Clear cell adenomatoid odontogenic tumour and dentigerous cyst: an uncommon hybrid combination – case and review

Abstract

Odontogenic tumours and cysts have a characteristic presentation, histopathologically and clinically. The diagnostic criteria and nomenclature are distinct as elaborated in 2017 WHO classification. But one can occasionally and infrequently find an association between different odontogenic tumours and cysts, like calcifying epithelial odontogenic tumour (CEOT) and adenomatoid odontogenic tumour (AOT), CEOT and ghost cell tumour. Some of the odontogenic tumours and cysts share the site of occurrence, intraosseous location, teeth involved/quadrant involved and histopathology too. Hence these lesions are considered for differential diagnoses in most cases. But some instances report hybrid or associated tumours and cyst cases. Here we present a case of dentigerous cyst in association with AOT that showed variation in cell type, pattern and induction pattern.

Background

Odontogenic tumours are of rare occurrence accounting for about 1% of all tumours in the head and neck area.¹ They have classical clinical and histopathological presentation most of the time. In some instances, we get to see features which are rare or shared between different odontogenic lesions in maxillary canine/premolar region of young individuals. Most of the odontogenic cysts and tumours such as dentigerous cyst (DC), follicular variant of adenomatoid odontogenic tumour (AOT), ameloblastoma and odontogenic keratocyts are located intraosseously, related to an unerupted tooth. Association between diverse odontogenic tumours is common like odontomas and ameloblastic fibroma, calcifying epithelial odontogenic tumour (CEOT) and AOT. But there are not many associations of odontogenic cysts with odontogenic tumours. One such example of cyst and tumour association is that of calcifying odontogenic cyst (COC) with many odontogenic tumours such as odontomas, ameloblastomas.^{1 2}

The follicular variant of AOT, which is commonly associated with an impacted canine (40% cases), is confused for a DC clinically and radiologically, though AOT itself is a cystic tumour in many cases.^{3 4} There are case reports of AOT associated with various other cysts and neoplasms such as COC, DC, ameloblastomas, odontomes.³ Their coexistence may be expression of aberrant odontogenesis⁵ or progression/conversion of one lesion to another, but as they present, it is difficult to assess whether they are coexisting or converting (true cyst converting to an AOT).⁴ Occurrence of AOT with DC is a rare event. The present case is an addition to the set of such rare events of hybrid cysts and tumours which showed clear cell differentiation.

Case presentation

A 17-year-old male reported to the Dental Clinic with a large swelling on the left side of the face leading to facial asymmetry. Extraorally, the swelling was noticed on the left maxillary anterior region, around 4 cm in diameter, extending from the left ala of the nose and adjoining lip till the zygomatic process of maxilla, obliterating the nasolabial fold and stretching the lateral ala of the nose. The skin overlying was stretched and shiny but was of the same colour as that of the normal surrounding area (figure 1A). On palpation, bony hard consistency of the swelling and the diameter of 4 cm were confirmed.

Figure 1.

(A) Extraoral image showing a swelling on the left maxillary anterior region. (B) Intraoral image shows a 4 cm diameter ovoid swelling extending from 21 to 24 region obliterating the buccal vestibule. (C) Orthopantomogram shows unilocular well demarcated cystic lesion with sclerotic border extending from left central incisors to first premolar region with impacted left lateral and canine teeth. (D) Gross specimen showing an ovoid lesion with impacted canine teeth. (E) Cut section shows thick wall close to the impacted teeth (black arrow).

Intraoral examination revealed a large spherical bony hard mass extending from left maxillary central incisors (21) to left maxillary second premolar (25) teeth region. The tennis ball-like mass was completely obliterating the buccal vestibule, expanding the buccal cortical plate, though the palatal plate was intact. In the maxillary arch, the permanent maxillary left lateral incisor (22) and permanent maxillary canine (23) were missing with retention of deciduous left maxillary canine (63) (figure 1B).

