The World Health Organization Classification of Odontogenic Lesions: A Summary of the Changes of the 2022 (5th) Edition

The 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumors opened to online access in March 2022. This edition is conceptually similar to the previous classification of odontogenic lesions. The only newly defined entity in odontogenic lesions is adenoid ameloblastoma, which is classified under benign epithelial odontogenic tumors. While not odontogenic, the surgical ciliated cyst is a new entry to the cyst classification of the jaws. In other respects, a very important change was made in the new blue books that added ‘essential and desirable diagnostic criteria’ for each entity to highlight the features considered indispensable for diagnosis. In this article, we review the odontogenic tumors and cysts of the jaw sections of the Odontogenic and Maxillofacial Bone Tumors Chapter, outlining changes from the 2017 WHO classification and summarizing the essential diagnostic criteria and new developments.


INTRODUCTION
The new 5 th edition of the "World Health Organization (WHO) Classification of Head and Neck Tumours" is available in a convenient digital format for the first time and opened to online access in March 2022 (1). Actually, this is the first time that the WHO Classification of Tumours Series presents the authoritative content of the tumor classification book series in a digital format. This online version allows the user to access the book anytime and anywhere with electronic devices. Other significant changes made for the first time in the WHO series include the availability of at least one whole slide imaging to significantly improve users' appreciation of the histologic spectrum of each lesion. Additionally, the addition of essential and desirable diagnostic criteria should improve the user's ability to interpret and diagnose this area of pathology.
The 2022 5 th edition is not conceptually very different from the previous 2017 classification of odontogenic lesions. The odontogenic tumor classification, like earlier editions, is mainly divided into two categories, based on biologic behavior, as malignant and benign. Unlike past editions where malignant odontogenic tumors were discussed first, in the current edition, the odontogenic tumors are still organized by tumor behavior, but the malignant tumors are placed last. Benign tumors are classified into three major categories according to their histogenetic origin; epithelial, mesenchymal and mixed types. The only new entity added to benign epithelial tumors is adenoid ameloblastoma (2). Additionally, subtypes of certain odontogenic tumors and odontogenic cysts are more clearly defined and explained. Some challenging aspects of the 2017 classification still remain uncertain, controversial and debatable, such as the classification of metastasizing ameloblastoma, ameloblastic fibroodontoma/dentinoma, and the mural type of unicystic ameloblastoma (3,4). The odontogenic cyst classification, which was removed in the 2005 3 rd edition and added in 2017 4 th edition, continues in the new edition with the same entities. Surgical ciliated cyst, not a new entity but new to the classification, has been added to cysts of the jaws.
The aim of this review is to discuss updates in the new 2022 WHO odontogenic lesions classification, outlining changes from the 2017 WHO classification and summarizing the essential diagnostic criteria and current molecular advances. Although not an odontogenic cyst, we will also emphasize the new entry of surgical ciliated cysts to the cyst classification of the jaws and nasopalatine duct cyst. Table  I summarizes the current classification of odontogenic tumors and cysts of the jaws (1). Table II highlights the essential diagnostic criteria along with age, gender, localization preference of all odontogenic tumors.

