Cystic Plexiform Ameloblastoma – an important diagnostic challenge

doi:10.21203/rs.3.rs-5148787/v1

Background Ameloblastoma is a benign, locally aggressive neoplasm of the jaws and accurate diagnosis is important to provide timely treatment and reduce the risk of recurrence and local destruction. Ameloblastoma may show various histologic patterns, including a cystic plexiform pattern that lacks the typical ameloblast-like features and causes difficulties in the interpretation of incisional biopsies.

Objectives This is a retrospective study to identify and characterize cases of ameloblastoma that presented only a cystic plexiform epithelial proliferation lacking the pathognomonic features of ameloblastoma on incisional biopsy.

Methods We reviewed cases of ameloblastoma in our diagnostic biopsy service from 2004 to 2023 inclusive. Cases with a microscopic description that included cystic plexiform epithelial proliferation were retrieved for review of histopathologic features and associated clinical and radiographic information.

Results We identified a rare subset of ameloblastoma (3.7%, 7 of 188 ameloblastoma cases) that presented exclusively the cystic plexiform pattern, with absent or inconspicuous ameloblast-like features (CP-AM). The histologic appearance was characteristically uniform throughout the incisional biopsy and differed from the plexiform subtype of conventional ameloblastoma and plexiform unicystic ameloblastoma. Careful clinical and radiographic correlation with histologic findings was essential for a definitive diagnosis to guide treatment. Immunohistochemical staining for the BRAF p.V600E mutation was performed retrospectively and shown to be a useful adjunct for diagnosis that should be considered for future cases of CP-AM.

Conclusion Our study highlighted an uncommon and challenging histologic pattern of ameloblastoma. A coordinated approach using clinical, radiographic, histologic, and molecular studies are needed for a timely and accurate diagnosis.

odontogenic tumor

ameloblastoma

diagnosis

BRAF mutation

immunohistochemistry

Odontogenic tumors are uncommon jaw tumors that arise from tissues involved in tooth development [1, 2]. Ameloblastoma is the predominant epithelial odontogenic tumor, categorized into 3 types based on growth pattern and relation to bone: conventional solid/multicystic, unicystic, and peripheral ameloblastoma [2, 3]. The conventional solid/multicystic ameloblastoma (AM) is the major type, constituting approximately 80% of cases, and presents as a unilocular or multilocular radiolucent lesion that may grow to a large size (5 + cm). It is a locally invasive tumor with a high risk of recurrence after conservative excision and marginal resection or segmental resection are recommended for long-term control of this tumor [1, 2, 4, 5]. Inadequate or delayed treatment may lead to extensive destruction of the jaws and adjacent structures [4, 6].

All 3 types of ameloblastoma are defined histologically by the presence of ameloblast-like cells around loosely attached epithelium that resemble stellate reticulum. Ameloblast-like cells are columnar peripheral/basal cells with palisaded nuclei, reverse polarization and cytoplasmic vacuolization [2, 7]. Conventional ameloblastoma (AM) consists of solid, macrocystic and microcystic tumor presenting as 6 histological subtypes with variable presence of ameloblast-like cells to support the diagnosis [2, 8–10]. Unicystic ameloblastoma (UAM) has clinical, radiographic, and gross features of a single cystic structure that show typical ameloblastoma features on histologic examination of the cyst lining, with or without intraluminal or mural tumor growth [11–13]. A subset of UAM has been reported to show an intraluminal, plexiform epithelial proliferation that lacks ameloblast-like features as described above [1]. If more typical features of ameloblastoma cannot be found elsewhere in the biopsy, such cases may be difficult to distinguish from non-neoplastic jaw cysts, such as dentigerous cyst or radicular cyst with florid epithelial proliferation that require less aggressive treatment [2, 11].

