case of AFO and review the literature on AFO among Japanese patients between 1971 and 2016. Treatment and outcomes Under local anesthesia, enucleation of the lesion with careful Materials and Methods curettage involving the fi rst and second molars was performed using Case presentation a transoral surgical approach. No bone augmentation was needed. In June 2009, a 12-year-old Japanese girl presented with a chief There was no penetration into the maxillary sinus. Wound closure was complaint of tooth eruption disturbance in the left posterior maxilla performed with a trapezoidal fl ap. There has been no recurrence during to an orthodontic clinic. Because an asymptomatic posterior left the two- year follow-up. maxillary lesion was discovered on panoramic radiography performed for routine evaluation, the patient was referred to the Division of Oral Histopathological and immunohistological studies and Maxillofacial Surgery at Kagawa Prefectural Central Hospital. The The resected specimen was examined by hematoxylin and eosin medical, social, and family histories of the patient were unremarkable. (HE) staining and immunofluorescent (IF) staining. The target An extraoral examination revealed no obvious abnormality, without proteins assessed included the following: Wnt1 (Abcam, Cambridge, swelling or facial asymmetry. An intraoral examination showed slight UK), a signal transduction protein acting on epithelial-mesenchymal tenderness at the left upper molar area. Despite eruption of the right interaction. Wnt signaling is implicated in cell proliferation and first and second upper molars, there was no eruption of the left first diff erentiation., β-catenin (E274, Abcam, Cambridge, UK), a maker of and second molars of the first dentition (Fig. 1A, B). A panoramic activation of Wnt/β-catenin signal pathway. Wnt signaling involve in radiograph revealed a radiolucent lesion (20 × 15 mm in diameter) the nuclear localization of β-catenin. with irregular borders around the unerupted first and second molars. Search strategy of the literature Correspondence to: Dr. Sukegawa Shintaro, Division of Oral and Maxillofacial An electronic search without time or language restrictions was Surgery, Kagawa Prefectural Central Hospital, 1-2-1, Asahi-cho, Takamatsu, Kagawa 760-8557, Japan; Tel.: +81 87 811 3333; Fax: +81 87 802 1188; Email: gouwan19@ conducted in 2016 using the PubMed, Medline, and ScienceDirect gmail.com databases. The following terms were used in the search: ameloblastic

425 J.Hard Tissue Biology Vol. 26(4): 425-430, 2017

Figure 2. Panoramic radiograph and CT image. A: A panoramic radiograph Figure 1. A: Extraoral examination revealed no obvious abnormality., B: shows a radiolucent lesion (20 × 15 mm in diameter) with irregular borders Intraoral examination shows unerupted upper left first and second molars around unerupted first and second molars., B: CT images revealed a despite eruption of the upper right fi rst and second molars. radiolucent lesion containing punctate calcifi cations in the left maxillary area.

Figure 3. Histological fi ndings (HE: A-D). A: Dentin like hard tissues (*) located in the tumor tissue. The background is composed of fi brous stroma and epithelial tumor nests. Scale bar= 100μm., B: Epithelial islands and mesenchymal fi brous components. Scale bar= 20μm., C: like epithelial tumor nests supported by dental papilla like tumor tissue. Scale bar= 20μm., D: Dentin (arrow), enamel matrix (arrowhead) and enamel (*) formation in the intermediate zone between epithelial and mesenchymal components. Scale bar= 20μm.,

426 Shintaro Sukegawa et al.: Clinicopathology of Japanese Ameloblastic Fibro-Odontoma Table 1. Summary of the literature review of Japanese patients with ameloblastic fi bro-odontoma Age Mean Standard Deviation Range Median 11.5 9.0 0.5-60 9.0 Sex Male Female 31 26 % 54.4 45.6 Location Lt/ Rt Left Right 32 25 % 56.1 43.9 Mxilla/Mandible Maxilla Mandible 19 38 % 33.3 66.7 Anterior/ Posterior Anterior Posterior Anterior and Posterior 10 45 2 % 17.5 78.9 3.5 Impacted teeth Yes No 52 5 % 91.2 8.8 Treatment Exclusion Exclusion of the tumor (Retention of the involved teeth) 18 39 % 31.6 68.4