Benign Epithelial Odontogenic Tumors
Adenomatoid odontogenic tumor (AOT) has molecular updates and a detailed differential diagnostic section. It is emphasized that some odontogenic lesions, such as odontomas, adenoid ameloblastoma (new entity), adenomatoid odontogenic hamartoma, and adenomatoid dentinoma (the last two not being included in the 2022 classification) may contain AOT-like areas (5,6), and conversely AOT can include calcifying epithelial odontogenic tumor-like areas (7). To avoid misdiagnosis due to the histopathologic overlapping, detailed clinicradiologic evaluation is necessary as with all bone lesions. Regarding the molecular profile, KRAS mutations and MAPK pathway activation are the most common features of AOT that shows KRAS p.G12V and p.G12R mutations in about 70% of cases (8).
Squamous odontogenic tumor has no major changes from the previous edition.
Calcifying epithelial odontogenic tumor (CEOT) has relatively important changes in that three subtypes have been described as clear cell CEOT, cystic/microcystic CEOT, and non-calcifying/Langerhans cell-rich CEOT (1). In the previous edition, these different variants were explained in the histopathological and macroscopic features sections, but they were not included as separate subtypes (4). However, no clear differential diagnostic criteria are proposed to separate the non-calcifying/Langerhans cellrich CEOT from the amyloid-rich subtype of odontogenic fibroma. These are likely the same tumor but are classified as CEOT by some and as central odontogenic fibroma by others. However, most cases are more suitable for amyloidrich odontogenic fibroma in terms of morphological and molecular features (9). Although different mutations (PTCH1, ABMN, PTEN, CDKN2A, JAK3, MET) have been reported in studies for CEOT, none of them currently affect treatment and diagnosis (1).
Ameloblastoma, Unicystic, still has three subtypes according to the distribution of the proliferation of the ameloblastomatous epithelium: luminal, intraluminal and mural. There is general agreement that the first two subtypes can be treated conservatively, but the last one might need to be treated as ameloblastoma (10). The debate continues on whether the mural type is a type of conventional ameloblastoma or not. However, in the new and previous edition it was left under unicystic ameloblastoma.  Table II: Age, gender, localization preferences, and essential diagnostic criteria of odontogenic tumors, modified from the 2022 WHO classification (1).

Odontogenic Tumors Age/Gender/Localization Essential Diagnostic Criteria
Adenomatoid odontogenic tumor (Figure 1)    these tumors do not show the essential criteria of AA. Clear cell odontogenic carcinoma and odontogenic carcinoma with dentinoid are also in the differential diagnosis, but the first tumor includes EWSR1 rearrangement, while distinguishing AA from the latter can be difficult as there are few clear distinctions so far (1).
Metastasizing ameloblastoma, defined as an ameloblastoma that has metastasized despite its benign histopathological appearance (1), is still controversial in terms of its classification. This tumor, which was classified under the odontogenic carcinoma section in 2005 (19), was classified under the benign epithelial odontogenic tumors in 2017 (4), as well as in the current edition. The challenge is characterizing metastasizing ameloblastoma at the molecular level and whether its genotype is sufficiently distinct to allow metastasis despite its bland morphology histologically. The solution of the classification issue, which contradicts its name, seems to be left to the next classification.

