Metamorphosis of Dentigerous cyst: A case Series with Insight into Molecular Profiling

Abstract

The objective of this study was to review the clinical, radiologic, and histologic aspects of cases of dentigerous cysts metamorphosing into different entities along with comments on the molecular factors involved in the process. A series comprising 8 cases of dentigerous cysts was performed retrospectively along with a comprehensive literature review. Two cases of dentigerous cyst converting into mucous metaplasia were included, out of which one case was transformed into ameloblastoma after a year. The other two cases were reported as acanthomatous and unicystic ameloblastoma, whereas four transitioned to AOT. The complete review of cases and literature with molecular profiling concluded that the lining of dentigerous cysts has the potential for transforming into benign odontogenic tumors. Therefore, a careful clinical and histopathological examination is crucial for the correct diagnosis. Also, a thorough molecular understanding of the cystic lining is required.

Introduction

Dentigerous cyst (DC), also known as the follicular cyst is reported as one of the most frequently occurring developmental cysts in the oral cavity [1]. Paget et al. were the first to define the term “dentigerous cyst” as a cyst bearing a tooth [2]. It is thought to be derived from the epithelium of the growing enamel organ, although other researchers have found that embryonic remains of the enamel organ in the periodontal membrane can give rise to the cyst [3, 4].

Clinically, DCs are typically asymptomatic, but they can expand significantly leading to cortical expansion and erosion. They are more common in male patients in their second and third decades of life, according to reports [5]. They often appear as well-circumscribed, unilocular, symmetric radiolucency associated with the crowns of mandibular third molars and maxillary cuspids on radiographs. The cyst is bordered by non-keratinized stratified squamous epithelium, which may contain mucous cells, ciliated cells, and, in rare cases, sebaceous cells [6]. Even though recurrence of DC is rare, it may occasionally give rise to a variety of odontogenic tumors, prominently ameloblastoma (AMB), adenomatoid odontogenic tumor (AOT), complex odontoma, and malignant tumors like squamous cell carcinoma and mucoepidermoid carcinoma. Studies have shown that neoplastic and hamartomatous aberrations during odontogenesis may lead these tumors to develop from pre-existing odontogenic cysts [7, 8].

In this review, we provide our institutional experience of cases of DC reported between 2017 and 2022, manifesting as mucous metaplasia, transforming into ameloblastic variants, and adenomatoid odontogenic tumor (AOT). We further contend that the conversion spectrum, which now only includes mucous metaplasia, AMB, and AOT, should be expanded to encompass new entities. With a focus on the pathophysiology and clinicopathologic characteristics, this article aimed to study DC and its related lesions.

Methods

The diagnostic database of the Department of Oral Pathology and Microbiology, King George’s Medical University, Lucknow, was searched for cases with the diagnostic code of DC (as a definitive diagnosis). Cases of odontogenic cysts that had been histopathologically diagnosed were included, and the DCs that had shown conversions were isolated and thoroughly examined by two different observers. Clinical information including age, gender, and location of the tumor was gathered from 2017 to 2022, and radiology, as well as histopathology reports, were comprehended. In parallel with the study of our single institution’s experience with DC and its related lesions, we attempted to explore the literature on the pathogenesis and clinicopathologic parameters of DC transformation.

Results

The five-year analysis revealed a total of 214 odontogenic cysts out of which 135 were inflammatory and 79 were developmental in nature. Out of the 79 developmental odontogenic cysts 26 were diagnosed as DC, among which potential complications were perceived in 8 cases. Two cases (1 and 2) showed transformation into mucous metaplasia, out of which case 2 later transformed into Follicular AMB (2’). Two cases transformed into AMB (acanthomatous and unicystic variants), while four cases converted into AOT (Table 1).

Table 1.