The molecular genetic abnormalities of ameloblastoma have been elucidated in recent studies. The most common abnormality is the BRAF p.V600E mutation, but mutation in other components of the MAPK (Mitogen Activated Protein Kinases) pathway, such as KRAS, HRAS, NRAS and FGFR2, have also been found in a mutually exclusive pattern, which supports the hypothesis that aberrant MAPK signaling plays a role in the development of ameloblastoma. Mutations that activate the Hedgehog signaling pathway, particularly the SMO p.L412F mutation, have also been described in ameloblastomas [14–16]. There is an association between prevalence of each mutation type and site of ameloblastoma, notably the BRAF p.V600E mutation is reported in 72% (86/119) of mandibular tumors but only 19% (6/31) of maxillary tumors [17]. Unicystic ameloblastoma (UAM), which predominantly affects the posterior mandible, has a high prevalence of the BRAF p.V600E mutation. In a study of the mutational profile of UAM compared to AM, 94% (29/31) of mandibular UAM exhibited the BRAF p.V600E mutation [18]. Conversely, the SMO p.412F mutation is seen mostly in maxillary ameloblastoma [17]. Immunohistochemical staining for the BRAF p.V600E mutation is an accurate indicator of BRAF mutation status and has been shown to be useful in distinguishing between UAM and histologic mimics such as dentigerous cyst and odontogenic keratocyst [19–21].

Ameloblastoma with an intraluminal plexiform growth pattern presents a diagnostic challenge in incisional biopsies when they do not meet the histopathologic criteria for ameloblastoma. To gain a better understanding of this presentation of ameloblastoma, we conducted a review of ameloblastoma cases in the outpatient oral pathology diagnostic service at the Faculty of Dentistry, University of Toronto to identify cases of cystic plexiform ameloblastoma with no or inconspicuous ameloblast-like features (CP-AM). The clinical, radiographic, and histologic features were compared with ameloblastoma that showed typical ameloblast-like morphology (AM). Immunohistochemical staining for the BRAF p.V600E mutation was performed on archival material to assess the usefulness of BRAF mutation status in the diagnosis of CP-AM.

The archives of the oral pathology diagnostic service at the Faculty of Dentistry, University of Toronto (Toronto Oral Pathology Service, TOPS) were searched for cases of ameloblastoma diagnosed between 2004–2023 inclusive. Cases without paraffin blocks were excluded. Where multiple biopsies of ameloblastoma were found for the same patient, representing recurrence(s) of a lesion, the earliest biopsy within the study period was taken for analysis. Peripheral ameloblastomas are excluded as they do not show the intraluminal plexiform growth pattern. A total of 188 unique biopsies diagnosed with ameloblastoma were retrieved for study. The reports of all cases were reviewed (MH, GB, MM) to search for potential cases of CP-AM, indicated by microscopic description of a plexiform epithelial tumor with central areas of loosely attached epithelium that resembled stellate reticulum, and a peripheral layer of cuboidal epithelial cells with only focal, vague palisading and lacking reverse polarization and cytoplasmic vacuolization. H and E-stained slides of all potential cases were reviewed to exclude cases with plexiform growth as described above, but also showed areas with typical histomorphology of ameloblastoma that did not pose a problem with diagnosis. 7 cases met the criteria for CP-AM. The remaining 181 cases were designated as ameloblastoma with typical histology, either solid/multicystic (AM) or unicystic (UAM). Clinical and radiographic information were obtained from the biopsy files for CP-AM, AM and UAM.

Immunohistochemical staining

Immunohistochemical staining for the BRAF p.V600E mutation was performed on 3 µm thick formalin-fixed paraffin-embedded (FFPE) sections. Monoclonal antibody for BRAF p.V600E (clone 14, ready-to-use format, Roche Ventana, Oro Valley, AZ, USA) was applied after antigen retrieval (pH 8.0-8.5 buffer, 52 mins. at 95^oC), and incubated at 37 ^oC for 16 minutes in the Ventana BenchMark Ultra autostainer. Staining was completed using the Ultraview Universal DAB Detection system, with DAB as chromogen and enhanced with OV AMPLIFIER.

The staining protocol is validated with known cases with the BRAF p.V600E mutation demonstrated by NGS (next generation sequencing).