Benign Mixed Epithelial & Mesenchymal Odontogenic Tumors
Odontoma is now considered a hamartomatous odontogenic lesion with compound and complex types. The section has a very detailed discussion about ameloblastic fibroodontoma (AFO) and ameloblastic fibrodentinoma (AFD), which were excluded from the 2017 and current classification because most examples were presumed to represent developing odontomas. However, the presence of BRAF p.V600E mutations in AFD and AFO similar to ameloblastic fibroma, but different from odontoma, has supported the arguments that at least some of these lesions are in fact neoplastic, particularly those with a locally aggressive biological behavior, large size, and recurrence (20,21). A recent study suggests that the combination of age and lesion size may be used to distinguish between lesions of a true neoplastic nature (i.e., AFO) and hamartomatous formation (i.e., OD) (22). On the other hand, it is obvious that we need further molecular and genetic specifications to better understand their true nature.
Primordial odontogenic tumor, a new entity to the 2017 classification does not have any significant changes due to its rarity.
Ameloblastic fibroma also has a detailed discussion about the relationship of AF with AFO, AFD, and odontoma in the histopathology and pathogenesis sections. Both odontoma and ameloblastic fibroma sections of the new edition have a discussion about AFO and AFD compared to previous editions, and this may indicate a need for further clarification of these lesions in the next classification.
BRAF p.V600E mutations have been found in all types (11). The mural type seems to be somewhere in between conventional and unicystic ameloblastoma in terms of recurrence and might require consideration of more extensive surgery for aggressive and destructive lesions (12). In addition, BRAF-targeted therapy can be a consideration for the treatment of mutation-positive cases (13).
Ameloblastoma, Extraosseous/peripheral still has a separate entity status while other peripheral odontogenic lesions do not have such distinction, but this has not changed from previous editions. Peripheral ameloblastoma is explained in detail without any major changes from the previous edition.
Ameloblastoma, Conventional, the most common odontogenic neoplasm, excluding odontoma that is considered a hamartoma, is a benign but locally infiltrative neoplasm composed of ameloblast-like cells and stellate reticulum (1).
In the 2017 edition, the genetic profile of ameloblastoma was updated broadly. BRAF p.V600E is the most common activating mutation, affecting the MAPK pathways, and is an early and critical event in the etiopathogenesis of ameloblastoma (14,15). BRAF inhibitor therapy has been proposed for selective cases in the treatment (13,16). It can be predicted that data on these target therapies will increase and will be included in the next classification.
Adenoid ameloblastoma (AA) is the only new entity added in the odontogenic lesions and it represents the most important change. It is defined as an epithelial odontogenic neoplasm composed of cribriform architecture and ductlike structures, and frequently includes dentinoid ( Figure  5C-D). Approximately 40 cases have been reported in the literature so far (17). It usually presents as a painless swelling with an incidence peak in the 4th decade, and with slight male preference (5,17). The essential diagnostic criteria have been described as an ameloblastoma-like component, duct-like structures, whorls/morules, and cribriform architecture, while dentinoid, clear cells, focal ghost-cell keratinization are reported as desirable features (1). Variable staining for CK14, CK19, p40, p16 and p53 has been reported (18). Ki-67 proliferation index is usually high and that can explain the local aggressive behavior with a high recurrence rate (45.5%-70%) (5,17). Interestingly, in contrast to other intraosseous ameloblastomas, BRAF p.V600E mutations have not been found in AA. The lack of BRAF reactivity and the finding of nuclear β catenin reactivity in these tumors calls into question their relation to ameloblastoma and whether adenoid ameloblastoma is the best designation for this new tumor. The main differential diagnosis for AA includes AOT and DHGT but  Sclerosing odontogenic carcinoma is a very rare odontogenic carcinoma that was added to the classification in 2017 (4). Due to the rarity of cases, there are no molecular updates or developments. As a 'minor' change, not having the potential for metastasis was added to the definition of SOC, which was characterized by bland cytology, markedly sclerotic stroma and locally aggressive infiltration (1). Because the original publication (27) suggested and the WHO now concurs that this neoplasm has "no metastatic potential", should it be categorized as a carcinoma?
Ameloblastic carcinoma has a definition change from the previous edition that was accepted and described as a malignant counterpart of ameloblastoma (1). Now, it is considered a primary odontogenic carcinoma histologically resembling ameloblastoma. BRAF p.V600E mutations, the most common activating mutation in conventional ameloblastoma, have been reported in AC (28) but it has no defined diagnostic value yet.
Clear cell odontogenic carcinoma has no significant changes. It is well known that more than 80% of cases harbor a translocation involving EWSR1 and ATF1 (29), a common pathogenesis also of hyalinizing clear cell carcinoma (30). The differential diagnosis is broad and includes almost all clear cell rich tumors, including odontogenic tumors, salivary gland tumors, and metastatic tumors, particularly renal cell carcinoma. Distinction may require IHC/ molecular studies in some challenging cases.
Ghost cell odontogenic carcinoma has limited update on molecular aspects because of the rarity of the tumor. In the new edition, a single case-documented mutation of CTNNB1 (β-catenin) (31) has been added to the previous molecular profile including multiple changes in the SHH signaling pathway, and a novel APC mutation (32).
Primary intraosseous carcinoma-NOS is usually squamous carcinoma with variable differentiation, but mostly moderately. A recent systemic review found that the majority arise from odontogenic cysts, more commonly residual and radicular cysts and less often dentigerous and odontogenic keratocysts (33). This diagnosis should be made carefully after excluding other malignant odontogenic and intraosseous salivary gland tumors, metastatic lesions, and carcinomas invading bone from other anatomic structures.
Odontogenic carcinosarcoma is an extremely rare malignant odontogenic tumor containing both malignant epithelial and mesenchymal components that require very careful examination. Any sarcomatoid change in a malignant epithelial odontogenic tumor should be evaluated carefully to avoid misdiagnosis of a spindle cell odontogenic carcinoma (34).
Dentinogenic ghost cell tumor is a rare benign odontogenic tumor, which kept its entity status without any important updates.

