Calcifying Odontogenic Cyst Demonstrates Recurrent WNT Pathway Mutations and So-Called Adenoid Ameloblastoma-Like Histology: Evidence Supporting Its Classification as a Neoplasm.

Calcifying odontogenic cyst (COC), once called calcifying cystic odontogenic tumor, is classified under the category of odontogenic cysts. However, the proliferative capacity of the lesional epithelium and consistent nuclear ß-catenin expression raise questions about its current classification. This study aimed to determine whether COC would be better classified as a neoplasm in the histologic and molecular context. Eleven odontogenic lesions diagnosed as COC or calcifying cystic odontogenic tumor were included in this study. The growth patterns of the lesional epithelium were analyzed histologically in all cases. ß-catenin immunohistochemistry and molecular profiling using Sanger sequencing and whole-exome sequencing were performed in 10 cases. Of the 11 cases studied, histologic features reminiscent of so-called adenoid ameloblastoma were observed in 72.7% (8/11), and small islands of clear cells extended into the wall in 36.4% (4/11). Intraluminal and/or mural epithelial proliferation was found in 72.7% of the cases (8/11). Nuclear ß-catenin expression was observed focally in all 10 cases studied, mainly highlighting epithelial cells forming morules and adjacent to dentinoid. CTNNB1 hotspot mutations were detected in 60.0% of the cases (6/10). All the remaining cases had frameshift mutations in tumor-suppressor genes involved in the WNT pathway, including APC and NEDD4L. Recurrent WNT pathway mutations leading to nuclear translocation of ß-catenin and distinct epithelial growth patterns found in COC are the neoplastic features shared by its solid counterpart, dentinogenic ghost cell tumor, supporting its classification as a tumor rather than a cyst.

The evolving molecular characterisation, histological criteria and nomenclature of adenoid ameloblastoma as a World Health Organisation tumour type.

Adenoid ameloblastoma (AA) was recently recognised as a separate tumour type in the most recent World Health Organisation (WHO) classification of head and neck tumours. This decision has been considered controversial by several groups, who have described AA as a subtype of ameloblastoma, a hybrid odontogenic tumour or to fall within the spectrum of other recognised odontogenic tumours, including dentinogenic ghost cell tumour and adenomatoid odontogenic tumour. Here we review the reasons for the WHO decision to classify AA as a separate tumour type. We also critique molecular and histological findings from recent reports published since the WHO classification. While acknowledging that the classification of tumours is constantly evolving, the balance of current evidence suggests that AA should remain a distinct tumour type, and not a subtype of ameloblastoma, pending further molecular characterisation.

Adenoid Ameloblastoma Shares Clinical, Histologic, and Molecular Features With Dentinogenic Ghost Cell Tumor: The Histologic Spectrum of WNT Pathway-Altered Benign Odontogenic Tumors.

An epithelial odontogenic tumor called adenoid ameloblastoma (AA) has recently been included in the new WHO classification. However, AA has considerable overlapping features with a preexisting entity, dentinogenic ghost cell tumor (DGCT). This study compared the clinical, histologic, and molecular characteristics of AA and DGCT. Eight cases of odontogenic tumors initially diagnosed as AA or DGCT were included in this study. Quantitative histologic analysis, ß-catenin immunohistochemistry, and molecular profiling using next generation sequencing were performed. Additionally, accumulated clinical data of AA and DGCT were statistically analyzed. Nuclear ß-catenin accumulation was detected in all cases in common, although the tumors studied histologically consisted of varying combinations of the AA-like phenotype, ghost cells, and dentinoid. However, CTNNB1 hotspot mutations were not found in any case. Instead, loss-of-function mutations in tumor suppressor genes involved in the WNT pathway, including the APC, SMURF1, and NEDD4L genes, were found regardless of histologic type. In addition, KRT13 mutations were detected in 2 cases with a high proportion of ghost cells. Finally, a literature analysis revealed clinical similarities between the previously reported cases of AA and DGCT. These findings suggest that from a clinical and molecular point of view, AA and DGCT represent a histologic spectrum of WNT pathway-altered benign odontogenic tumors rather than 2 distinct tumors. Moreover, previously unidentified keratin mutations may be associated with ghost cell formation found in specific types of odontogenic lesions.