The cystic plexiform histological pattern (CP-AM) is a rare presentation of ameloblastoma

A review of biopsies accessioned from January 2004 to December 2023 revealed a total of 117,306 cases in the 20-year study period. Our search strategy using the terms ‘ameloblastoma’ or ‘consistent with ameloblastoma’ (Table 1) yielded 188 unique cases of ameloblastoma. Among the 188 cases, 7 cases (3.7%) met the criteria for CP-AM, showing no ameloblast-like peripheral columnar cells with nuclear palisading, reverse polarization or cytoplasmic vacuolization (Table 2). There was a uniform appearance of interconnected sheets and strands of epithelium consisting of a peripheral layer of compact cuboidal cells with eosinophilic cytoplasm and central areas of loosely attached stellate cells or more closely packed small squamous or ovoid cells (Fig. 1 B, C, F; Fig. 2 D, F; Fig. 3 C, D; Fig. 4 C, D, E). The plexiform epithelial proliferation was attached to a loose connective tissue stroma that varied from basophilic (Fig. 1 F; Fig. 4 C, D, E) to edematous and vascular (Fig. 1 B, C; Fig. 2 D, F; Fig. 3 C, D), and was distinct from underlying mature collagenous fibrous tissue. Some cases showed areas of cyst wall lined by thin, non-keratinizing stratified epithelium associated with nodular masses of intraluminal plexiform epithelial proliferation (Fig. 3 B, Fig. 4 B, D; Table 2). One case (Fig. 2 D, E) showed cyst wall with a thick, nodular lining of plexiform epithelial proliferation. Other cases did not show cyst wall but the plexiform epithelial proliferation formed nodular masses that were consistent with intraluminal growth (Table 2). A mixed inflammatory infiltrate was present in all cases but was more pronounced in the tumors that surrounded erupted teeth and caused loss of alveolar bone including the alveolar crest (Fig. 1A; Fig. 2A). Additional tissue was obtained for histologic examination for 2 of the cases. In case 1 (Fig. 1 B – D), a second and larger incisional biopsy was performed to confirm the diagnosis of ameloblastoma. In case 6 (Fig. 4 B – E), the lesion was removed by curettage and submitted for histologic examination. The size of the tissue specimens and the microscopic structure are shown in Table 2. The additional tissue showed the same uniform histologic appearance of plexiform epithelial proliferation. In only 2 of the 7 cases, there were inconspicuous foci of follicular ameloblastoma in the cyst wall adjacent to the bulky plexiform tumor, constituting less than 0.1% of the tumor (Fig. 1D, 3E; Table 2). The histologic findings in the incisional biopsy were insufficient for a definite diagnosis of ameloblastoma and correlation with clinical and radiographic findings was required for diagnosis.

Radiographic findings supported the diagnosis of ameloblastoma

Panoramic radiograph, multidetector CT or cone-beam CT studies were reviewed in cases 1 to 6. All cases presented with characteristic radiographic features of ameloblastoma, seen as unilocular or multilocular radiolucent lesions with a ‘soap bubble’ appearance, expansion, marked thinning and focal perforation of the cortical bone, root resorption and displacement of unerupted and erupted teeth (Fig. 1 A, E; Fig. 2 A, B, C; Fig. 3A; Fig. 4A). Case 7 was described as a large, multilocular radiolucency of the posterior mandible. The panoramic radiograph was reviewed by the attending oral pathologist at the time of diagnosis but was not available for review in this study.

Comparison of ameloblastoma with and without typical histologic features

In each of the remaining 181 cases of ameloblastoma, there were areas diagnostic of ameloblastoma, consisting of ameloblast-like columnar cells with palisaded nuclei, reverse polarization and cytoplasmic vacuolization, adjacent to loosely attached epithelial cells that resembled stellate reticulum. Most cases (n=168) were diagnosed as AM and demonstrated a mixture of growth patterns that included follicular, acanthomatous, plexiform, desmoplastic, and less commonly granular cell and basal cell morphology. Within this group, there were 2 cases that showed areas of CP-AM as described above, but these were mixed with prominent areas of follicular, acanthomatous and desmoplastic ameloblastoma (Fig. 5 A – D). A small proportion of cases (n=13) were diagnosed as UAM, based on clinical, radiographic and histologic criteria. This group included luminal, intraluminal and mural histologic subtypes and all cases demonstrated areas of typical ameloblast-like histomorphology (Table 1). Comparison of clinical features showed that CP-AM and UAM shared a predilection for younger age groups, in contrast to AM, which was seen over a wide age range. All 7 cases of CP-AM were located in the posterior mandible. Conventional ameloblastoma and UAM both showed a predilection for the mandible, but there was insufficient information in some of the cases to allow further subdivision of lesion site into posterior versus anterior. Males were more often affected than females in all 3 presentations of ameloblastoma – CP-AM, AM and UAM (Table 1).