Benign Mesenchymal Odontogenic Tumors
Odontogenic fibroma now clearly has subtypes; amyloid subtype, granular cell subtype, ossifying subtype, and hybrid odontogenic fibroma with central giant cell granuloma (1). Amyloid type characterized by amyloid deposits with Langerhans cells is a well-known entity but a controversial tumor as pointed out earlier in CEOT and needs to be classified as a CEOT or odontogenic fibroma, not both.
Cementoblastoma now has some molecular updates that it shows c-FOS overexpression and harbors the same FOS rearrangement (23) as osteoblastoma, a histologic mimicker. This raises the question of cementoblastoma being a unique odontogenic tumor or a bone neoplasm simply within the spectrum of osteoid osteoma and osteoblastoma.
Cemento-ossifying fibroma (COF) was classified under mesenchymal odontogenic tumors in the 2017 classification for the first time but discussed in detail with the other ossifying fibromas in the fibro-osseous lesions section (4). While COF has always been a benign fibro-osseous lesion as well as an odontogenic neoplasm, it is now defined and updated under the odontogenic tumor section. A variety of infrequent molecular alterations have been reported in COF but no pathogenic alterations were identified when 50 oncogenes or tumor suppressor genes were examined by NGS (24).
Odontogenic myxoma (OM) has some updates in its pathogenesis that shows MAPK/ERK pathway activation, and this pathway inhibition may have the potential to reduce tumor growth (25). It is worth emphasizing, as the previous edition did, that the most important differential diagnosis of OM is the dental papilla of a developing tooth or a normal/hyperplastic dental follicle that is almost identical histologically to OM ( Figure 6C-D), but familiarity with these anatomic structures and the clinical and radiologic features will avoid misdiagnosis ( Figure 6).

Malignant Odontogenic Tumors
There are not many significant differences between the last two editions of the Blue Book in terms of histopathological description and classification of malignant odontogenic tumors. Due to the lack of defined UICC staging guidance, the use of International Collaboration on Cancer Reporting minimum data set reporting is encouraged for all malignant odontogenic tumors (26).

Developmental Odontogenic Cysts
Gingival cysts (adult and infant types), dentigerous cyst (eruption cyst, a superficial subtype of dentigerous cyst over an erupting tooth), orthokeratinized odontogenic cyst, lateral periodontal cyst, and botryoid odontogenic cyst continue in the 2022 classification without important changes from the previous edition. Regarding molecular updates, BRAF p.V600E mutations found in ameloblastomas have not been found in dentigerous cysts (38).
Calcifying odontogenic cyst (COC) has continued in the cyst classification with an important change in the definition that also affects the diagnostic criteria. In the definition of the 2017 classification, 'ameloblastoma-like epithelium' was excluded and COC is now defined as "a developmental odontogenic cyst characterized histologically by ghost cells, which often calcify." While most COCs still have ameloblastoma-like epithelium, that feature was moved from an essential feature to a desired one (39). Mutations of CTNNB1 which encodes β-catenin has been added to the COC pathogenesis (40).
Glandular odontogenic cyst (GOC) also has some differences from the fourth edition in terms of diagnostic histopathologic features. In 2017, ten different histopathologic features were described and observation of at least seven criteria was suggested to make a GOC diagnosis (4,41). The new edition emphasized that even if characteristic, not all features are present in all cases but more features provide more confidence in the diagnosis (1). Among these features, the essential criterion is presence of a lining epithelium with varying thickness, but it was stated that hobnail cells are observed in almost all cases and seem to be the most characteristic feature. It was also emphasized in this classification that the most important differential diagnosis of GOC is intraosseous mucoepidermoid carcinoma. Demonstrating the MAML2 rearrangement for intraosseous MEC is important in the differential diagnosis of these two lesions (42). That is still generally accepted; however, one GOC case has been reported with MAML2 rearrangement (43). It is believed that this situation needs further studies.
Odontogenic keratocyst (OKC) is the most frequently researched cyst due to high recurrence rate, aggressive clinical behavior, and association with the nevoid basal cell carcinoma syndrome. In the 2022 edition, OKC continues in the cyst classification and has the longest section among the cysts of the jaw. There is extensive literature characterizing the molecular landscape of OKC. Most show mutations of the tumor suppressor gene PTCH 1, but rarely PTCH2 or SUNU (44)(45)(46).
Odontogenic carcinoma with dentinoid (36), is reported but not included as a separate entity in the 2022 classification. It is mentioned frequently in the differential diagnosis of other odontogenic tumors and its justification and placement in the classification remains controversial but an area in need of clarification. Table III highlights the essential diagnostic criteria along with age, gender, and localization preference of all odontogenic cysts, surgical ciliated cyst and nasopalatine duct cyst. In the 2017 classification, the cysts of the jaws were divided into two primary parts; odontogenic cysts of inflammatory origin and odontogenic/non-odontogenic developmental cysts (4). Now, in the 2022 classification, the umbrella term of 'cysts of the jaws' has been used without any subdivision. However, here we prefer to discuss them under the subheadings of inflammatory odontogenic cysts, developmental odontogenic cysts, and other cysts of the jaws for greater clarity and to emphasize their origin.

