Introduction

Primordial odontogenic tumor (POT) is a rare mixed epithelial-mesenchymal neoplasm that was first described by Mosqueda-Taylor et al. [1] in 2014 and recognized by the World Health Organization in 2017 [2]. There are now twenty-three cases reported in the literature [1, 3,4,5,6,7,8,9,10,11,12,13,14,15,16]. This tumor has a predilection for children and adolescents and usually presents as a radiolucency in the mandible [17]. Histopathologically, POT consists of abundant fibromyxoid stroma with spindled and stellate-shaped cells resembling dental papilla. The tumor mass is surfaced by epithelium resembling enamel epithelium characterized by cuboidal to columnar cells with reverse nuclear polarization. Conventional treatment of POT is enucleation or excision with removal of the involved tooth, and there have been no reported recurrences [4, 17].

This is a report of a recurrent POT, the first that we are aware of in the English literature, emphasizing the clinicopathological characteristics and features that distinguish the current case from other reported POTs.

Case Report

A 19-year-old Hispanic female presented with a swelling on the right side of her face of 4-month duration. The patient had a POT excised four years ago in the same area, and this case had been previously reported in 2018 [7]. The patient had been lost to follow-up until this visit. Radiographic examination revealed a 4.5 × 4.0 cm well-demarcated, multilocular radiolucency in the area of missing right mandibular molars (removed during previous surgery) with extension to involve the entire right ramus (Fig. 1). The patient underwent right hemi-mandibulectomy from the right first premolar posteriorly with disarticulation. Mandibular reconstruction was performed, and a prosthetic condyle was placed (Fig. 2).

Fig. 1
figure 1

Panoramic radiograph revealed a well-demarcated, multilocular radiolucency, measuring 5.5 × 4.0 cm in the right posterior mandible, in the area of missing right mandibular molars, extending to the right ramus and causing perforation of the superior cortex

Full size image
Fig. 2
figure 2

Panoramic radiograph after tumor resection with the mandible reconstruction plate and condyle replacement

Full size image

Gross examination of the resected mandible showed a multilobulated tumor with perforation of the buccal and lingual cortical plates and extensive involvement of the ramus and the inferior portion of the coronoid process (Fig. 3, upper images). The tumor was a yellow to tan multilobulated mass with a bosselated surface, with gelatinous and solid components (Fig. 3, bottom image). Histological examination revealed a partially encapsulated tumor with both epithelial and primitive, and cellular ectomesenchymal components with cystic change, and myxoid stroma (Fig. 4A). The tumor had an undulating surface and was covered by epithelium that formed deep invaginations (typical appearance of a POT), but also contained organoid structures that resembled rudimentary enamel organ-like structures (Fig. 4B). The epithelium was composed of columnar cells with clear cytoplasm and ovoid-to-round nuclei exhibiting reverse nuclear polarization, resembling ameloblasts or enamel epithelium; it was sometimes associated with stellate reticulum; there was no evidence of nuclear atypia or mitotic figures (Fig. 4C). There was subepithelial cellular condensation of mesenchymal cells forming a cambium layer (Fig. 4C). The epithelium often formed interconnected trabeculae in a plexiform pattern surrounding coalescent hypercellular cambium zones. There was abundant enameloid and focal dentinoid deposition (Fig. 4D). The enameloid was associated with epithelial cells with moderate amounts of brightly eosinophilic cytoplasm. Wispy basophilic material reminiscent of enamel matrix was also present (Fig. 4E). The stroma was myxoid and variably collagenous, and the spindle cells had benign vesicular nuclei. Mitotic figures were not seen (Fig. 4F). These features were similar to the POT removed from the same site four years prior, except that the organoid/enamel organ-like structures were more abundant [7].

Fig. 3
figure 3

Upper left and right hemi-mandible: Multilobulated tumor with buccal and lingual cortical perforation. Bottom: The gross specimen consisted of a yellow-tan solid mass with a papillary surface measuring 4 cm × 3.8 cm in the greatest dimensions

