INTRODUCTION
Primordial odontogenic tumour (POT) is a novel entity that was added as a benign, mixed odontogenic tumour in the World Health Organization (WHO) classification of Head and Neck Tumors (fourth edition) in 2017.[1] First reported in 2014 in the British Journal Histopathology, this tumour has been wrongly diagnosed as other entities in the past, owing to its histopathologic similarity to other odontogenic tumours such as ameloblastic fibroma (AF), odontogenic fibroma as well as to the histology of hyperplastic dental follicles.[2] POT is characterized histologically by a variably cellular immature connective tissue stroma which resembles dental papilla (DP) and is covered by cuboidal or columnar epithelium that is similar to the inner enamel epithelium of the enamel organ.[3] It is because of this histologic similarity to the primordial (early) stages of tooth development that the term POT was selected for this entity.[4]
Only 19 cases of POT that adhere to its clinico-pathologic criteria have been reported till date. Most of these reported cases were observed as well-defined unilocular or multilocular radiolucent lesions close to the crown of an unerupted tooth. Patients were mostly in the first two decades of life, manifesting with bone swelling, root resorption of the involved teeth and buccal or lingual cortical expansion. Majority of these cases were reported to occur in the mandible. This case report presents a rare occurrence of POT which manifested as a lytic lesion in the posterior mandible of a 3-year-old female patient with extension into the surrounding tissues.
CASE REPORT
The clinical history, radiographic details and paraffin-embedded tissue blocks pertaining to a 3-year-old female child were sent to our department from a team of Oral and Maxillofacial Surgery Specialists for review and our opinion on its final diagnosis. A study of the clinical details revealed that the child patient was brought to the team of surgeons by her parents with a complaint of progressive discomfort in the left posterior mandible. There was no obvious extra-oral swelling. The child showed progressive discomfort with difficulty in opening the mouth and reluctance to chew the food on the affected side. The surgeons detailed that the child was extremely non-cooperative and hence an intra-oral examination could not be carried out to a satisfactory extent. However, a fullness of the buccal vestibule was appreciated intra-orally on the affected side. Though the child did not show any obvious features of tenderness on palpation, the parents informed the surgeons that the child often complained of pain in the eye and forehead on the left side.
The images provided by the surgeons were 3D reconstructed cone-beam computerized tomography slices. They showed a lytic lesion in the left posterior mandible, which appeared to be multilocular, in close association to the developing teeth and extending upwards into the posterior zygomatic arch, infra-temporal fossa as well as the orbital floor, causing resorption in these regions [Figures 1 and 2]. These features explained the pain in the eye and forehead region experienced periodically by the child. Correlating the clinical and radiographic findings, which were suggestive of an expansile lytic lesion arising in the jaws and progressing to cause destruction in the zygomatic, infra-temporal and the orbital regions, the surgeons considered the differential diagnosis of an aggressive odontogenic tumour or a connective tissue pathology arising within the mandible.
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Figure 1: 3D Cone-beam computerized tomography image: A lytic lesion in close relation to the developing teeth in the left posterior mandible
Figure 2: 3D Cone-beam computerized tomography image: The lesion extending upwards to involve zygomatic arch, infratemporal fossa and orbital floor
They performed incisional biopsy of the lesion from the left posterior mandibular region. The micro-slides stained with haematoxylin and eosin (H&E), along with their paraffin-embedded tissue blocks, were sent to our department for review and final diagnosis.
On reviewing the H&E-stained sections, a myxo-collagenous connective tissue stroma resembling the primitive DP, enveloped by a continuous thin layer of epithelium showing ameloblastomatous characteristics, was observed [Figure 3]. Under higher magnification, the epithelium showed a basal tall columnar cell layer with 'reversal of nuclear polarity' (nuclei displaced away from the basement membrane), sub-nuclear vacuolation and loosely arranged stellate reticulum like cells above this basal layer. The underlying stroma strongly resembled the primitive mesenchymal tissue of the odontogenic apparatus, showing loose and myxoid fibrous tissue with small spindle-shaped cells dispersed uniformly within. Moderate amount of vascularity was also noticed within this stroma [Figure 4]. Since these histopathologic features matched with the handful of earlier reported cases in literature, a final diagnosis of POT was made. This was conveyed to the team of surgeons so as to enable them to carry on with the further management of the lesion.