Demographic details of Dentigerous cyst with metamorphosis variants

Cases	Age/Years	Sex	Site	Clinical Features		Radiographic Details (Panoramic View)		Histological Features	Metamorphosis Variant
				Inspection	Palpation	Appearance	Extent
Case 1	57	M	Right posterior mandible	Localized, bluish color dome-shaped swelling	Non-tender, compressible, soft consistency	Well-defined, unilocular radiolucency	Lower right gingival alveolus region	Squamous and mucous cells in cystic wall	Mucous Metaplasia
Case 2	20	F	Left posterior mandible	Diffuse bony hard swelling	Non-tender, hard consistency	Unilocular, well-defined radiolucency	37 to angle of mandible	Squamous and mucous cells in cystic wall.	Mucous metaplasia
Case 2’	20	F	Left posterior mandible	Diffuse bony hard swelling	Non-tender, hard consistency	Unilocular, well-defined radiolucency destruction of cortical bone	34 to angle of mandible	Peripheral ameloblast-like cells and central stellate reticulum cells. Areas of cystic degeneration and squamous metaplasia.	Follicular AMB
Case 3	19	M	Left posterior mandible	Diffuse bony hard swelling elliptical shape	Non-tender, hard consistency	Well-defined radiolucency	From 36 to 37	Peripheral ameloblast-like cells and central stellate reticulum cells Squamous metaplasia in center	Acanthomatous AMB
Case 4	24	F	Left anterior mandible	Diffuse bony hard swelling	Non-tender, soft consistency	Well-defined unilocular radiolucency	From 33 to 43	Intraluminal proliferation of cystic epithelium into CT stroma	Unicystic AMB
Case 5	13	F	Left anterior maxilla	Diffuse bony hard swelling elliptical shape	Non-tender, hard consistency	Well-circumscribed radiolucency impacted deciduous canine	From 23 to 25	Encapsulated area arranged in pseudo-glandular pattern lined by single layer of columnar cells with nucleus polarized away from lumen i.e., lined by eosinophilic rim	AOT
Case 6	12	F	Right anterior maxilla	Diffuse bony hard swelling	Non-tender, hard consistency	Well-circumscribed radiolucency	distal root of 36 to anterior border of left ramus	monomorphic spindle cells in rosette arrangement with plump nuclei and numerous duct like proliferation	AOT
Case 7	13	F	Left posterior maxilla	Diffuse bony hard swelling oval shape	Non-tender, hard consistency	Ill-defined radiolucency	From 26 to 27	Proliferation of tumor islands into lumen with monomorphic spindle cells, plump nuclei arranged in whorls and numerous duct like structure	AOT
Case 8	13	F	Left anterior maxilla	Dome-shaped swelling elevation of nasolabial fold facial asymmetry	Tender, soft consistency	Well-defined, unilocular radiolucency Impacted 12 and 13	Left alae of nose to anterior border of zygomatic bone	Multiple nodules of spindle cells in whorl and numerous duct-like structures with cuboidal cells and eosinophilic coagulum	AOT

2’: recurrence of case 2 with complication, AMB: Ameloblastoma, CT: Connective tissue, AOT: Adenomatoid odontogenic tumor

Demographic Data

The age range of 8 cases showing complications was between 10 and 24 years with a mean of 17 years, while only one case was 57 years of age. The incidence was seen in 6 females and 2 males in the ratio of 3:1. In three cases mandibular posterior, three cases anterior maxilla, one case anterior mandible, and one case posterior maxilla regions were involved. There was a side predilection as out of 8, six happened to be on the left side and two on the right side [Figure 1]

Fig. 1.

(A) Gender distribution of dentigerous cyst cases in this study (B) Age distribution of dentigerous cyst cases in this study

Fig. 2.

Flowchart depicting the mechanism of action and genes related to the metamorphosis of dentigerous cyst

Clinical Features

In all 8 cases, facial asymmetry due to extraoral swelling was present. In all seven cases, the swelling was non-tender whereas one case of AOT was tender. On palpating, five of the cases were hard in consistency, whereas each case of mucous metaplasia, unicystic AMB, and AOT was soft in consistency. Sentinel lymph nodes were not palpable.

Radiologic Features

Well-defined unilocular radiolucency was observed in seven cases whereas only one case showed ill-defined radiolucency along with irregular margins observed in AOT. All the cases were associated with an impacted tooth with attachment at the cementoenamel junction (CEJ) [Fig. 3].

Fig. 3.