Full size image
Fig. 4
figure 4

A The tumor was partially encapsulated and consisted of both epithelial and cellular ectomesenchymal components with cystic spaces, and myxoid stroma (H&E, original magnification × 40), Inset: the tumor showed an undulated surface lined by columnar epithelium (H&E, original magnification × 100). B The surface epithelium formed deep invaginations and organoid structures that resemble rudimentary enamel organ-like structures. Note the fibrous capsule of the tumor and cortical perforation (H&E, original magnification × 40). C The epithelium consisted of columnar epithelial cells with clear cytoplasm and reverse nuclear polarization with no evidence of nuclear atypia or mitotic figures with subjacent ectomesenchymal condensation (cambium layer) (arrows) (H&E, original magnification × 200), Inset: Some areas showed stellate reticulum-like tissue (H&E, original magnification × 200). D The epithelium formed interconnected trabeculae that surrounded the ectomesenchymal component that consisted of cellular spindled and stellate-shaped cells in a delicately collagenous and myxoid stroma with subepithelial condensation. Extensive enameloid deposition (arrows) and focal dentinoid like material (arrowheads) were present (H&E, original magnification × 100). E Brightly eosinophilic material resembling enameloid globules are associated with epithelial cells with abundant eosinophilic cytoplasm, and there is wispy basophilic material reminiscent of enamel matrix (arrows) (H&E, original magnification × 400). F The ectomesenchymal component of POT was myxoid with spindle cells in exhibiting benign vesicular nuclei, without cellular atypia or mitotic figures (H&E, original magnification × 200)

Full size image

The epithelial cells demonstrated strong positivity for CK14, and the spindled and stellate-shaped cells within the ectomesenchymal condensation beneath the epithelium were positive for CD34 and CD56 (Fig. 5A-B). Nuclear positivity for MIB-1 was noted in less than 5% of the cells. Calretinin and BRAF were negative in the tumor cells. Based on the histologic features, a diagnosis of recurrent POT, epithelium-rich variant, was made. There was no evidence of recurrence at a thirteen-month follow-up.

Fig. 5
figure 5

A The study for CK14 showed strong cytoplasmic positivity in the epithelium (IHC, original magnification × 40). B The study for CD34 showed cytoplasmic positivity in the spindled and stellate-shaped cells in the ectomesenchymal condensation beneath the epithelium (IHC, original magnification × 200)

Full size image

Discussion

POT is a rare benign biphasic odontogenic tumor that was described in 2014 [1]. It has epithelial and mesenchymal components with the latter appearing to differentiate towards dental papilla. Since then, twenty-three cases of POT have been reported in the English literature [1, 3,4,5,6,7,8,9,10,11,12,13,14,15,16]. The age of patients with POT ranged from 2–19 with a mean of 11 years old, and there is equal sex predilection (Table 1). One of the cases was extra-osseous [14]. Most (82.6%) cases of POT presented with asymptomatic buccal and/or lingual cortical swelling with well-defined, unilocular (77.3%), multilocular (13.6%), or bilocular (9.1%) radiolucency associated with the crown of a developing tooth. The most commonly involved teeth in POT were the permanent third molars (12/23, 52.3%), primary molars (8/23, 34.8%), permanent first molars (1/23, 4.3%), permanent second premolars (1/23, 4.3%), and primary maxillary canines (1/22, 4.3%). All cases occurred in the posterior jawbones, with 69.6% involving the mandible. Radiographically, there was cortical expansion (36.4%), and tooth resorption (27.3%), and displacement (22.7%) to variable degrees. Two cases had small radiopacities within the radiolucency [8, 15]. Two cases reported cortical perforation, including the current case in both initial and recurrent presentations (Table 1) [7, 12]. The maximum dimension ranged from 1.2 to 9.0 cm with a mean of 3.8 cm.

Table 1 Summary of clinical and radiographic features of published cases of POT
Full size table

Grossly, all POT cases, including the current case, showed a solid, multilobulated mass with focal gelatinous texture [17]. Histopathologically, POT is well-circumscribed, and a few cases showed, at least partial encapsulation by a thin fibrous band, although in many cases this feature was not described. There are two key histopathological features of POT: 1) Abundant delicately collagenous, fibromyxoid tissue with many plump spindled and stellate-shaped fibroblasts resembling dental papilla; 2) Odontogenic epithelium composed of cuboidal to columnar cells with clear cytoplasm and reverse nuclear polarity resembling the inner enamel epithelium, present at the tumor periphery. Stellate reticulum-like areas were present adjacent to the odontogenic epithelium in almost half of the cases (11/23; 47.8%) (Table 2). The majority of the cases (16/23; 69.6%) showed cell-rich mesenchymal condensation beneath the odontogenic epithelium forming a cambium layer. The cells here were CD34 positive. Surface undulation and epithelium invaginations were also noted (13/23; 56.5%) (Table 2). Unlike other cases, the current case showed florid epithelial invagination and proliferation in a plexiform and interlacing pattern, even in the original tumor from four years ago (Fig. 4D); this is similar to one other case reported by Zeng et al.[12]. Six cases (26.0%) exhibited dystrophic calcifications and five cases (21.7%) enameloid globules, including the current case in both the original and recurrent tumor [5, 7, 8, 11, 12, 15, 16]. Two cases exhibited a prominent, clear cell population within the tumor [1, 7] while one case contained dentinoid [12]. The current case is the only reported case with rudimentary organoid or rudimentary enamel organ-like structures in both initial and recurrent presentation characterized by odontogenic epithelium with mesenchymal condensations often seen before hard tissue is deposited [7].