fi brodentinoma OR ameloblastic fi bro-odontoma OR ameloblastic fi bro- Immunohistochemical fi ndings (IF) odontome OR ameloblastic fi broodontoma. Moreover, Google Scholar Wnt1 was detected in almost epithelial and mesenchymal and Web Japan Medical Abstractis Society were checked. The titles and components. The peripheral columnar cells of epithelial tumor nest abstracts of all publications identifi ed through the electronic searches were strongly positive to Wnt1 (Fig. 3E). Although β-catenin was were read by the authors. The clinical aspects and the histological clearly localized on the cell membrane of tumor cells, nuclear trans- description of the lesions were thoroughly assessed to confirm the location was observed in stellate reticulm cells and in many papilla-like diagnosis of AFO. mesenchymal cells (Fig. 3F). Wnt1 and β-catenin were present in the tumor nests mainly. The both positive area were almost maerged (Fig. Ethics statement and confi rmation of patient permission 3G). The authors confirm that the patient undergoing the procedure described in this clinical note was fully informed about the condition Results of the literature review and consented to the clinical and surgical procedures, which included The results of the literature review and our case are summarized in taking photographs of the lesion and the procedure. The authors confi rm Table 18-56). that personal details of the patient included in any part of the paper and in any supplementary material have been removed before submission. Patient characteristics Age and sex Results There were 57 patients, including 31 (54.4%) male and 26 (45.6%) Histopathological fi ndings (HE) female patients (male:female ratio, 1.19). The mean age of the patients Microscopically, the lesions were composed of soft tissue was 11.5 years (standard deviation, 9.0 years; range, 0.5-60 years). components and calcified components (Fig. 3A). The soft tissue included tooth bud like nest and exhibited mainly strands and cords of Location odontogenic epithelium that resembled the . The stromal The lesion was located in the maxilla in 19 (33.3%) patients and components were consisted of fi broblast like cell with plump nucleus mandible in 38 (66.7%). The lesion occurred on the left side in 32 which proliferating with produce dense collagen fi bers (Fig. 3B). The (56.1%) patients and on the right side in 25 (43.9%). The lesion was lesion also contained epithelial islands that consisted of a peripheral anterior in 10 (17.5%) patients, posterior in 45 (78.9%), and large in layer of columnar palisading cells, which enclosed loosely arranged size from anterior to posterior in 2 (3.5%). cells resembling the enamel organ. The epithelial elements were supported by loose connective tissue containing randomly oriented Impacted teeth fibroblasts that resembled the dental papilla of a developing tooth There were 52 cases (91.2%) involving unerupted teeth in the lesion (Fig. 3C). The calcifi ed elements showed the characteristic component and 5 (8.7%) without unerupted or impacted teeth. of irregular dentin (Fig. 3D arrow). The dentin contained entrapped epithelial and mesenchymal cells. Near the dentin like structures, Discussion enamel matrix and hollow spaces with mature enamel that was removed AFO belongs to the family of mixed odontogenic tumors. The term during decalcifi cation (Fig3. D star). The spaces also contained enamel AFO was fi rst used by Hooker4) and was originally termed ameloblastic matrix (Fig. 3D arrowhead). odontoma. It can be defi ned as a neoplasm composed of proliferating odontogenic epithelium embedded in cellular ectomesenchymal tissue