Adenoid ameloblastoma with dentinoid is molecularly different from ameloblastomas and adenomatoid odontogenic tumors.

BACKGROUND: Adenoid ameloblastoma is a rare epithelial neoplasm, histologically characterized by the presence of ameloblastoma-like features, duct-like structures, epithelial whorls, and cribriform architecture. Dentinoid material is usually present. Some advocate adenoid ameloblastoma is an ameloblastoma variant. However, there are overlapping features not only with ameloblastoma, but also with adenomatoid odontogenic tumor. Most ameloblastomas are characterized by the presence of BRAF p.V600E mutations and adenomatoid odontogenic tumors harbor signature KRAS mutations. The molecular features of adenoid ameloblastoma remain unknown. METHODS: Nine adenoid ameloblastoma cases were screened by TaqMan allele-specific qPCR to assess BRAF p.V600E, ameloblastoma signature mutation, and KRAS p.G12V and p.G12R, adenomatoid odontogenic tumor signature mutations. RESULTS: BRAF and KRAS mutations were not detected in any of the adenoid ameloblastoma cases. CONCLUSION: The molecular results support adenoid ameloblastoma as an entity distinct from adenomatoid odontogenic tumor and ameloblastoma.

Adenomatoid odontogenic tumor: A histopathologic profile of 43 cases with evidence supporting a mixed odontogenic origin.

BACKGROUND: Adenomatoid Odontogenic Tumor (AOT) accounts for 3% of all odontogenic tumors. It has been classified by WHO as an odontogenic tumor of purely epithelial origin. The current study attempts to establish the origin of the tumor along with detailed histopathological and clinicoradiographic analysis of 43 cases of AOT. MATERIAL AND METHODS: Forty-three cases were reviewed from the departmental archives for demographic data, radiographic features and histological features. Further, histopathological slides were stained with Picrosirius Red (PSR) and observed under polarised light. RESULTS: A majority of the cases were seen in the anterior jaws (76.7%), and were less than 3 cms (76.7%) in greatest dimension. Equal number of cases were of follicular and extra-follicular location while one was peripheral. Predominantly solid histological pattern was noted in 53.5%. Varied sub-patterns were observed with most cases exhibiting solid nodules and strands of tumor cells. Few cases showed melanin pigmentation. Over a third of cases (37.2%) showed dentigerous cyst like areas and one case each showed features of ossifying fibroma and focal cemento-osseous dysplasia. Tumor droplets, hyaline rings within duct-like structures, dentinoid material and osteodentin showed reddish yellow birefringence when observed under polarised microscopy post PSR staining. CONCLUSION: This study highlights the diverse histopathological variation of AOT with evidence to reclassify it as a mixed odontogenic tumor based on the polarising microscopic findings with PSR staining.

A Systematic Review of Adenoid Ameloblastoma: A Newly Recognized Entity.

BACKGROUND: Recently, a new odontogenic tumor has been described, the so-called adenoid ameloblastoma (AdAM). The aim of this review was to determine the clinical and imaging features of AdAM and to describe its main histopathological findings. METHODS: The systematic review included published cases with a diagnosis of AdAM in the gnathic bones, which had sufficient clinical, imaging, and histopathological data to confirm its diagnosis. The following histopathological diagnostic criteria were adopted: presence of ameloblastoma-like components, duct-like structures, spiral cellular condensations, and a cribriform architecture. RESULTS: Fifteen articles, corresponding to 30 cases of AdAM, were selected. Most cases affected men (63.3%), with a slight preference for the mandible (16:14) and the posterior region of gnathic bones was the most commonly affected site. The mean age at diagnosis was 40.8 years. Clinically, the lesions usually presented as a swelling (53.3%) and, radiographically, as a well-defined radiolucency (33.4%). Surgical resection (40%) was the most frequently adopted treatment and recurrence occurred in 30% of cases. Microscopic examination showed cribriform areas in most AdAM cases (93.3%); duct-like structures and spiral cellular condensations were seen in 100% of the cases. CONCLUSION: The small number of reported cases, the existence of erroneous diagnoses, and the adoption of initial conservative management make it difficult to determine whether AdAM has a higher risk of recurrence or more aggressive biological behavior than conventional ameloblastomas.