(A) Panoramic view showing large unilocular radiolucency with well-defined borders and destruction of cortical bone in the left mandibular ramus with impacted 38 (B) Panoramic view showing large unilocular radiolucency with well-defined borders and destruction of cortical bone in the right anterior maxillary region with impacted 13 (C) Cone beam computed tomography imaging of massive destruction of cortical bone in left mandibular ramus region

Histopathological Features

Initially, the two cases of mucous metaplasia were presumed to be either glandular odontogenic cysts (GOC) or mucoepidermoid carcinoma (MEC) both exhibiting clinical characteristics that are different from those of DC. Differentiating MEC and GOC from DCs with mucosal metaplasia has therapeutic and prognostic significance. It resembled MEC because of the high number of mucous cells present as a result of metaplastic alterations, but there were no elements that matched intermediate cells or squamous cells. Also, with the help of p63 myoepithelial immunohistochemical marker, the possibility of MEC was excluded due to negative expression in both the aforementioned cases. GOC is a rare lesion with a varying width of epithelium, numerous papillary projections, mucous goblet cells, and hob-nail cells with an apocrine-like snouting [9]. However, in the current instance, mucous cells with reduced enamel epithelium-like cells are evident throughout. Therefore, the final diagnosis was given as the dentigerous cyst showing mucous metaplastic changes.

Three cases of AMB proliferating from the lining of DC were documented in the current context with one case originating from mucous metaplasia. Proliferation was discovered intraluminally from the lining epithelium of DC, forming a stellate reticulum comprising peripheral columnar cells with a palisading appearance and reverse nuclear polarity in the follicular type. In the second type of AMB, extensive squamous metaplasia along with keratin production in the epithelial islands of follicular AMB was described as an acanthomatous type originating in the DC lining. The cystic aspect of the DC lining was the most obvious finding in one instance, and its periphery was lined with ameloblastomatous epithelium, diagnosed as unicystic AMB originating from the DC lining.

The challenge of determining the correct diagnosis based on the radiograph and histopathology is what renders the current series interesting and relevant, whether it was a DC that developed into an AOT or cystic changes within AOT. The follicular type of AOT can be challenging to differentiate on radiographs from other cystic tumors, such as DC, unicystic AMB, OKC, or calcifying cystic odontogenic tumor (CCOT). Hence, the diagnosis is exclusively histological. The cystic lining of non-keratinized stratified squamous epithelium with localized areas of the luminal proliferation of islands of spindle-shaped and pseudo-glandular cells was present in all four cases of conversion into AOT. Noteworthy would be the occurrence of calcifying epithelial odontogenic tumors (CEOT) like areas in AOT which was believed to be an altered phenotype in some portions of the tumor. A rare variation of AMB called adenoid ameloblastoma with dentinoid (AAD) can also be misinterpreted as an AOT. Although, the typical presentation of this tumor is as a cystic odontogenic tumor with signs of plexiform AMB containing tubular dentin and odontoblastic differentiation, neither of which was present in our case [Fig. 4].

Fig. 4.

Characteristic histopathologic features observed in the present dentigerous cyst series. (A) Transition of a typical dentigerous epithelial lining into mucous metaplasia (original magnification X10). (B) Unicystic ameloblastoma arising from thin non-keratinized epithelium of dentigerous cyst (original magnification X10) (C) DC revealing conversion into AOT with tumor proliferation (original magnification X4) (D) Acanthomatous Ameloblastoma arising from dentigerous cyst lining with central cells showing squamous differentiation (original magnification X10) (E) Proliferation of dentigerous cyst lining leading to formation of ameloblastic follicles in the CT stroma (original magnification X10) (F) AOT histology demonstrating duct or rosette-like structures with focal luminal eosinophilic material (original magnification X40)

Discussion

Odontogenesis is an intricate process where malignant or hamartomatous lesions can emerge at any step. The odontogenic epithelium surrounding impacted teeth has a large range of tissue types that can differentiate into a cyst or tumor. Among the odontogenic cysts, DC lining consists of mucus cells, sebaceous cells, respiratory-type epithelium, and even lymphoid follicular-type tissue. Few cases in the literature demonstrated the epithelium of DC having a neoplastic propensity for developing AMB and AOT [10].

The current case series deals with eight separate cases with DC as the primary pathology. Among the concomitant lesions are two mucous metaplasia, three cases of AMBs, and four cases of AOT. In the current series, we discovered a correlation between the development of mucous metaplasia from a conventional DC lining epithelium and the subsequent development of an AMB whereas in other cases the emergence of mural ameloblastoma nodules was evident in DC lining. These patients were diagnosed as DC both clinically and radiographically. However, the true nature of these lesions could only be revealed following a thorough histopathologic examination of the tissue.