427 J.Hard Tissue Biology Vol. 26(4): 425-430, 2017 that resembles dental papilla at varying degrees with regard to inductive radiolucent areas differs from one lesion to another. Sometimes, the change and dental hard tissue formation. In 1971, WHO suggested that mineralized element in the tumor predominates, and the lesion may this term was inappropriate as it encompasses two types of odontogenic resemble an odontoma63). Panoramic radiographs are very suitable for tumors that share diff erent histology and biological behavior. Therefore, fi rst-time lesion screening. For accurate localization of the tumor and it was defi nitively separated from other benign odontogenic tumors in for preparing a surgical treatment strategy to preserve adjacent vital 1971 by Pindborg and Kramefi. However, despite numerous efforts, structures, a CT scan is recommended. there was still considerable confusion concerning the nature and The treatment of odontogenic tumors is based on their clinical and relationship between mixed odontogenic tumors and related lesions4). biological behavior64). However, there is no consensus on the treatment According to the 2005 WHO classifi cation, it is a benign tumor without of AFO. Many authors have reported that small lesions are not invasive growth in contrast to ameloblastoma5). AFO represents aggressive and can be adequately treated with enucleation of the lesion approximately 1% of all odontogenic tumors in Japan. To the best of without removing the adjacent teeth1,65,66). Enucleation remains the gold our knowledge, the cases of only 58 Japanese patients, including our standard owing to the non-invasive advancement of the disease. This case, have been reported in the literature6-56). Most of these tumors surgical method shows good results with a good prognosis. Enucleation occurred in the fi rst two decades of life, with a mean age at diagnosis will allow the maintenance of adequate periosteum and jawbone for of 11.5 years1). There is almost no predominance of male patients4). spontaneous regeneration in defects among patients. Recurrences are AFO is usually found in the molar area, with roughly equal distribution rare and have been attributed to inadequate surgical removal at the time between the maxilla and mandible4, 57), and it does not show signifi cant of initial treatment. If recurrence is accompanied by a change in the gender predilection4, 58). In our review, the mean age was 11.5 years, histological pattern toward a more unorganized fibrous stroma, with and there was no difference between the left and right sides for the displacement of the epithelial component, more extensive treatment site of occurrence (left, 56.1%; right, 43.9%). In addition, it occurred procedures are indicated67). With regard to the maintenance of the more frequently in the mandible than in the maxilla (mandible, 66.7%; involved unerupted teeth, we believe that if the teeth do not interfere maxilla, 33.3%). Moreover, occurrence was more common in the with the enucleation of the tumor, there is no reason to remove them, posterior than in the anterior area (posterior area, 78.9%; anterior area, and there is a possibility of spontaneous eruption2,68). In the literature 17.5%). The fi ndings of our literature review of Japanese patients did review of Japanese patients, 52 of the 57 tumors were associated with not diff er much from the fi ndings of past reports from patients around unerupted teeth. Treatment for the unerupted teeth was confirmed in the world. 34 of the 52 cases. Most of the cases were treated with retention of the AFO has the histologic features of ameloblastic fibroma in unerupted teeth, and the prognosis of eruption of the teeth appeared conjunction with the presence of dentin and enamels. This pathological to be good. Follow-up revealed no signs of recurrence, indicating that classifi cation was defi ned in the 2005 WHO classifi cation of head and conservative procedures associated with the related tooth removal can neck tumours 5). In the 2017 WHO classifi cation of odontogenic tumor, be successful in the treatment of these lesions if considerable bone is AFO is described that they in most cases represent developmental present. stages of either complex or compound odontoma and that retaining AFO recurrence is associated with inadequate surgical removal and them as separate entities would therefore be illogical 59). Accordingly, may occur if tumor remnants persist in the resection margins and in in the new classification of odontogenic tumors are defined AFO as the tooth involved, especially for large tumors67). Although malignant immature odonotoma. In the other hand, there are clinical reports of transformation of AFO was not found in the Japanese patient series, a AFO recurrence, whether it is a tumor or a hamartoma is controversial. few cases of malignant transformation were reported in studies from Gardner60) described that odontomas develop during the period of other countries68, 69). However, potential transformation alone does not normal odontogenesis and, therefore, any apparent ameloblastic justify radical treatment for this benign lesion. As noted in the literature fibroma found after that time is unlikely to represent the early stage review, not all lesions previously classified as AFO are aggressive of a developing odontoma. These data suggested that AFO have true lesions, and they are not expected to recur following conservative neoplastic conditions. surgical intervention. In our present case, immunohistochemical analysis clarified that In conclusion, AFO is a rare benign neoplasm with low recurrence. Wnt1 and β-catenin was detected in almost epithelial and mesenchymal We recommend tumor enucleation as the fi rst step in treatment, which components. In general, Wnt signaling is responsible for cytological is consistent with the recommendation of most authors. Only in the regulation of cell fate, morphogenesis and/or development. In the tooth case of repeated recurrence or evident malignancy, we recommend development, it controls epithelial-mesenchymal interaction. Besides performing a more extensive treatment. With regard to retention of that, the excessive activation of Wnt signaling induce tumorigenesis. the involved unerupted teeth, if the teeth do not interfere with the There are some report that mentioned the epithelial-mesenchymal enucleation of the tumor, there is no reason to remove them and there is interaction was activated in ameloblastic fi broma70). Our examination a possibility of spontaneous eruption. results suggest that Wnt signaling plays the tumorigenesis through activation of epithelial and mesenchymal interactions and inducing the Acknowledgment neoplastic feature of the ameloblastic fi broma. We would like to thank Jitsuo Nishihara whose comments and The most common complaints patients present with are suggestions were of inestimable value for our study. asymptomatic swelling and delayed tooth eruption in the affected region1). The lesion may displace the erupted teeth, but other symptoms, Confl icts of interest such as pain and paresthesia, are uncommon. 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