Adenoid 'ameloblastoma': Clinicopathological description of 4 additional BRAF-negative cases.

OBJECTIVE: Adenoid ameloblastoma (AA) is an epithelial odontogenic tumor that was recognized as a separate entity in the last odontogenic classification of WHO in 2022. The etiology is unknown, and the pathogenesis remains controversial. The objective of this study is to contribute the clinicopathological features of 4 additional BRAF-negative cases to the existing literature, aiming to enhance the molecular understanding of this unique tumor in the forthcoming classification. MATERIALS AND METHODS: This study consists of a case series of four patients diagnosed with AA. The patients' demographic and clinical information were collected from the universities' medical achieves. Histopathologically, all cases were reexamined according to the latest update of the WHO odontogenic tumor classification. In addition to H&E and immunohistochemical stains, cytogenetics was also evaluated. RESULTS: Well-defined unilocular radiolucent lesions were observed in all cases. Ameloblastoma-like components exhibited reserved nuclear polarity, suprabasal stellate reticulum-like epithelium, duct-like structure, whorls/morules, and cribriform architecture were common features. Variable immunoreactivity to CK7, CK19, CK14, p63, and p40 were determined, and proliferative activity was greater than 15%. The BRAF molecular study revealed no mutations. CONCLUSIONS: When diagnosing AA, the essential histopathological characteristics must be rigorously applied, and a significant portion of the lesion should contain these features. Additionally, despite limited molecular data, since the BRAF mutation commonly observed in ameloblastomas is not present in the majority of AA cases, we propose changing the term "ameloblastoma" to "ameloblastic" and referring to it as "adenoid ameloblastic tumor" in the forthcoming classification.

Dentinogenic ghost cell tumor revisited from a single institution in China with focus on adenoid ameloblastoma-like features.

OBJECTIVE: The present study aims to identify adenoid ameloblastoma (AdAM) from previously diagnosed cases of dentinogenic ghost cell tumor (DGCT), and gain insight to the possible relationship between AdAM and DGCT. METHODS: DGCT cases diagnosed between 2006 and 2022 were re-examined with focus on the AdAM-like features. RESULTS: A total of nine patients were included. Seven patients were males and two were females. The mean age was 38.0 ± 16.0 years. Five tumors occurred in the maxilla and four in the mandible, with a remarkable predilection for the posterior regions of both jaws. Microscopically, dentinoid material deposition was present in all cases. The ghost cells were absent in two cases. Rare ghost cells (<1%) were observed in three cases, and a higher proportion of ghost cells (5%-20%) were present in the remaining four cases. All cases showed prominent AdAM-like features, including duct-like structures, whorls/morules, and cribriform architecture. According to the diagnostic criteria proposed by the 2022 WHO classification, five cases without or with rare ghost cells were reclassified as AdAM. The other four cases including a higher proportion of ghost cells consisted of a mixture of DGCT and AdAM histopathologic patterns. CONCLUSION: Our results confirmed that the AdAM-like features had been largely overlooked in the diagnosis of DGCT at our institution in the past. Whilst a subset can now be more accurately classified as AdAM, some tumors showed overlapping morphological features between AdAM and DGCT, suggesting that the two may represent a spectrum of the same entity.

Adenoid Ameloblastoma Versus Dentinogenic Ghost Cell Tumor.

BACKGROUND: A recent systematic review published in Head and Neck Pathology found that 3.8% of dentinogenic ghost cell tumors harbor duct-like/ cribriform architecture. Herein we discuss this finding regarding the differential diagnosis of this tumor with adenoid ameloblastoma. METHODS: A critical review of some microscopic findings reported in a recent paper published in the Head and Neck Pathology Journal was done. RESULTS: Although there are overlapping microscopic features with dentinogenic ghost cell tumor, adenoid ameloblastoma is distinguished by the combination of duct-like structures and whorls/morules. In our opinion, at least some cases previously diagnosed as dentinogenic ghost cell tumors may now be more accurately classified as adenoid ameloblastoma. CONCLUSION: We conclude that a reassessment of dentinogenic ghost cell tumor cases using the diagnostic criteria proposed by the new WHO classification of Head and Neck Tumors (2022) is warranted.

Adenoid Ameloblastoma with BRAF p.V600E Mutation Revealing Ameloblastomatous Origin: A First Case Report.

