Developmental Odontogenic Lesions Associated with the Crown of an Impacted Tooth: A Guide to the Distinct Histologic Features Required for Classification

Abstract

Odontogenic cysts are categorized as inflammatory and developmental. Of the developmental odontogenic cysts, the dentigerous cyst is the most common and by definition is attached to the cervical region of an unerupted tooth. The cyst envelops the crown forming a sac. However, there are other developmental cysts, and rarely, odontogenic tumors, that can have a similar clinical and radiographic presentation as dentigerous cyst, including odontogenic keratocyst, orthokeratinized odontogenic cyst and ameloblastoma, unicystic type. Understanding the key histologic differences of these cysts will aid the pathologist to correctly diagnose these lesions, ensuring appropriate clinical management.

Introduction

Developmental odontogenic cysts, although common, may present diagnostic challenges to pathologists unfamiliar with the clinical, radiographic, and histologic differences. These challenges are compounded when the lesion is associated with the crown of an impacted tooth as the clinical and radiographic presentation of developmental odontogenic lesions are often indistinguishable. The dentigerous cyst is the most common developmental cyst and by definition is an odontogenic cyst attached at the cemento-enamel junction, forming a sac around the crown of the tooth. Although not always associated with an impacted tooth, other odontogenic cysts, including odontogenic keratocyst (OKC), orthokeratinized odontogenic cyst (OOC), and although technically a tumor, ameloblastoma, unicystic variant, can share a similar presentation to dentigerous cyst. Recognizing the key histologic features of the various odontogenic cysts associated with the crown of an impacted tooth will aid in arriving at the correct diagnosis and appropriate clinical management.

Case Presentation

A 46-year-old female presented for routine dental examination. Panoramic radiograph revealed a radiolucent lesion in the right mandible presumed to be a dentigerous cyst. Upon surgical extraction the surgeon encountered a cyst associated with the crown of an unerupted third molar containing abundant intraluminal keratinaceous debris. The specimen was submitted for microscopic evaluation labelled as “rule out OKC”. The panoramic radiograph shows a large, expansile, well-demarcated unilocular radiolucency with smooth, corticated margins (Fig. 1). The radiolucency was associated with the crown of a full-bony, horizontally impacted third molar. No resorption of the roots of the adjacent tooth is present. Low-powered histologic examination shows a cyst with a thin, uniform epithelial lining, surfaced by orthokeratin (Fig. 2). A prominent granular cell layer is noted, and rete ridges are absent. The cyst lumen contains numerous flakes of keratin. The cyst wall is composed of dense fibrovascular connective tissue. No evidence of nuclear palisading of the basal cells or reverse polarity is seen (Fig. 3).

Fig. 1.

Panoramic radiograph shows a well-defined unilocular radiolucent lesion associated with a full bony impacted third molar in the right mandible

Fig. 2.

Low-magnification photomicrograph shows a cyst with abundant keratin flakes with the cyst lumen. H&E stain, original magnification X4

Fig. 3.

The cyst is of uniform thickness with marked orthokeratosis and a prominent granular cell layer with a fibrous connective tissue wall. H&E stain, original magnification X10

Discussion

The primary differential diagnosis when encountering an odontogenic cyst with abundant keratin is an odontogenic keratocyst (OKC), particularly when the specimen is labelled as “OKC” by the surgeon due to the keratinaceous debris encountered at the time of surgery. As early as 1910, the French pathologist Malassez gave the first microscopic description of a cyst composed of a very thick orthokeratinized layer and prominent granular cell layer with abundant keratinaceous debris from a surgical specimen reported in 1886 by Jeannel as “Kyste dermoїde” [1]. The term orthokeratinized odontogenic cyst (OOC) was first coined by Wright in 1981 as a variant of odontogenic keratocyst (OKC) [2]. Subsequent studies have demonstrated that the OOC does not share the clinical behavior, histologic characteristics, PTCH1 gene mutation, nor association with the nevoid basal cell carcinoma syndrome (NBCCS) seen in OKC [3–7]. The OOC is much rarer than OKC, accounting for about 1% of all odontogenic cysts compared to OKC which accounts for up to 20% of odontogenic cysts [6]. The exact pathogenesis of OOC is unknown but is thought to arise from remnants of the dental lamina [6]. There is a male predominance and the average age of presentation is the third to fourth decade [8]. The posterior mandible is the most common location for OOC and up to two-thirds of the reported cases are associated with an unerupted tooth [4, 7, 9]. Up to 50% of OOC are asymptomatic and > 90% of cases present as a well-demarcated unilocular lesion [6, 8–10]. Most OOC are solitary, but cases of multiple OOCs have been reported. However, to date, loss of heterozygosity of the PTCH gene has not been reported in OOC [9].