BRAF mutation by immunohistochemical staining

Immunohistochemical staining for the BRAF p.V600E mutation was performed on 9 cases: 7 cases of CP-AM and 2 cases of AM that contained areas of cystic plexiform pattern. One case of CP-AM was negative (Fig. 1 G) while the other 8 cases showed strong, diffuse cytoplasmic staining (Fig. 1 H; Fig. 2 G; Fig. 3 F; Fig. 4 F; Fig. 5 E, F). Areas of CP-AM and adjacent areas of follicular ameloblastoma (Fig. 1 G; Fig. 5 E, F) were concordant in BRAF staining, supporting the concept that these represent different growth patterns within ameloblastomas.

CP-AM is a rarely seen pattern of ameloblastoma that may be mis-diagnosed as non-neoplastic odontogenic cysts because they lack the classical features of hyperchromatic palisaded columnar cells with reverse polarization and cytoplasmic vacuolization [7]. Correct identification of CP-AM is critical since this locally aggressive jaw tumor can lead to high morbidity due to bone destruction, invasion of overlying soft tissues and recurrence. Our main goal was to highlight the specific clinical, radiographic and histologic characteristics, and BRAF p.V600E status of CP-AM to improve the recognition of this challenging entity.

Regarding the clinical presentation of CP-AM, the age of patient and the location of lesion were similar to those of UAM, but the radiographic and gross (surgical) findings did not fit the characteristics of UAM [2, 11] and were more in keeping with AM with a dominant cystic structure and intraluminal tumor. Thus, we propose to use the term ‘cystic plexiform ameloblastoma’ (CP-AM) to describe this histologic pattern of ameloblastoma.

The histologic appearance of our cases of CP-AM is similar to that described for the intraluminal growth in some cases of UAM and referred to as plexiform unicystic ameloblastoma. It was noted that the diagnostic features of ameloblastoma should be sought elsewhere in the tumor, particularly areas of follicular pattern in the cyst wall [1, 2, 11]. The significant histologic finding in common for our 7 cases is the uniform appearance of nodular intraluminal epithelial tumor with a plexiform arrangement of cuboidal cells that lack ameloblast-like features. The diagnostic features of ameloblastoma were either absent, or only present in microscopic foci accounting for less than 0.1% of the area of epithelial tumor, despite thorough examination of incisional biopsies of adequate size. This contrasted with the histologic appearance of the rest of our file cases of ameloblastoma: conventional ameloblastoma that demonstrated a mixture of growth patterns including follicular, plexiform, acanthomatous, desmoplastic, granular cell and basal cell patterns, and unicystic ameloblastoma that showed luminal, intraluminal and mural subtypes, all of which showed areas of palisaded columnar cells with reverse polarization and cytoplasmic vacuolization that allowed histologic diagnosis of ameloblastoma. The distinctive histologic growth pattern that we describe as CP-AM were not included in published reports of intraosseous ameloblastoma [8–10, 22–25]. Due to the difficulties in histologic diagnosis of CP-AM, correlation of the histologic findings with radiographic appearance was required for diagnosis, since all 7 cases showed the characteristic radiographic appearance of ameloblastoma.

Six of the 7 cases (86%) of CP-AM in our study were found to have the BRAF p.V600E mutation by immunohistochemical staining. This is in agreement with published reports of 72–94% of mandibular ameloblastomas carrying this mutation [17, 18]. In the 2 cases of ameloblastoma with mixed histologic pattern showing both AM and CP-AM, staining for the BRAF p.V600E mutation was seen in all the growth patterns, suggesting that the mutation was an early event in the development of ameloblastoma. Previous studies have shown that the BRAF p.V600E mutation was consistently absent in dentigerous cysts [19, 20, 26]. Our findings indicate that immunohistochemical staining for the BRAF p.V600E mutation is a useful adjunct to distinguish CP-AM from dentigerous cysts with hyperplastic epithelial lining.