On orthopantomogram, a large unicystic, unilocular, well-demarcated lesion with sclerotic border was evident. The teeth 22 and 23 were seen in the wall of the radiolucent lesion with incomplete root formation. Root resorption was noticed with respect to 21, 63 and the rest of the teeth were normal. Other than that, it was noted that all the permanent canines-13, 23, 33, 43 were impacted in different stages with retained deciduous canines-53, 63, 73, 83 (figure 1C).

Aspiration of the cyst revealed a straw-coloured fluid. A provisional diagnosis of DC was given and a conservative surgical approach was adopted to remove the cyst. The cystic lesion on surgical excision shelled out in toto, without much resistance. On grossing, the large cystic lesion measured 4 cm in diameter with a uniform thick wall, except for a region closer to the impacted 22, 23, where a more thicker wall with haemorrhagic patches was noted (figure 1D, E).

On histopathological examination, the lesion predominantly showed a classic 4–5 cell layers thick cystic epithelium, made of non-keratinised stratified squamous epithelium resembling the reduced enamel epithelium (figure 2A). The connective tissue was immature, hypocellular with myxoid areas and numerous scattered odontogenic cell rests (figure 2B). Few areas showed inflammatory cells. The area on grossing that showed a thick, haemorrhagic cystic wall, showed increased epithelial proliferation consisting of cuboidal cells with well-defined central hyperchromatic nucleus histopathologically (figure 2C). These thick areas in the cystic wall also showed ductal structures and rosettes; a couple of classical ductal structures lined by single layer of tall odontogenic epithelial cells in small and large configuration were evident. These were surrounded by odontogenic rosettes formed by plump spindle cells and areas of dystrophic calcification (figure 2D).

Figure 2.

(A) Photomicrograph showing cystic connective tissue wall lined by 4–5 cell layered stratified squamous non-keratinised epithelium (×40, H&E staining). (B) The immature connective tissue wall shows odontogenic rests (black arrow heads) (×100, H&E staining). (C) Increased proliferation of the epithelial cells seen in the lining consisting of cuboidal cells with hyperchromatic nuclei (×40, H&E staining). (D) The thick cystic areas showing proliferation of cells in ductal pattern (black star) and rosette pattern (black arrow head) with interwening spindle shaped cells along with dystrophic calcification (black arrow) (×100, H&E staining).

In many foci, the rosettes were interwined by large areas of oval cells with clear cytoplasm (figure 3A) and a centrally placed nucleus that tested negative for glucose with periodic acid Schiff (PAS) staining (figure 3B). The areas of AOT were merged with the cystic epithelium and connective tissue wall of the DC. The areas of AOT did not have an independent thick-wall capsule of mature collagen and connective tissue. Other than the presence of classic ducts and rosettes, the tumour showed numerous areas of eosinophilic tumour droplets (figure 3C). The tumour droplets were seen in association with rosettes, in-between rosettes and in association with the tall ductal cells. In few areas the tall columnar cells appeared to have differentiated better, with polarisation of nucleus and secretions of eosinophilic tumour droplets. Such areas showed a better differentiation towards ameloblast-like cells, along with inductive changes (figure 3D).

Figure 3.

(A) Photomicrograph showing numerous cells with clear cytoplasm (×100, H&E staining). (B) Photomicrograph showing the clear cells to be negative for periodic acid Schiff stain (×200, PAS staining). (C) Numerous areas of eosinophilic material (black arrow head) scattered among the tumour islands, rosettes and in association with the ductal structures (×200, H&E staining). (D) Few areas showed tall columnar cells with reversal of polarity with inductive changes (black arrow) (×40, H&E staining). Inset I: High power view of the tall columnar cells showing reversal of polarity (×200, H&E staining).

The case was thus diagnosed as DC with clear cell AOT.

Investigations

PAS staining was carried out to know the nature of the clear cells. The cells stained negative for the stain and thus proved not to contain glycogen (figure 3B).

Differential diagnosis

The clinical differentials considered were conventional AOT, calcifying odontogenic cyst and ameloblastoma. These were ruled out on histopathology.