Although the OOC has distinctive histologic features, the presence of abundant keratin may mislead the pathologist to diagnosis the cyst as OKC. The OOC is characterized by a thin, uniform epithelium of 5–9 cell layers, lacking rete ridges. Thick, lamellated orthokeratin is present on the surface and a prominent granular cell layer is seen (Fig. 3). These microscopic features are similar to cholesteatoma and epidermal inclusion cyst. The basal cells lack palisading and hyperchromatic nuclei (Fig. 4a). These histologic characteristics contrast with OKC which shows corrugated parakeratin, lacking a granular cell layer, with prominent palisaded and hyperchromatic nuclei (Fig. 4b). Other histologic findings in OKC include budding of the basal layer. The dense fibrous connective tissue wall usually lacks inflammation unless secondarily inflamed which may be the result of prior biopsy or marsupialization [11]. Both OOC and OKC can lose their typical histologic phenotype when inflamed. In both cases the lining may show nonspecific stratified squamous epithelium with or without epithelial hyperplasia (Fig. 5). However, on careful examination of the specimen, typical histologic features of OOC or OKC can usually be noted. On occasion odontogenic rests and/or nests of OOC can been seen in the wall. Unlike daughter cysts of OKC, these nests recapitulate the histologic finding of OOC (Fig. 6a). The satellite or daughter cysts of OKC are more commonly seen in syndromic OKC (Fig. 6b).

Fig. 4.

On higher magnification, the distinct histologic differences between OOC (a) and OKC (b) are apparent. The OKC shows parakeratin with a slight corrugated surface, and hyperchromatic, palisading basal cells. c The dentigerous cyst is characterized by nonkeratinized epithelium of uniform thickness. The cyst wall may be fibrous as illustrated here, or fibromyxoid (see Fig. 6c). d Characteristic features of unicystic ameloblastoma with reverse polarity (black arrows) and overlying loosely arranged cells. H&E stain, original magnification x20

Fig. 5.

Secondary inflammation can alter the typical histologic features of OOC (a) and OKC (b), but upon careful review will generally show diagnostic features. H&E stain, original magnification X10

Fig. 6.

Satellite cysts are more commonly seen in OKC (b) than in OOC (a). Notice that in OOC the histologic features including orthokeratin (blue arrow) are retained. Occasional odontogenic rests (black arrows) are noted in the cyst wall, a common feature of cysts associated with impacted teeth. The satellite or daughter cysts of OKC (b) preserves the feature of parakeratin (asterisk) and palisaded basal cells. Quiescent odontogenic rests or cords (black arrows) may be present in dentigerous cyst (c). When there is mural involvement of unicystic ameloblastoma the islands of odontogenic epithelium show the typical features of hyperchromatic nuclei with peripheral palisading and reverse polarity (black arrow) (d) H&E stain, original magnification X20

Immunohistochemistry studies comparing OKC and OOC has shown differences between these two entities. Higher Ki67, p63, and cyclin D1 expression has been reported in OKC compared with OOC [8]. The treatment of OOC is simple enucleation and recurrence rates of OOC are less than 2%.

As mentioned above, not only does OKC have histologically distinct features from OOC, but molecular and clinical differences in behavior are seen. Most OKCs are sporadic, but up to 5% of cases are associated with the nevoid basal cell carcinoma syndrome (NBCCS) [12, 13]. The PTCH1 gene inactivation has been identified in about 90% of OKCs [14]. Less common are gene mutations in SUFU and PTCH2, which are part of the sonic hedgehog (SHH) signaling pathway. OKCs associated with NBCCS are usually multiple, involving all jaw quadrants and occur in a younger age group. In contradistinction to OOC, OKC is associated with recurrences as high as 25% [15]. Recurrence rates are dependent on surgical management of OKC. Treatment includes marsupialization ± cystectomy, decompression ± cystectomy, and enucleation followed by Carnoy’s solution. Long term follow-up is recommended in patients with a history of OKC, particularly in syndromic patients.