Inflammatory Odontogenic Cysts
Radicular cyst (RC) is still the most common cyst of the jaws and accounts for about 60% of all odontogenic cysts (37). RCs arise from periradicular inflammation secondary to the spread of odontogenic infection resulting from tooth devitalization. Residual cyst, which was clearly mentioned as a subtype of RC, is found as a well-defined radiolucency at a site of previous tooth extraction when the RC was not removed when the offending tooth was extracted. Lateral RC terminology of 2017 has been abandoned and only mentioned as RC that can be located on the lateral aspect of the root associated with a lateral root canal (1,4).
Inflammatory collateral cysts have no major changes and continue with two distinct subtypes as paradental cyst and mandibular buccal bifurcation cyst. The histology is not specific, and indistinguishable from RC features.

Cysts of the Jaws Age/Gender/Localization Essential Diagnostic Criteria
Radicular cyst -Residual cyst (Figure 9)     cells are common ( Figure 13B-D). A history of previous surgery is an essential criterion for diagnosis. Treatment is simple enucleation and recurrence is rare.
Nasopalatine duct cyst is the most common nonodontogenic cyst of the jaws (about 80%) (37,49). The cyst is lined by non-keratinized squamous epithelium or respiratory epithelium in variable proportion with focal areas of cuboidal, columnar, or ciliated changes. Generally, the neurovascular bundle is seen in the wall of the cyst, but this is a feature of sectioning and this feature is included in the desirable diagnostic criteria (1).
In conclusion, the new 2022 WHO classification of odontogenic tumors and jaw cysts includes some modifications and developments that we briefly summarized. It is hoped that this summary becomes a resource for readers to find recent changes and critical diagnostic information. Lastly, rapid developments in technology and molecular fields signal that the time between the editions of WHO classification of Head and Neck Tumours (1 st 1971, 2 nd 1992, 3 rd 2005, 4 th 2017 and 5 th 2022) will become shorter, and new classifications seem inevitable in the next 5 years.
These mutations have fueled the continued spirited debate about whether OKC is a cyst or a cystic neoplasm. In 2005, OKC was changed to a cystic neoplasm and designated a keratocystic odontogenic tumor (19). It was moved back into the cyst category in 2017 (4) and continues as a cyst in the 5th current classification. The debate continues.

Other Cysts of the Jaws
Surgical ciliated cyst, not a new entity but new to the classification, is a rare non-odontogenic cyst lined by respiratory epithelium as a result of the traumatic implantation of sinus or nasal mucosa. Surgical ciliated cyst of the maxilla, postoperative maxillary cyst or (respiratory) implantation cyst are other terms used for this entity. The most common age range is the 5 th to 6 th decades with no gender predilection (47). As the definition indicates, it occurs most commonly in the posterior maxilla; but very rarely in the mandible due to implantation of sinus epithelium by contaminated instruments or using nasal bone or cartilage with epithelium for augmentation genioplasty (47,48). Histopathologically, the cyst is lined by ciliated pseudostratified columnar epithelium and mucous