Mucous and ciliated cells are believed to exist as a result of metaplasia. However, uncertainty persists regarding the etiology and biological importance of this condition. Both inflammatory and developmental cysts of the mandible can contain mucous cells, with or without ciliated cells [11]. In the included cases, various numbers of clear or vacuolated cells were observed near the mucous cells in the cases showing mucous metaplasia. It is believed that during the first stages of metaplasia, the keratinocytes become vacuolated and mucin granules begin to emerge and aggregate within some vacuolated cells, ultimately producing mucous cells [12]. It may be related to the shared origin of odontogenic structures and salivary glands (mucous cells), as evidenced by similarities in the mucin characteristics of mucous cells in odontogenic cysts and salivary glands [13].

Robinson et al. [14] proposed that as the epithelium of odontogenic cysts and AMB have a common ancestry, a transition from a non-neoplastic cyst to a neoplastic one could be possible, even though it has been reported rarely. Earlier etiologic factors proposed for AMB arising from odontogenic cysts were nonspecific irritational factors like extraction, trauma, infection, nutritional deficit disorders, or viral infections. But recent investigations claim the odontogenic etiological origin of AMB, supported by similarities in the expression of cytokeratin and vimentin between the odontogenic epithelium, cyst, and AMB. The immunohistochemical results on Ki-67 expression in AMBs that develop from DC support the idea that these tumors have a biological behavior comparable to primary AMB [15]. Researchers also revealed that elevated osteopontin (OPN) and CD10 expression cause increased neoplastic potential in DC and AMB. Also, elevated expression of OPN in AMB has locally invasive behavior and high osteolytic ability [16, 17]. The expression of p53, fragile histidine triad (FHIT) has been studied in a range of odontogenic lesions, including dental follicles, AMB, and DC [18]. Several genes such as PTCH, MMP2, and MMP9 have been reported to be dysregulated in DC as well as AMB samples [19, 20]. This states that genetic polymorphisms may increase the risk of DC transforming into AMB. Hence, it is crucial to comprehend the events taking place at the molecular level and the clinical behavior of the cysts, to gain insight into the nature of the DC. Figure 2 depicts the mechanism of action and genes involved in the process of metamorphosis of dentigerous cysts. Additionally, the walls of DC may have proliferation like AMB but can lack the peculiar appearance of peripheral cells of true AMB. Hence, small mural thickenings of the cyst wall of DC may contain proliferating odontogenic epithelium, and these strands also may show follicular enlargements that can be identified by using various expression profiling methods. On the contrary, Shear asserted that AMB and DC have similar clinical and radiographic features and may be incorrectly interpreted on radiographs. When subsequently the lesion is removed and diagnosed histologically as an AMB, the erroneous conclusion may be reached that it is developed from DC [6]. The presence of DC cystic lining distant from the neoplastic epithelium and the unerupted tooth in our case implies that DC is transforming into AMB.

Adenomatoid odontogenic tumors are uncommon benign epithelial odontogenic tumors that primarily affect the maxilla and are derived from the odontogenic epithelium. It frequently encapsulates and reflects a quiescent clinical behavior. The DC epithelial lining may develop into an odontogenic tumor that resembles an AOT [21]. The current cases are particularly fascinating due to the histological characteristics of DC lining, which are present in conjunction with AOT in the form of nodules and rosettes, validating the transformation of cystic lining to neoplasm, and the multifocal cellular proliferation representing a typical glandular and mural development in the lining of DC. However, it is not evident if the lining of an associated cyst genuinely corresponds to a DC or a cystic change within an AOT, or a completely distinct entity. Although previous research has shown that AOT develops from a sophisticated system of dental laminae or their remnants, the histogenesis of pseudo-ductular structures showed invaginations of odontogenic epithelium. According to a hypothesis, the ectomesenchymal stroma carried by the epithelium is largely deprived of blood supply, causing its atrophy or necrosis, while the stroma that survives at the edge of the pseudo-ductular structures retains its inductive ability and encourages the columnar cells to lay down the pre-dentine matrix [22].