Unlike the OKC and OOC which does not always occur in the setting of an impacted tooth, by definition the dentigerous cyst is the most common developmental odontogenic cyst associated with an impacted tooth. The vast majority of dentigerous cysts are associated with unerupted third molars, but can also be associated with impacted maxillary canines, maxillary third molars, and maxillary premolars. The cyst is attached at the cemento-enamel junction, where the crown of the tooth and root meet. Dentigerous cyst are lined by nonkeratinizing epithelium of uniform thickness of 2–4 cell layers, overlying fibrous or fibro-myxoid stroma (Fig. 4c). Small odontogenic rests may be seen, more commonly when the stroma has a myxoid character (Fig. 6c). Scattered mucous cells, cilia, hyaline bodies, and calcifications can be encountered in the cyst lining. If secondarily inflamed the epithelium can become hyperplastic and/or ulcerated with degenerating epithelial cells, keratin, and inflammation in the cyst lumen. If the dentigerous cyst lumen has abundant cellular debris and cholesterol clefts the surgeon may misinterpret the cyst clinically as an OKC [16]. Treatment of dentigerous cyst is enucleation with extraction of the impacted tooth.

Finally, in the clinical and radiographic differential diagnosis is ameloblastoma, technically an odontogenic tumor. Second only to odontomas, ameloblastomas account for about 10% of all odontogenic tumors. Ameloblastomas are benign tumors but can have aggressive growth characteristics and a propensity for local recurrence. Ameloblastomas are subdivided into the conventional (solid/multicystic) type or unicystic type. Both conventional and unicystic ameloblastomas (UA) are often associated with BRAF V600E mutations, and less commonly, mutations such as KRAS, NRAS, HRAS, FGFR2, and SMO [17]. Conventional ameloblastoma and unicystic ameloblastoma can be associated with impacted teeth, particularly mandibular third molars, however the majority of UA have this clinical presentation [18, 19]. UA presents in a younger age group with 50% of cases reported in patients in the second decade of life in contrast to conventional ameloblastoma which has a peak incidence in the fourth and fifth decades [18, 19]. Unicystic ameloblastoma has characteristic histologic features that will allow the pathologist to readily distinguish this cyst from other cysts associated with the crown of an impacted tooth. Three histologic growth patterns of unicystic ameloblastoma are recognized: luminal, intraluminal, and mural [18]. The purely luminal variant is most associated with an impacted tooth, presenting clinically and radiographically as a dentigerous cyst. The epithelium has the characteristic peripheral palisading and nuclear polarization (reverse polarity) seen in ameloblastoma (Fig. 4d). Overlying the basal cells may be vacuolated cells and loosely arranged epithelium reminiscent of the stellate reticulum. When unicystic ameloblastoma is purely luminal without intraluminal extension into the cyst the diagnosis can be challenging, particularly on a small biopsy or if secondary inflammation is present. Mural involvement of unicystic ameloblastoma is common, requiring thorough examination of the submitted specimen as a biopsy may not be representative. The ameloblastic islands in the cyst wall recapitulates the typical findings of ameloblastoma (Fig. 6d). There is lack of consensus on the treatment of unicystic ameloblastoma [17, 20–22]. Conservative management is generally recommended for the treatment of unicystic ameloblastoma, however long term follow up is prudent given the potential for recurrence, even after decades [22].

Conclusion

Although the dentigerous cyst is the most common cyst surrounding the crown of an impacted tooth, awareness of clinical and radiographic mimics, along with the distinct histologic differences will result in appropriate patient management. Both OOC and dentigerous cyst are adequately treated with enucleation of the cyst with tooth removal and no long term follow up is required. In contrast, due to the propensity for recurrence, the OKC and unicystic ameloblastoma requires long term clinical and radiographic monitoring as recurrences can arise several years after the initial presentation and treatment.

Funding

No external funding was obtained for this study.

Compliance with Ethical Standards

Conflict of interest

The author declares that they have no conflict of interest as it relates to this review paper.

Ethical Approval

This review article was performed in accordance with ethical standards and did not require informed consent.