BACKGROUND: Adenoid ameloblastoma (AdAM) is a frequently recurrent tumor that shows hybrid histological features of both ameloblastoma and adenomatoid odontogenic tumor (AOT). AdAM is expected to be classified as a new subtype of ameloblastoma in the next revision of the World Health Organization (WHO) odontogenic tumor classification. However, whether AdAM is a histologic variant of ameloblastoma or AOT remains unclear. To establish a new category, genetic evidence indicating the tumor category is necessary. METHODS: We present a case of a 23-year-old Japanese woman with AdAM who underwent genetic/DNA analysis for ameloblastoma-related mutation using immunohistochemical staining, Sanger sequencing, and next-generation sequencing (NGS) analyses with reliable clinicopathological evidence. RESULTS: Immunohistochemical expression of BRAF p.V600E was diffusely positive for both ameloblastoma- and AOT-like components. Sanger sequencing and NGS analyses showed missense mutations in BRAF p.V600E (c.1799T > A), a gene that is commonly altered in ameloblastomas but not in KRAS, another gene associated with AOT. CONCLUSION: This case report is the first to provide genetic evidence on the ameloblastomatous origin of AdAM with a BRAF p.V600E mutation. A larger series of AdAM groups' molecular testing is needed to aptly classify them and prognosticate the best treatment.

Proceedings of the 2023 North American Society of Head and Neck Pathology Companion Meeting, New Orleans, LA, March 12, 2023: Odontogenic Tumors: Have We Achieved an Evidence-Based Classification.

BACKGROUND: The World Health Organization's (WHO) chapter on odontogenic and maxillofacial bone tumors provides a global reference for diagnosis of these tumors. In the fifth edition, the inclusion of consensus definitions and development of essential and desirable diagnostic criteria help improve recognition of distinct entities. These are key enhancements since the diagnosis of odontogenic tumors is largely based on histomorphology which is taken in combination with clinical and radiographic appearances. METHODS: Review. RESULTS: Despite delineation of diagnostic criteria for ameloblastoma, adenoid ameloblastoma, and dentinogenic ghost cell tumor, a subset of these tumors continues to show overlapping histological features that can potentially lead to misdiagnosis. Accurate classification may be challenging on small biopsies, but potentially enhanced by refining existing diagnostic criteria and utilization of immunohistochemistry and/or molecular techniques in a specific cases. It has become clear that the clinical and histologic features of the non-calcifying Langerhans cell-rich subtype of calcifying epithelial odontogenic tumor and the amyloid-rich variant of odontogenic fibroma converge into a single tumor description. In addition, this tumor shows remarkable clinical, histological overlap with a subset of sclerosing odontogenic carcinoma located in the maxilla. Benign perineural involvement vs perineural invasion is an underexplored concept in odontogenic neoplasia and warrants clarification to reduce diagnostic confusion with sclerosing odontogenic carcinoma. CONCLUSION: While controversial issues surrounding classification and discrete tumor entities are addressed in the WHO chapter, ambiguities inevitably remain. This review will examine several groups of odontogenic tumors to highlight persistent knowledge gaps, unmet needs and unresolved controversies.

Diagnostic Enigma of Adenoid Ameloblastoma: Literature Review Based Evidence to Consider It as a New Sub Type of Ameloblastoma.