Treatment

The lesion was enucleated completely and the specimen along with impacted lateral incisors and canines were submitted for histopathological diagnosis.

Outcome and follow-up

The patient is on regular follow-up every 6 months. So far there have been no signs of recurrence in 1 year follow-up.

Discussion

DCs are developmental odontogenic cysts that enclose the crown of unerupted tooth and are attached to the cervical region of the crown. Though DC has a rare association with other tumours, it has reported ones with ameloblastoma, AOT, mucoepidermoid carcinoma and oral squamous cell carcinoma.^{4 6} The cyst is very rarely seen to be associated with AOT. A careful literature search without any timeline limitations was carried out (print and online) in the Google Scholar, National Centre for Biotechnology Information (NCBI) database Wiley InterScience data base and ScienceDirect data bases using the keywords ‘AOT associated with dentigerous cyst’, ‘AOT arising from dentigerous cyst’ and ‘AOT with cystic lining similar to dentigerous cyst’. A manual search of all the related Oral Pathology, Oral Medicine and Oral Surgery journals was performed on June 2021.

The eligibility criteria included case report articles with clinical, radiological and histopathological arrangement confirming the diagnosis of an AOT in association with DC with an added note on suggested pathogenesis. The criteria presented individually for diagnosis of AOT and DC in the WHO classification¹ and histopathological criteria mentioned in articles with AOT associated with DC were considered. The case reports with complete details supported by histopathological images were only considered. The initial search with the keywords helped to identify a total of 31 case reports. Out of which full text articles with complete case details could not be retrieved for five case reports and thus were excluded. The rest of the 26 case reports (table 1)3–5 7–31 for which full texts and complete case details were available were only considered and analysed. Any disagreements with the details and presentation of the case were discussed among the authors who were all expert oral pathologists and resolved.

Table 1.

Demographics related to cases of adenomatoid odontogenic tumour associated with dentigerous cyst

Sl no	Author	Age/sex/year reported	Site/region involved
1.	Warter et al8	8/M 1990	Right mandibular canine and first premolar region
2.	Tajima et al9	15/M 1992	Left maxillary sinus region with crown of unerupted 28
3.	Takahashi et al10	22/M 2001	Left maxillary sinus region with left third molar
4.	Bravo et al12	14/M 2005	Left maxillary canine region
5.	Chen et al13	15/M 2007	Left maxillary canine region
6.	Nonaka et al14	13/F 2007	Left maxillary canine region
7.	John and John15	39/F 2010	Left maxillary second molar region
8.	Sandhu et al16	25/F 2010	Maxillary right sinus with impacted canine
9.	Khot and Vibhakar17	17/F 2011	Right mandibular canine to molar region
10.	Manjunatha et al18	12/M 2011	Left mandibular canine region
11.	Moosavi et al19	13/F 2011	Left mandibular lateral incisor
12.	Agarwal et al20	15/F 2012	Left maxillary canine region
13.	Singh et al21	28/F 2012	Right maxillary canine region
14.	Saluja et al22	18/F 2013	Mandibular left canine region
15.	Shivesh Acharya et al24	14/M 2014	Maxillary right canine region
16.	Geetha NT et al5	14/M 2014	Impacted left maxillary canine region
17	Valverde et al25	17/F 2014	Left maxillary canine region
18	Jitendra V Kalburge et al26	18/F 2015	Right maxillary canine region
19	Jitendra V Kalburge et al26	15/F 2015	Left maxillary canine region
20	Manjunatha et al27	20/F 2015	Maxillary left canine region
21	Manjunatha et al28	19/F 2015	Impacted mandibular left first premolar
22	Sreenivas et al4	14/M 2015	Right maxillary canine and lateral incisor
23	Sumit Majumdar29	14/F 2015	Left maxillary canine region
24.	Shika Gupta et al3	12/M 2016	Right mandibular canine region
25.	Tomar et al30	12/F 2018	Left maxillary canine region
26.	Sadiya et al	15/M 2021	Right maxillary lateral incisor and canine region

