REVIEW ARTICLE: Current concepts of ameloblastoma pathogenesis

J Oral Pathol Med (2010) 39 : 585–591 Ameloblastoma is a locally destructive and invasive tumour that can recur despite adequate surgical removal. Molecular studies have offered interesting findings regarding ameloblastoma pathogenesis. In the present review, the following topics are discussed regarding its molecular nature: clonality, cell cycle proliferation, apoptosis, tumour suppressor genes, ameloblastin and other enamel matrix proteins, osteoclastic mechanism and matrix metalloproteinases and other signalling molecules. It is clear from the literature reviewed that translational studies are necessary to identify prognostic markers of ameloblastoma behaviour and to establish new diagnostic tools to the differential diagnosis of unicystic from multicystic ameloblastoma. Finally, molecular biology studies are also important to develop more effective alternative approaches to the treatment of this aggressive odontogenic tumour.     

The relationship of adamantinomatous craniopharyngioma to ghost cell ameloblastoma of the jaws: a histopathologic and immunohistochemical study

The objective of this investigation was to study the relationship of the ghost cell ameloblastoma (GCA). which is a form of type II calcifying odontogenic cyst (COO, to the adamantinomatous craniopharyngioma (ACP). H&E sections of 26 examples of ACP were compared to three cases of GCA and to the reported microscopic features of that tumor. Clinical records of the ACPs were studied to determine their biologic behavior compared to that of the ameloblastomas. Immunohistochemical studies of nine examples of ACP were performed for KL1 (high mol.wt cytokeratins), 5D3 (low mol.wt cytokeratins) and involucrin (characteristic of terminally differentiated keratinocytes) using the peroxidase–amiperoxi–dase method. The results were compared with those reported for COC and ameloblastoma. ACP and GCA exhibited similar microscopic features, including pre–ameloblasts, tissue resembling stellate reliculum, ghost cells and calcifications; both tumors grew slowly and were invasive. ACP and COC. and by interpolation GCA. exhibited similar features with all three antibodies. The ghost cells did not exhibit any immunoreactivity but the adjacent cells stained positively for involucrin. The immunological features of ACP were similar to those reported in ameloblastomas for squarnous differentiation. However, because of their rarity, no ameloblastomas exhibiting keratinization. including ghost cells, have yet been studied with these antibodies. We conclude that ACP and GCA are homologous lesions.     

Clinicopathological characteristics of desmoplastic ameloblastoma: A systematic review

The aim of the present review was to systematically present the clinicopathological data of desmoplastic ameloblastoma (DA) from articles published in the literature. A comprehensive search of the databases (PubMed, Medline, SCOPUS, Web of Science, and Google Scholar) for published articles on DA was conducted. A total of 238 cases were identified and analyzed from 76 published papers. DA showed a slight male predilection (male: female=1.07:1) with a predominance in the fourth and fifth decades of life. Mandibular involvement (52.55%) was most commonly seen with a marked tendency for the anterior region (mandible: 40.9%, maxilla: 48.07%). The size of the lesion ranged from .5 cm to 20.4 cm, with the majority of cases measuring more than 3 cm in size (53.84%). Radiologically, most of the lesions presented mixed radiolucency and radiopacity (62%), and root resorption was observed in only seven cases. The majority of the lesions showed ill‐defined margins upon radiographic examination (65.78%). Most of the cases were treated with resection (78.57%), and five of the 10 recurrent cases were treated by enucleation/curettage. DA is characterized by the unique presentation of clinicopathological parameters. It is not possible to comment on its aggressive/recurrent nature and best treatment modality due to inadequate follow‐up data.     

Expression of hMSH2 and hMLH1 proteins of the human DNA mismatch repair system in ameloblastoma

The human DNA mismatch repair (hMMR) system plays an important role in reducing mutation and maintaining genomic stability. The MMR system in human cells is composed of at least six genes (hMSH2, hMLH1, hMSH3, hPMS1, hPMS2 and GTBP/hMSH6). In particular, hMSH2 and hMLH1 are expressed in human cells that are undergoing rapid renewal; their reduced expression has been reported in several tumors. We examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in 25 ameloblastomas. All ameloblastomas expressed hMSH2 and hMLH1 proteins in the outer layer of epithelial cells. The localization of the staining was exclusively nuclear. These data suggest that the development and progression of these tumors do not depend on a defect in the hMMR system.     

Clear-cell ameloblastoma of the mandible (a case report)

An ameloblastoma with histologic evidence of clear cells in a 15-year-old Nigerian male patient, who presented with a slow-growing, intraosseous, anterior mandibular swelling, is reported. The lesion was treated by surgery alone, and has not shown any recurrence 5 years after initial surgery.     