In our cases of AM and UAM, columnar cells with reverse polarization were displayed with varying prominence and extent across the histologic spectrum of cases, providing the diagnostic criteria for ameloblastoma and in agreement with published reports [1, 2, 8–10]. The reverse-polarized columnar cells resembled the epithelium of the enamel organ during tooth development, particularly the internal enamel epithelium (pre-ameloblasts) [27] The development of epithelial apicobasal polarity requires spatiotemporal regulation of protein polarity complexes [28]. Intraluminal growth and lack of contact with collagenized stroma may underlie the lack of columnar differentiation, nuclear palisading and reverse polarization in CP-AM. Further studies employing spatial transcriptomics and proteomics are needed to determine which signaling pathways are required to produce typical ameloblast-like morphology in the development of ameloblastomas.

Ameloblastoma uncommonly presents with a histological appearance of a cystic plexiform proliferation without typical ameloblast-like features. The diagnostic challenge in these cases may lead to delay in treatment. A coordinated approach using clinical, radiographic, histologic and molecular studies is required to achieve timely and accurate diagnosis.

AM - conventional solid/multicystic ameloblastoma; CP-AM - cystic plexiform ameloblastoma with no or inconspicuous ameloblast-like features; MAPK - Mitogen Activated Protein Kinases; NGS - next generation sequencing; UAM - unicystic ameloblastoma

Acknowledgement

The authors wish to thank Jeff Comber in Information and Instructional Technology Services, Faculty of Dentistry, University of Toronto, for his expert assistance in the preparation of the Figures.

This study was not supported by any funding. The authors declare that they have no conflict of interest. For this type of study formal consent is not required. This study has been approved by the appropriate Institutional Review Board: University of Toronto Research Ethics Board Protocol #46076. For this type of study consent for publication is not required. Statements on Availability of data and materials and Code Availability are not applicable for this study.