The clinical and radiological presentation validated were intraosseous location, association with impacted teeth and confirmation of a single cystic lesion on imaging. The histopathological features considered were:

1. Cystic space lined by 2–5 layers of squamous epithelium attached to the tooth with intraluminal proliferations showing solid nests of columnar or cuboidal cells arranged in nests or rosette-like areas with intervening spindle shaped cells and eosinophilic amorphous material. The squamous epithelial lining being continuous or merging with AOT areas.⁷

2. Cystic space lined by 2–5 layers of squamous epithelium with wall showing proliferation of solid nests or rosettes of columnar or cuboidal cells with intervening spindle shaped cells and eosinophilic amorphous material.¹⁰

3. Solid proliferation of columnar or cuboidal cells arranged in nests or rosettes with intervening spindle shaped cells, eosinophilic amorphous material and cystic spaces lined by 2–5 layers of squamous epithelium.¹⁰

The clinical data such as age, sex, site, radiological presentation, histopathological presentation and suggested pathogenesis for the particular histological presentation as per the criteria mentioned was extracted from all the articles and reviewed. Measures of central tendency were used to analyse the data. Most of them were associated with maxillary left canine (34.6%), seen in teenagers (73%) and three cases (11.5%) involved the maxillary sinus. Among these 17 cases (65%) presented with 2–5 layers of squamous epithelium with intraluminal proliferations of columnar or cuboidal cells arranged in nests or rosettes and the cystic lining merged with the AOT areas as seen in our case.

The main limitation of the review was that there were no set criterias defined by renowned authority such as WHO to define AOT associated with DC.

AOT itself is a rare odontogenic tumour with a 2.2%–7.1% occurrence rate.⁵ The central variant of AOT especially the follicular type is the the most common and is seen in around 71% of cases and 77% of them are associated with impacted tooth, mimicking DC clinically and radiographically.⁴ Follicular AOT associated with unerupted teeth generally shows an extension of the cystic lining below the cementoenamel junction (CEJ) whereas in DC the lining is seen attached to CEJ. In cases where AOT is associated with DC this radiographic distinction cannot be made out.²¹

AOT with CEOT like areas are common and considered as a continuous histomorphological spectrum of AOT. AOT can be associated with calcifying epithelial ghost cell cyst, odontomas and other odontogenic cysts/tumours. Such lesions are considered as histological variants of AOT.²

The rare instance of association of DC and AOT was seen in the current case, presenting as a large cystic tumour of the maxillary quadrant. It is of interest to note, if these lesions are coexisting lesions or are hybrid pathogenesis ie multiple pathologies in single lesion.^{4 7 21} The most common theory, that explains the pathogenesis, is the envelopmental theory. The theory explains the association of the erupting tooth, cyst and the AOT. The AOT tumour proliferates from rests mainly dental lamina rests close to the dental sac and later merges with the reduced enamel epithelium (REE) lining, which is the cystic lining of the DC, resulting in the tumour with a cystic epithelium around a tooth (coexisting lesions).

The various hybrid pathogenesis that should be contemplated include:

1. AOT arising from dental lamina rests of dentigerous cyst either in the wall of DC or arising elsewhere and later merging with DC lining.^{5 7}

2. Follicular types of AOT arising from reduced enamel epithelium lining of DC around an unerupted tooth with intraluminal proliferations.

3. A cystic change in pre-existing AOT.¹⁶

The suggested pathogenesis are illustrated as figure 4 (illustrations designed by one of the authors). The occurrence of multiple pathologies in the same lesion may be due to neoplastic aberrations during the process of odontogenesis. The cases and authors supporting these various concepts of pathogenesis are listed in table 2.3–5 7–31

Figure 4.

Illustrations designed by one of the authors. (A) Envelopmental theory—adenomatoid odontogenic tumour (AOT) arising from dental lamina rests (DL) close to erupting teeth. The forming AOT envelops the erupting tooth leading to AOT with dentigerous cyst (DC) lining. (B) AOT from the dental lamina rests of DC. (C) AOT arising from reduced enamel epithelium of DC lining. (D) Cystic change in solid AOT lined by DC like lining.