Immunolocalization of cell signaling molecules in the granular cell ameloblastoma

BACKGROUND: Bone morphogenic protein (BMP) and Wnt signaling pathway molecules play important roles in cytodifferentiation and cell proliferation. We attempted to localize these signaling molecules in the granular cell ameloblastoma. MATERIALS AND METHODS: Four samples of paraffin-embedded ameloblastoma with granular cells were studied. Immunohistochemistry was performed to detect basement membrane type heparan sulfate (HS) (JM403), cell surface type HS (10E4), heparanase, Wnt-5a, Wnt-2, beta-catenin, and BMP-4. RESULTS: In all four samples, strong expression of beta-catenin and Wnt-5a was detected within the granular cells, while BMP-4 expression was weak and Wnt-2 was negative. Immunoreactivities of basement membrane type HS, cell surface type HS, and heparanase were variable within granular cells in ameloblastoma. CONCLUSION: Granular cells in ameloblastoma exhibit abnormal biological behaviors, particularly synthesis and secretion of protein. Synthesis of signaling molecules is upregulated, but secretion is arrested in some cases, while both are lost in other cases.     

Synchronous ameloblastoma and orthokeratinized odontogenic cyst of the mandible

The simultaneous occurrence of ameloblastomas with odontogenic cysts or other non-odontogenic lesions have already been described as combined lesions. However, we are unaware of any report in the English literature of simultaneous occurrence of ameloblastoma and orthokeratinized odontogenic cyst (OOC) occurring as completely distinct lesions. This report shows a case of synchronous ameloblastoma and OOC, located on posterior regions of the mandible, but in distinct sides.     

Peripheral ameloblastoma of the gingiva: the importance of diagnosis

BACKGROUND: Peripheral ameloblastoma is an extremely rare epithelial odontogenic tumor, limited to the soft tissues of the gums or oral mucosa. Although the lesion is benign, it may be locally aggressive. METHODS: The present study describes the case of a 31-year-old male presenting a firm, symptomless tumor mass of irregular appearance and measuring approximately 12 mm in diameter, located in the distal zone of 4.7. RESULTS: An excision biopsy was performed. The lesion was covered with hyperplastic squamous epithelium, with islets of epithelial cells located at subepithelial level. The cells in the peripheral zone adopted a palisade distribution, and presented the appearance of a lax reticulum at central level. A fibroblastic stroma was observed between the islets. The diagnosis was peripheral ameloblastoma. CONCLUSIONS: Although the origin of the lesion remains unclear, it is able to recur and undergo malignant transformation. Consequently, peripheral ameloblastoma should not be viewed as a harmless mass.     

A comparative study of epithelial cell proliferation between the odontogenic keratocyst, orthokeratinized odontogenic cyst, dentigerous cyst, and ameloblastoma

OBJECTIVES: The aim of the present study was to compare the proliferation index of the epithelial cells between odontogenic keratocysts (OKC), orthokeratinized odontogenic cysts (OOC), dentigerous cysts (DC), and ameloblastomas. MATERIALS AND METHODS: The proliferation index, employing a novel cell proliferation marker IPO-38, was studied by the immunohistochemical technique in 10 OKC, seven OOC, eight DC and 10 ameloblastomas. RESULTS: The ameloblastoma had no higher labeling index (LI) of IPO-38 than the OKC (P = 0.910) but had higher LI than the OOC (P = 0.001) and DC (P = 0.000); the OKC had higher LI than the OOC (P = 0.002) and DC (P = 0.000); and the OOC had higher LI than the DC (P = 0.011). IPO-38-positive cells in the OKC and OOC were located principally in the suprabasal cell layers while the ameloblastoma were found in the peripheral portion in particularly, the follicular and plexiform types. CONCLUSION: These findings support previous studies that the proliferation indices are useful in predicting the different biological behavior of the odontogenic lesions and the OKC should be regarded as a benign tumor rather than simply an odontogenic cyst.     

A immunohistochemical study of the peripheral ameloblastoma

AIM: Peripheral ameloblastoma (PA) is a rare variant of ameloblastoma occurring in the extraosseous region. With regard to the histogenesis of the tumor, two major sources of origin are considered: odontogenic epithelial remnants and the gingival epithelium. In this study, we examined the immunohistochemical profiles of cytokeratins (CKs) and Ki-67 labeling index (LI) of PAs, and discuss the histogenesis and the biologic behavior of the PA. MATERIALS AND METHODS: Eight cases of PA were retrieved from the pathology files of 212 cases of ameloblastoma that had been registered at our hospital. Immunohistochemical staining was performed in seven cases using monoclonal antibodies of six CKs (7, 8, 13, 14, 18, and 19) and Ki-67. RESULTS: All cases of PA expressed CK13, 14, and 19. CK18 was positive staining in six cases, and CK8 in five cases. This staining pattern was similar to that in intraosseous ameloblastomas (IAs). The mean of Ki-67 LI of PAs (1.91%) was significantly lower than that of IAs (4.82%) (P = 0.002). CONCLUSION: We consider that the PA originates from odontogenic epithelial remnants rather than from the gingival epithelium, and the Ki-67 LI of the tumor is a good prognostic indicator.     