Neville BW, Damm DD, Allen CM, Chi AC. Odontogenic Cysts and Tumors. Oral and Maxillofacial Pathology 5th ed. St. Louis, Missouri: Elsevier; 2024. p. 685-746.
Tilakaratne WM, Odell E, Muller S. Odontogenic and maxillofacial bone tumours. In: Bishop J, Chan JKC, Gale N, Helliwell T, Hyrcza M, Lewis JS, Jr., editors. WHO classification of head and neck tumours 5th ed. Lyon, France: International Agency for Research on Cancer; 2022.
Robinson L, Martinez MG. Unicystic ameloblastoma: a prognostically distinct entity. Cancer. 1977;40(5):2278-85. Epub 1977/11/01. doi: 10.1002/1097-0142(197711)40:5<2278::aid-cncr2820400539>3.0.co;2-l. PubMed PMID: 922668.
Effiom OA, Ogundana OM, Akinshipo AO, Akintoye SO. Ameloblastoma: current etiopathological concepts and management. Oral diseases. 2018;24(3):307-16. Epub 2017/02/01. doi: 10.1111/odi.12646. PubMed PMID: 28142213.
Petrovic ID, Migliacci J, Ganly I, Patel S, Xu B, Ghossein R, et al. Ameloblastomas of the mandible and maxilla. Ear Nose Throat J. 2018;97(7):E26-E32. Epub 2018/07/24. doi: 10.1177/014556131809700704. PubMed PMID: 30036443; PubMed Central PMCID: PMCPMC6104513.
Smit C, Robinson L, Ker-Fox J, Fonseca FP, van Heerden WFP, Uys A. Clinicoradiologic features of ameloblastomas: A single-centre study of 155 cases. J Oral Pathol Med. 2024. Epub 2024/01/12. doi: 10.1111/jop.13510. PubMed PMID: 38212674.
Vickers RA, Gorlin RJ. Ameloblastoma: Delineation of early histopathologic features of neoplasia. Cancer. 1970;26(3):699-710. Epub 1970/09/01. doi: 10.1002/1097-0142(197009)26:3<699::aid-cncr2820260331>3.0.co;2-k. PubMed PMID: 5458275.
Hertog D, Bloemena E, Aartman IH, van-der-Waal I. Histopathology of ameloblastoma of the jaws; some critical observations based on a 40 years single institution experience. Medicina oral, patologia oral y cirugia bucal. 2012;17(1):e76-82. Epub 2011/12/14. doi: 10.4317/medoral.18006. PubMed PMID: 22157674; PubMed Central PMCID: PMCPMC3448205.
Milman T, Ying GS, Pan W, LiVolsi V. Ameloblastoma: 25 Year Experience at a Single Institution. Head and neck pathology. 2016;10(4):513-20. Epub 2016/10/28. doi: 10.1007/s12105-016-0734-5. PubMed PMID: 27272180; PubMed Central PMCID: PMCPMC5082058.
Smit C, Robinson L, van Heerden MB, Meyer PW, Ogunsakin RE, Fonseca FP, et al. A radiologic-pathologic study of the histopathologic variants of ameloblastomas and their proliferation indices. Oral surgery, oral medicine, oral pathology and oral radiology. 2024;138(3):403-13. Epub 2024/06/14. doi: 10.1016/j.oooo.2024.03.007. PubMed PMID: 38871622.
Li TJ, Wu YT, Yu SF, Yu GY. Unicystic ameloblastoma: a clinicopathologic study of 33 Chinese patients. The American journal of surgical pathology. 2000;24(10):1385-92. Epub 2000/10/07. doi: 10.1097/00000478-200010000-00008. PubMed PMID: 11023100.
Titinchi F, Brennan PA. Unicystic ameloblastoma: analysis of surgical management and recurrence risk factors. The British journal of oral & maxillofacial surgery. 2022;60(3):337-42. Epub 2022/01/09. doi: 10.1016/j.bjoms.2021.07.022. PubMed PMID: 34996630.
Yang R, Lin X, Zhang W, Gokavarapu S, Lin C, Ren Z, et al. Unicystic ameloblastoma: A retrospective study on recurrent factors from a single institute database. Oral diseases. 2024;30(3):1475-82. Epub 2022/12/25. doi: 10.1111/odi.14477. PubMed PMID: 36564985.
Brown NA, Rolland D, McHugh JB, Weigelin HC, Zhao L, Lim MS, et al. Activating FGFR2-RAS-BRAF mutations in ameloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(21):5517-26. doi: 10.1158/1078-0432.CCR-14-1069. PubMed PMID: 24993163.
Kurppa KJ, Caton J, Morgan PR, Ristimaki A, Ruhin B, Kellokoski J, et al. High frequency of BRAF V600E mutations in ameloblastoma. The Journal of pathology. 2014;232(5):492-8. doi: 10.1002/path.4317. PubMed PMID: 24374844; PubMed Central PMCID: PMC4255689.
Sweeney RT, McClary AC, Myers BR, Biscocho J, Neahring L, Kwei KA, et al. Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nature genetics. 2014;46(7):722-5. doi: 10.1038/ng.2986. PubMed PMID: 24859340; PubMed Central PMCID: PMC4418232.
Brown NA, Betz BL. Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries. Biomark Cancer. 2015;7(Suppl 2):19-24. Epub 2015/10/21. doi: 10.4137/BIC.S29329. PubMed PMID: 26483612; PubMed Central PMCID: PMCPMC4597444.
Heikinheimo K, Huhtala JM, Thiel A, Kurppa KJ, Heikinheimo H, Kovac M, et al. The Mutational Profile of Unicystic Ameloblastoma. Journal of dental research. 2019;98(1):54-60. Epub 2018/09/15. doi: 10.1177/0022034518798810. PubMed PMID: 30216733.
da Silva Marcelino BMR, Parise GK, do Canto AM, Sassi LM, Sarmento DJS, Costa ALF, et al. Comparison of Immunohistochemistry and DNA Sequencing for BRAF V600E Mutation Detection in Mandibular Ameloblastomas. Appl Immunohistochem Mol Morphol. 2021;29(5):390-3. Epub 2021/01/15. doi: 10.1097/PAI.0000000000000904. PubMed PMID: 33443847.
Ji YD, Johnson DN, Faquin WC, Peacock ZS. Utility of BRAF V600E immunohistochemistry in the diagnosis of mandibular ameloblastomas. International journal of oral and maxillofacial surgery. 2024;53(2):122-6. Epub 2023/06/22. doi: 10.1016/j.ijom.2023.06.001. PubMed PMID: 37344275.
Mendez LD, Wolsefer NS, Asa SL, Wasman J, Yoest JM, Stojanov IJ. The diagnostic utility of BRAF VE1 mutation-specific immunohistochemistry in ameloblastoma. Mod Pathol. 2022;35(11):1570-7. Epub 2022/06/09. doi: 10.1038/s41379-022-01105-8. PubMed PMID: 35676332.
Adebiyi KE, Ugboko VI, Omoniyi-Esan GO, Ndukwe KC, Oginni FO. Clinicopathological analysis of histological variants of ameloblastoma in a suburban Nigerian population. Head Face Med. 2006;2:42. Epub 2006/11/28. doi: 10.1186/1746-160X-2-42. PubMed PMID: 17125498; PubMed Central PMCID: PMCPMC1675998.
Boffano P, Cavarra F, Tricarico G, Masu L, Brucoli M, Ruslin M, et al. The epidemiology and management of ameloblastomas: A European multicenter study. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 2021;49(12):1107-12. Epub 2021/09/30. doi: 10.1016/j.jcms.2021.09.007. PubMed PMID: 34583885.
Fregnani ER, da Cruz Perez DE, de Almeida OP, Kowalski LP, Soares FA, de Abreu Alves F. Clinicopathological study and treatment outcomes of 121 cases of ameloblastomas. International journal of oral and maxillofacial surgery. 2010;39(2):145-9. Epub 2010/01/05. doi: 10.1016/j.ijom.2009.11.022. PubMed PMID: 20045283.
Goh YC, Siriwardena B, Tilakaratne WM. Association of clinicopathological factors and treatment modalities in the recurrence of ameloblastoma: Analysis of 624 cases. J Oral Pathol Med. 2021;50(9):927-36. Epub 2021/08/07. doi: 10.1111/jop.13228. PubMed PMID: 34358362.
Sant'Ana MSP, Dos Santos Costa SF, da Silva MP, Martins-Chaves RR, Pereira T, de Oliveira EM, et al. BRAF p.V600E status in epithelial areas of ameloblastoma with different histological aspects: Implications to the clinical practice. J Oral Pathol Med. 2021;50(5):478-84. Epub 2020/12/31. doi: 10.1111/jop.13155. PubMed PMID: 33377543.
Nanci A. Development of the tooth and its supporting tissues. Oral Histology. 7th ed. St. Louis, Missouri: Mosby Elsevier; 2008. p. 79-107.
Pasquier N, Jaulin F, Peglion F. Inverted apicobasal polarity in health and disease. J Cell Sci. 2024;137(5). Epub 2024/03/11. doi: 10.1242/jcs.261659. PubMed PMID: 38465512; PubMed Central PMCID: PMCPMC10984280.