Figure 3: A thin ribbon-like epithelium lining a myxo-collagenous stroma resembling primitive dental papilla (H&E; 4×)
Figure 4: Higher magnification showing the ameloblastomatous characteristics of the lining epithelium – basal layer of tall columnar cells with reversal of polarity, resembling ameloblasts and upper layers loosely arranged cells; underlying dental papilla like stroma shows spindle cells dispersed within (H&E; 4a: 10×; 4b: 40×)
On follow-up of the case, the surgeons informed us that citing religious sentiments and beliefs, the parents of the patient strongly refused to undertake further management of their child's lesion. No further follow-up from the part of the surgeons was entertained by the parents and the case was thus lost to follow-up.
DISCUSSION
POT is a new entity classified under benign mixed odontogenic neoplasms in the fourth edition of the WHO Head and Neck Blue Book in 2017.[1] The term POT was proposed by Mosqueda-Taylor et al.[2] who reported a series of six cases in 2014, which did not fulfil the diagnostic criteria of any of the previously classified odontogenic tumours.[2] The term POT was designated to this entity as the lesions were seen to histologically mimic the early or primordial stages of tooth development.[4] According to the existing literature, POT may be defined and described as a benign odontogenic tumour that develops and is diagnosed during the first two decades of life; its histopathologic as well as immunohistochemical features suggest that it arises between the 10th and 20th week of embryonal life when the inner enamel epithelium of the enamel organ surrounds the primitive DP and there are no inductive effects towards normal histo-morpho differentiation so that dental hard tissue formation has not started yet.[567]
Till date, 19 cases that meet the clinico-pathologic criteria for POT as described above have been reported in literature. Three cases reported as POT – one by Sun et al. where significant dentine formation within the tumour was reported, a case by Kayamori et al. where presence of numerous calcified particles in the tumour stroma has been described and another case by Poomsawat et al. where prominent calcifications in the stroma and also within the ribbon like epithelium were reported – have not been included in the list of previously reported cases of POT as they do not meet the clinico-pathologic criteria as mentioned above.[8910] A summary of the previous reported cases of POT, along with their salient characteristics, is shown in Table 1. It was observed that all patients in the reported cases including the current case were of the very young age group ranging between 2 and 19 years, with almost an equal sex predilection. Posterior mandible was observed as the most predominant site of occurrence, as was seen in our case. Clinically, majority of the reported cases presented as asymptomatic in the initial stages, with swelling and bony expansion becoming evident in a span of the next 3–6 months. In the present case too, the parents became alert only when the child complained of pain and discomfort in the region, but without any obvious extra-oral swelling. Most of the cases appeared on the radiographs as unilocular radiolucent lesions in relation to the developing third molar tooth with well-defined borders giving the impression of dentigerous cysts. Contrary to this, our case showed multilocularity with expansion and extension into the infra-temporal, zygomatic and orbital floor areas, mimicking a highly aggressive lesion. This could be the reason for the pain and discomfort intermittently felt in the region of eye and forehead on the affected side in our case.
Table 1: Summary of previously reported cases of primordial odontogenic tumour
Histologically, POT presents with features characteristic of the lesion and these features hold the key to the final diagnosis of this entity. Majority of the previously reported cases presented with a thin, continuous and regular band of odontogenic epithelium showing ameloblastomatous characteristics and overlying a myxo-collagenous stroma. These features were evident in the present case where the ribbon like band of epithelium showed a row of tall columnar basal cell layer with reversal of nuclear polarity and sub-nuclear vacuolation. The upper cell layers comprised loosely arranged cells resembling stellate reticulum. The underlying stroma characteristically resembled primitive DP, appearing as myxo-collagenous with spindle shaped cells scattered within. Slater (2016) has described a case of POT showing two distinct zones within the stroma – the 'cambium' layer with more cells and less fibres immediately below the epithelium and the 'central' portion showing less cellularity and more fibres in the deeper part of the stroma. This 'lobulated' or 'bosselated' pattern as seen in the described case has been attributed to the areas of differential growth – with the cambium or peripheral zone showing more proliferation than the central zone.[3] However, no such zone distinction in the stroma was appreciated in the current case.