Table 2 Summary of histopathological features of published cases of POT
Full size table

The histological differential diagnoses for POT include dental papilla, odontogenic myxoma, archegonous cystic odontoma (primordial odontogenic cyst with induction phenomenon), ameloblastic fibroma, and ameloblastic fibro-odontoma. Dental papilla has similar mesenchymal stroma but is surfaced by odontoblasts, which are not epithelial in nature; it also does not attain the size of POT (mean size of 3.8 cm) (Fig. 1) [17]. Odontogenic myxoma is a mesenchymal odontogenic tumor with occasional inactive, scattered odontogenic epithelial islands and is not surfaced by epithelium [18]. There is only one case of archegonous cystic odontoma reported so far in the literature [19]. It is also referred to as a primordial odontogenic cyst with induction phenomenon because it develops in the area of a missing tooth, with hard tissue deposition. Unlike POT, archegonous cystic odontoma is purely cystic, although it is possible that it may be the cystic form of a POT [19].

The two most important differential diagnoses are ameloblastic fibroma (AF) and ameloblastic fibro-odontoma (AFO), the latter reclassified by WHO in 2017 as an immature odontoma [2]. These are biphasic tumors composed of a mesenchymal proliferation of spindle and stellate cells with fibrous and myxoid stroma, similar to the stroma seen in POT. The epithelial component of AF and AFO is composed of islands and strands of ameloblastomatous epithelium in a follicular pattern that exhibits reverse polarization of basal cells with central stellate reticulum. In contrast, POTs are surfaced by a single layer of columnar/cuboidal epithelium with reverse nuclear polarization and adjacent stellate reticulum in about half (47.8%) of cases. Occasionally, the epithelial component invaginates into the underlying mesenchymal stroma. AF does not form hard tissues while AFO produces enamel matrix, dentin, dentinoid, and cemento-osseous material. POT does not generally exhibit any dental tissue components except for five cases of POT that showed very focal enameloid deposition [7, 8, 11, 12] and one case that showed dentinoid deposition [12]. This current case showed both enameloid and dentinoid very focally.

Passador-Santos et al.[20] recently published a case of dental germ tumor in a 16-year-old female with well-defined mixed radiolucency associated with impacted right first mandibular molar. Histological examination revealed areas of cystic spaces lined by thin non-keratinized squamous epithelium, consistent with a dentigerous cyst. Within the lumen are POT-like areas with “dental germ-like formations” which resembled the rudimentary enamel organ-like structures noted in our case. In addition, there was extensive calcification and enameloid deposition. This might be the second case of an epithelium-rich variant of POT with extensive calcification and enameloid deposition. The patient was treated with tumor enucleation and curettage, and extraction of the first mandibular molar. The patient was free of disease after three years. Additionally, Zeng et al. [12] reported a case of an unusual mixed odontogenic tumor in a 12-year-old female, with features of POT that exhibited similar features to the current case, including florid epithelial proliferation and enameloid deposition with dystrophic calcification. Their case also showed dentinoid deposition. The patient was followed up for 13 years, with no sign of recurrence.

Sun et al.[21] reported a case of POT in a 10-year-old male that presented between the left mandibular canine and first premolar. This was a 0.5 cm radiolucency and the histology showed dental papilla-like tissue, enamel epithelium with stellate reticulum, and dentine deposition more consistent with a developing odontoma, as was noted by others [22]. Sato et al.[14] reported an intriguing case of peripheral POT in a 3 year-old-male that presented as gingival swelling associated with a radiolucency around an unerupted right maxillary second deciduous molar. This appears to be the only such case in the literature.

Most reported POT cases were treated with either enucleation/curettage (13/23; 56.5%) or tumor excision (9/23; 39.1%). In one case, the patient underwent partial mandibulectomy because the initial diagnosis was odontogenic myxoma [8]. None of the reported cases of POT showed recurrence on follow-up (range 6 months-20 years), except the current case where the patient exhibited recurrent tumor four years after the initial presentation.

This is a report of a POT, a rare mixed/biphasic odontogenic tumor that recurred four years after excision. The striking difference between the original and recurrent tumors that differentiates this POT from others that have been reported in the literature is the florid epithelial proliferation that forms organoid/rudimentary tooth germ-like structures with enameloid and dentinoid deposition. It may be that such epithelium-rich variants may be more likely to recur, but this will only become clearer as more cases are published.