Table 1. Clinical features of ameloblastoma

	Cystic Plexiform Ameloblastoma (CP-AM) (n=7)	Ameloblastoma with typical histology (n=181)
	Cystic Plexiform Ameloblastoma (CP-AM) (n=7)	conventional (AM) (n= 168)	Unicystic (UAM) (n=13)
Age range (median)	15-40 (21)	9– 90 (47)[1]	5-85 (17)
Female: Male	2:5	67:100[2]	5:8
Mandibular lesions (%)	7 (100%)	139 (83%)	11(85%)
Maxillary lesions (%)	0	29 (17%)	2 (15%)

[1] Age was unknown in 2 cases of AM

[2] Patient sex was unknown in one case of AM

Table 2. Gross and Microscopic features of cystic plexiform ameloblastoma

case	Gross description	Plexiform epithelial proliferation	Cyst wall associated with intraluminal tumor	Follicular ameloblastoma
1 repeat biopsy	Multiple pieces, 25x20x6 mm in aggregate Multiple pieces, 45x35x18 mm in aggregate	Yes Yes	No Yes	No Less than 0.1% of tumor
2	3 pieces, 18x12x7 mm in aggregate	Yes	Yes	No
3	2 pieces: 18x8x5 mm in aggregate	Yes	No	No
4	Multiple pieces, 40x36x10 mm in aggregate	Yes	Yes	Less than 0.1% of tumor
5	Multiple pieces, 21x9 mm in aggregate	Yes	Yes	No
6 excision	Multiple pieces, 17x16 mm in aggregate Oral mucosa, cyst wall, and multiple pieces measuring 22x20 mm in aggregate	Yes Yes	Yes Yes	No No
7	Multiple pieces, 20x14 mm in aggregate	Yes	No	No

No competing interests reported.

Cystic Plexiform Ameloblastoma – an important diagnostic challenge

Status:

Version 1

Abstract

Figures

Introduction

Materials and Methods

Immunohistochemical staining

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1