The pathogenesis of POT was hypothesized by Mosqueda-Taylor et al.,[2] based on their study of a series of six cases. They proposed that POT arises in the dental follicular tissue of a molar tooth as an independent proliferative ectomesenchymal nodule that induces the adjacent epithelium to surround it. However, Slater (2016) observed that there was limited morphologic support for this hypothesis and quoted an example of another reported case of POT where microscopic nodules exhibiting histologic features of POT, POT-like proliferations or POT bodies were seen in a complex odontoma located occlusal to the impacted right maxillary second molar tooth in a 10-year-old child. It was contended that as part of the tooth-forming process, the peripheral sub-capsular myxoid tissue proliferated and formed nodules that become enveloped in the ameloblastic epithelium and budded into the mass. If such a POT body were to enlarge massively, it would closely resemble POT. It can be assumed that POT arises from the odontogenic apparatus in the primordial stages, as is evident from the characteristic pathologic features of this lesion.[3]
Immunohistochemical profile studies in some of the reported cases have revealed that CK-19 is positive in the epithelial component. S-100 and α-SMA are not expressed. CK-19 has been shown to be positive in the epithelial component of odontogenic cysts and tumours and in the pre-ameloblasts as well as secretory ameloblasts.[19] With regards to expression of vimentin in POT, Sun et al.[8] contended that vimentin was strongly positive in the epithelial component and moderately positive in the mesenchymal component in their reported case. It has been demonstrated earlier that vimentin may be positively expressed in the dental epithelium of the enamel organ between the 10th and 20th gestational weeks and there was no detectable vimentin in the epithelium after 27 gestational weeks.[2021] These findings support the theory that POT originates from the primordial cellular components of the enamel organ and is derived from the early stages of dental morphogenesis around the 10th to 20th week (cap-to-bell stage). Most of the previously reported cases where IHC studies were carried out have reported a consistently negative expression of S-100 protein and α-SMA in POT.[5] The expression of ki-67 in the previously reported cases of POT was <2% in both epithelial and mesenchymal components and this was found to be similar to other benign odontogenic tumours such as odontogenic myxomas (OMs).[22]
The histologic differential diagnosis of POT includes the DP, AF, central odontogenic fibroma (COF) and OM. DP can be easily excluded as it is not surrounded by the thin ribbon-like ameloblastic epithelium as encountered in POT.[8] AF is a benign odontogenic neoplasm composed of DP like mesenchymal tissue, odontogenic epithelium in the form of cords and strands, with no dental hard tissue formation.[23] The DP like connective tissue is also seen in POT, but this is more cellular in AF. Though a few cords or nests of epithelium may be seen in the connective tissue stroma close to the epithelial band in POT, such cords and nests are more numerous in the stroma of AF and the ameloblastomatous epithelial component is more conspicuous in AF. No such ameloblastomatous islands have been reported in the connective tissue of POTs.[12] COF is a rare entity comprising only 0.1% of all odontogenic tumours. Neither the simple type (epithelium-poor) nor the WHO type (epithelium rich) of COF show a component of ameloblastic epithelium covering the tumour as seen typically in POT.[2425] OMs may present radiographically similar to POT in the posterior mandible showing multilocular appearance, but the ameloblastic epithelium overlying the DP like stroma is not encountered in OM.[3]
CONCLUSION
This case report highlights the possibility of POT as a probable diagnosis to be considered, especially in lesions affecting the posterior mandible in very young patients in the first two decades of life. Clinicians as well as pathologists need to be aware of the features of this newly introduced entity in order to make a timely and accurate diagnosis. This is extremely essential for the further management of the young patients and in bringing them back to normal life. Careful interpretation of the histopathologic findings holds the key to the final diagnosis of this tumour. Often, incisional biopsy may carry only the mesenchymal component which is abundant in this entity, and this can lead to misdiagnosis. However, in this case, correct diagnosis was possible as the epithelial component was also observed in the incisional biopsy. Due to the very few case numbers reported, certain amount of confusion still persists especially with regards to those cases where there is presence of dentinoid material or calcifications in the stroma, as most of the cases reported till date stress upon the criteria that inductive hard tissue formation is not seen in POT. Given the rarity of POT and this being only the 20th case to be reported in literature and only the third one from India, it is important to report every new case of POT to expand the understanding of this relatively new entity, to reach a more definitive consensus regarding its specific diagnostic criteria and help add to the information base of this condition.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgements
The authors wish to acknowledge Dr. Latha P Rao and Dr. Sherry Peter, Consultant Oral and Maxillofacial Surgeons for sharing the details of the case.
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