Table 2.

Suggested pathogenesis by various authors as prompted by case presentation

Sl no	Pathogenesis suggested	Authors in favour the concept of pathogenesis, based on the cases presented
1.	AOT arising from enamel organ cells, dental lamina cells, in the fibrous wall of DC	Takahashi et al (2001),10 Sandhu et al (2010),16 Manjunatha BS et al (2011),18 Saluja et al (2013),22 Jitendra V Kalburge et al (2015),26 Sumit Majumdar (2015),29 Sadiya et al (2021)
2.	AOT arising from lining of DC, showing intraluminal proliferations or cystic change in solid AOT	Warter et al (1990),8 Bravo et al (2005),12 Chen et al (2007),13 Nonaka et al (2007),14 Sandhu et al (2010),16 Khot and Vibhakar (2011),17 Manjunatha BS et al (2011),18 Moosavi et al (2011),19 Anisha Agarwal et al (2012),20 Vikramjeet Singh et al (2012),21 Valverde et al (2014),25 Jitendra V Kalburge et al (2015),26 Manjunatha et al (2015),27 Sreenivas et al (2015),4 Shika Gupta et al (2016),3 Tomar et al (2018)30
3.	Neoplastic aberrations can occur in any stage of odontogenesis, combined features of odontogenic tumours with epithelial and mesenchymal components may arise within odontogenic cysts. Thus cases of AOT associated with DC	Tajima et al (1992),9 Geetha NT et al (2014),5 Manjunatha et al (2015),27 Anisha Agarwal et al (2012),20 Vikramjeet Singh et al (2012)21
4.	Envelopmental theory hypothesis proposes that AOT grows next to or into a nearby dental follicle while forming a cystic space that is lined by DC like epithelium-coexistent theory	Philipsen et al, Takahashi et al (2001),10 John and John et al (2010),15 Shivesh Acharya et al (2014)24

The clinical presentation and behaviour of conventional AOT or DC is usually not aggressive and calls for conservative treatment. But a cystic lesion associated with AOT might present an aggressive behaviour, spread widely and show recurrence.¹⁶ The presence of clear cells is also an uncommon finding. In instances where it is PAS (glycogen) positive, aggressive behaviour of the lesion can be expected.³² In the present case, a large number of clear cells were found, but were found to be PAS-negative. Probably clearing was mainly a degenerative activity, which requires and allowed a conservative line of treatment and therapy.

In the present case of AOT a step-up was seen in the differentiation of the ameloblast-like cells. Generally, in AOT the tall ameloblast-like cell participates in the formation of duct like structures, but in the present scenario the ameloblasts were seen differentiating in larger number and aggregates. These ameloblast-like cells, showed nuclear polarisation and granular cytoplasm. The ends of ameloblast-like cell were inducting multiple tumour-like droplets. Such a level of differentiation and pattern of induction is not frequently reported in AOTs previously.

This case report draws our attention towards a rare association and/or conversion of DC into AOT and a still rarer association of a large number of clear cells. Clear cells were also seen in the case reported by Khot et al.¹⁷ It might be the first reported case of a clear cell AOT with DC along with an impacted lateral incisor & canine teeth. Such associations open up the pathogenetic theories of odontogenic cysts and tumours to be coexistent or hybrid pathologies or a complete new entity. This calls for a deeper insight into development of odontogenic cysts, tumours and their association in planning the management options to be followed.²⁴

Learning points.

• The present report and review describes another addition to previously diagnosed cases of AOT arising from DC.

• The whole of the lesion was cystic and lined by DC-like epithelium with areas showing luminal proliferation of AOT thus supporting the concept of considering AOT arising from DC to be another variant of AOT—a hybrid variety.

• It calls for a careful search of whole of the cystic lining to rule out a possibility of tumour arising out of the cystic epithelium.

• It opens up debate on the pathogenetic theories related to AOT associated with DC.

• Evaluation of clear cells in AOT or any other odontogenic tumours is important to recognise the aggressiveness of the pathology.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).