Adenoid ameloblastoma is a hybrid odontogenic tumour showing histopathological features of both ameloblastoma and adenomatoid odontogenic tumour (AOT), with approximately 40 cases reported in the literature. The aims of the report are to illustrate the diagnostic challenges of adenoid ameloblastoma using three new cases and to analyze evidence in literature to consider adenoid ameloblastoma as a new sub type of ameloblastoma. A literature review was performed with the key words-adenoid ameloblastoma, hybrid/composite odontogenic tumours, hybrid ameloblastoma and adenomatoid odontogenic tumour, ameloblastoma with inductive changes, dentinoid and dentinoma to select the cases compatible with the diagnosis of adenoid ameloblastoma. Out of the 40 cases reported in literature, 31 cases with sufficient information and 3 new cases were analyzed. Out of the 34 adenoid ameloblastomas majority of tumours (76.5%) occurred in adults with age ranging from 25 to 55 years. Slight female predilection with a male:female ratio of 0.9:1 was observed. Approximately, 64.7% occurred in the mandible. Radiologically, 82.4% of adenoid ameloblastomas presented as radiolucent lesions while 47.1% occurred with ill-defined margins and cortical perforation at diagnosis. Histopathologically, 70.8% of tumours presented as plexiform ameloblastomas, while duct like structures/glandular structures were the commonest feature supportive of adenomatoid odontogenic tumour observed in overwhelming majority of 95.9% of adenoid ameloblastomas. 91.6% of tumours showed inductive change in the form of dentinoid. Further, 45.4% of the tumours developed at least one recurrence following surgical excision. The report presents literature review based evidence to show the existence of adenoid ameloblastoma, which is demographically similar to conventional ameloblastoma but with histopathological differences and presenting with higher rate/multiple recurrences, indicating its biological aggressiveness. Thus, we would like to propose the inclusion of adenoid ameloblastoma as a sub type of ameloblastoma in the next revision of the WHO odontogenic tumour classification.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Odontogenic and Maxillofacial Bone Tumours.

The 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours (2022) comes out only five years after the previous edition, however it presents important updates that run in parallel with the rapid progression involving the increasingly sophisticated molecular investigation and its interpretation, some of which already have therapy-related impact. This manuscript provides an overview of the leading changes introduced in the classification of Odontogenic and Maxillofacial Bone Tumours that encompasses cysts of the jaws, odontogenic tumours, giant cell lesions and bone cysts, and bone and cartilage tumours. This is the first edition that Essential and Desirable Diagnostic Features were added for each entity, so that the most important clinical, microscopic and/or radiologic features were encapsulated and briefly highlighted. Surgical ciliated cyst was added to the group of odontogenic cysts, adenoid ameloblastoma was a newly recognized benign epithelial odontogenic tumour, and segmental odontomaxillary dysplasia was introduced in the group of fibro-osseous tumours and dysplasia. In addition, rhabdomyosarcoma with TFCP2 rearrangement, was introduced into the group of malignant jawbone tumours. The unique genetic aberrations distinguish it from other types of rhabdomyosarcomas. On the other hand, melanotic neuroectodermal tumour of infancy and osteoid osteoma were deleted from the benign bone and cartilageneous tumours, as was the hematolymphoid tumour of solitary plasmacytoma of bone. We systematically reviewed each entity in this chapter and provided important updated findings for selected topics that can further aid in the diagnostic process for challenging cases, broaden insights on the logic of the present classification, and finally, emphasize the potential that some of the molecular results may have in the near future to set new treatment approaches.

Update on Odontogenic Tumors: Proceedings of the North American Head and Neck Pathology Society.

Odontogenic tumors are rare entities, often derived from the epithelial remnants in the gnathic bones following odontogenesis. This brief manuscript will seek to address recent developments pertaining to odontogenic tumors as well as particularly uncommon odontogenic tumors and the difficulties in their diagnosis.

Adenoid ameloblastoma with dentinoid and cellular atypia: a case report and literature review.

Adenomatoid odontogenic tumor (AOT) is always benign. Given the very rare recurrence rate and the zero potential of malignant transformation, authors have considered it a hamartoma. Accordingly, 'AOT' is no more than a misnomer. This report, however, describes the first recognition of cellular atypia and plemorphism in a peripheral orophayrngeal AOT which embraces an ameloblastic component. The overall picture was diagnosed, after careful histological and immunohitochemical assessment, as a peripheral adenoid ameloblastoma. This find may promote a new pathogenetic scenario to the nosology of this debatable lesion.

Adenoid ameloblastoma with dentinoid.

Ameloblastomas seldom cause diagnostic difficulties due to classic histopathological presentations. Adenoid ameloblastoma is a rare variant in this category which can cause problem in diagnosis due to the presence of areas resembling adenomatoid odontogenic tumor (AOT) and occurrence of varying degrees of dentinoid formation. In this article, we report a case of adenoid ameloblastoma with dentinoid, which was diagnosed accurately after the third recurrence. To the best of our knowledge, so far, only 13 cases have been reported of tumors that histologically show features of amelobalstoma and AOT with hard tissue formation. The recurrences were due to under diagnosis of the lesion followed by a conservative treatment.