Recent studies on AOT indicated that transcription factor SHH and its receptors were present in pseudo-glandular neoplastic cells and GLI1 in the base membrane of a rose-like structure, PTCH, and SMO. Further research on the proliferative mural nodules of DC can help establish a link between SHH, PTCH, SMO, or GLI1 expression as it has been observed in the lining of DC, which opens up the possibility of treating patients with odontogenic tumors by blocking SHH signaling that could be a truly innovative treatment strategy [23]. According to Hinds et al. [24] in 1989, another theory is that the change of DC to AOT may be caused by mutations that cause the p53 proto-oncogene to cease its function. Given that the p53 gene is a tumor suppressor gene and is crucial for controlling cell proliferation, four key signaling groups, including Transforming Growth Factors (TGF), Fibroblast Growth Factors (FGF), Hedgehogs (Hh), and Wingless (Wnt), are involved in normal genetic control and any change in the route of these genes have been associated with a range of disorders. According to the genetic information now available, 70% of AOT have KRAS G12V/R KRAS codon 12 mutations, which are somatic oncogene mutations. The immunoexpression of the surrogate marker ERK1/2 phosphorylated form is evident, which is a sign of MAPK/ERK pathway activation, and was seen even in tumors with the wild-type version of the KRAS gene. In DC, similar phosphorylation mechanisms have also been found. If proliferative DC areas are subjected to molecular profiling or immunohistochemistry, potential progression towards odontogenic tumors can be identified at an earlier stage before it could lead to a life-threatening malignancy. Research focusing on targeted therapy, and MAPK/ERK cross-interactions with other signaling pathways may hold promising results in the future [20].

Treatment Outcome and Recurrence

In the first two cases of mucous metaplasia, cyst enucleation was initially combined with tooth extraction under local anesthesia. However, one of the cases did recur and, in a year, the same patient developed follicular AMB. These results suggest that odontogenic cysts may represent an initial or intermediate step in the development of the benign odontogenic neoplasms. The histological type, therapeutic approach, and tumor location may all have an impact on recurrence [25]. Both conservative and radical methods can be used to treat AMB, but the recurrence rate after conservative treatment is higher than in aggressive treatment [26]. Therefore, in our case, radical methods were preferred for all cases of AMB. The radical procedure involved segmental or marginal excision of healthy bone 1–2 cm beyond the radiological/ clinical boundary. During the post-treatment follow-up, no sign of recurrence was discovered. According to the literature, recurrence rates following radical surgery were 7.1% and 33.3% after conservative treatment [26]. According to Infante-Cossio et al., the solid/multicystic subtype is more aggressive and recurrent than the unicystic subtype, accounting for more than 80% of all cases [27]. In the current case of unicystic AMB, the tumor was proliferating intra-luminally, therefore aggressive surgery was performed whereas four AOT cases responded favorably to conservative treatment due to their indolent nature and non-invasive character, as well as the presence of a capsule. Enucleation and curettage were performed with impacted teeth being extracted in each case. For one of the cases, the Partsch II Technique with immediate suture was used and in neither of the cases, recurrence was reported.

Conclusion

The establishment of diagnostic criteria for a tumor is an evolving procedure, and the description and acceptance of its entities are impeded to some extent by a lack of sufficient molecular techniques to validate or disprove the placement of a specific tumor and its metamorphosis as a distinct entity. Further research into the possibility of small mural thickenings of the cyst wall of DC with proliferating odontogenic epithelium transforming into various tumors must be explored with molecular profiling or immunohistochemistry. This also highlights the importance of paying close attention to anatomical variety, gross specimen sectioning, and comprehensive histopathologic evaluation of biopsy specimens, which can reveal the enigma of tumor genesis. As a result, this needs to be investigated further with additional cases. Given the scarcity of reported cases, it was unable to predict if numerous diseases occurring in a single lesion could represent a separate variation. Thus, if precise diagnoses are confirmed, we can predict the metamorphosis of cysts in the early phases for the welfare of the patient.

Authors’ Contributions

All the authors contributed significantly to this manuscript.

Funding

Not Applicable.

Data Availability

Not Applicable.

Code Availability

Not Applicable.

Declarations

Conflicts of Interest/Competing Interests

The authors declare that they have no known conflict of interest.

Ethics approval

Not Applicable.

Consent to Participate

Not Applicable.

Consent for Publication

Not Applicable.