Desmoplastic ameloblastoma: correlative histopathology, radiology and CT-MR imaging

A desmoplastie variant of ameloblastoma with osteoplasia in the stroma is reported. This tumour presented in the canine/premolar region of the left maxilla of a 31 -year-old woman. It was treated by partial hemimaxiilectorny and immediate reconstruction with a non-vascularised iliac graft. The location of this lesion, its histology and radiological features differ from those of the conventional ameloblastoma. The behaviour and prognosis of the desmoplastie ameloblastoma (DA) cannot at this stage be predicted due to the small number of cases that have been reported and a lack of long-term follow-up. To our knowledge this is the first documentation of the CT and MRI features of desmoplastie ameloblastoma with pathologic correlation.     

Characterization of novel monoclonal antibodies raised against formalin-fixed, paraffin-embedded human ameloblastoma

To obtain monoclonal antibodies reactive with odontogenic but not other types of epithelium, mice were immunized wish honiogenates of fixed ameloblastoma tissues, and monoclonal antibodies Y4 and Mil were produced. Y4 reacted immunohistochemically with odontogenic epithelial components but not with those of squamous differentiation, while M11 reacted with odontogenic epithelial components and a part of keratotic epithelial tissues. Immunoglobulin isotypes of both antibodies were IgM as determined by Ouchterlonv immunodiffusion and enzyme-linked immunosorbent assays. Western blotting revealed that the antigen recognized by Y4 had a molecular mass of approximately 66 kDa; however, the antigen reactive with M11 was not identified by Western blotting in spile of various attempts in changing reaction conditions. These antibodies may be beneficial to histological analyses of odontogenic tissues and their related lesions.     

Immunoexpression of MMPs-1, -2, and -9 in ameloblastoma and odontogenic adenomatoid tumor

Objective:  The aim of this study was to evaluate and compare the expression of metalloproteinases-1, -2, and -9 in solid ameloblastoma and adenomatoid odontogenic tumor.
Methods:  A total of 20 cases of solid ameloblastoma and 10 cases of adenomatoid odontogenic tumors were selected and immunohistochemically assessed. Metalloproteinases-1, -2, and -9 immunoexpression and their distribution pattern were noted and semiquantitatively scored. The scores obtained were statistically analyzed.
Results:  Matrix metalloproteinase (MMP)-1 showed a predominant expression in both tumors and was found in stroma and parenchyma. For MMP-2, there was a varied expression, with 80% and 60% of immunoreactive tumor cells in ameloblastoma and adenomatoid odontogenic tumor respectively. Regarding stromal cells, 65% of ameloblastomas and 80% of adenomatoid odontogenic tumors showed positivity. There was immunoexpression of the MMP-9 in parenchymal and stromal cells in all cases of both tumors analyzed. A statistically significant difference in the expression of MMP-1 in relation to the expression of MMP-2 and -9 in ameloblastomas ( P  < 0.001) was observed.
Conclusion:  The results suggest that these metalloproteinases are related to growth and progression of tumors analyzed, and particularly in ameloblastoma, its highest aggressiveness may be, in part, a result of the active participation of the stromal cells and their products, such as the MMPs studied.     

Wnt信号通路相关基因在颌骨牙源性角化囊性瘤中的表达及意义

目的研究Wnt信号通路相关基因在颌骨牙源性角化囊性瘤中的表达,探讨其发挥的调控作用。方法收集颌骨牙源性角化囊性瘤新鲜标本及同一患者的正常口腔黏膜,提取RNA,基因芯片检测Wnt信号通路的相关基因,进行生物信息学分析。结果颌骨牙源性角化囊性瘤与正常口腔黏膜相比,在Wnt信号通路相关基因中发现5个共同差异表达基因,其中CAMK2A下调, FZD3、MAPK10、PRKX、WNT5a上调。结论牙源性角化囊性瘤中存在Wnt信号通路基因的异常表达,Wnt信号通路相关基因在颌骨牙源性角化囊性瘤中发挥一定的调控作用。     

Mutational analysis of Wnt signaling molecules in ameloblastoma with aberrant nuclear expression of β‐catenin

Background: To clarify the genetic background of ameloblastoma, expression of β‐catenin, and mutational status of genes involved in Wnt signaling pathway were investigated. Methods: We analyzed β‐catenin and cyclin D1 in 18 cases of ameloblastoma by immunohistochemical staining, and searched for mutations in CTNNB1 (gene for β‐catenin), APC, AXIN1, and AXIN2 by polymerase chain reaction (PCR) and direct sequencing method. Result: We detected membranous and occasionally cytoplasmic expression of β‐catenin in 16 of 18 cases (89%), and nuclear expression of β‐catenin principally in the peripheral columnar cells in 11 of 18 cases (61%). In nine of the 18 cases (50%), we detected the expression of cyclin D1 principally in the peripheral columnar cells. However, there was no correlation between nuclear expressions of β‐catenin and cyclin D1. No missense mutations were found in CTNNB1, APC, AXIN1, and AXIN2 in all cases except for silent mutation and already‐known single nucleotide polymorphism. Conclusion: Mutations in CTNNB1, APC, AXIN1, and AXIN2 are not implicated in nuclear accumulation of β‐catenin, and that the expression of cyclin D1 is accelerated independently of β‐catenin in ameloblastomas. Other Wnt signaling members or alternative pathways involved in the degradation of β‐catenin should be subject of further investigation.