Odontogenic Keratocyst or Keratocystic Odontogenic Tumour? A Debatable Dilemma
P. R. Sawant
The nature of odontogenic keratocyst (OKC)/ keratocystic odontogenic tumour (KCOT) as a cystic neoplasm or true cyst has long been under debate by leading oral pathologists all over the world. The OKC/KCOT is unique in its manifestation and progression compared to all other odontogenic cysts and tumors. It is this confounding nature which has led to a change in the designation and terminology to define it as a cyst or a neoplasm. This article focuses on a case of OKC/KCOT and aims to review existing literature on its dualistic nature.
Odontogenic keratocyst (OKC) is a developmental odontogenic cyst, which was first identified and classified by Phillipsen in 1956 and the histological criteria for diagnosis was put forth by Pindborg and Hansen in 1962.[1,2] In 2005, the World Health Organisation (WHO) classified the parakeratinized variant of OKC as a ‘cystic neoplasm’ and introduced the term Keratocystic Odontogenic Tumor (KCOT) for the same. However, the 2017 WHO classification has reclassified the Keratocystic Odontogenic Tumour (KCOT) as an odontogenic cyst. OKC/KCOT is believed to arise from dental lamina and its remnants or offshoots of the basal layer of oral epithelium. OKC is unique from other odontogenic cysts and is characterized by an aggressive growth pattern and a high recurrence rate.[5,6]
A 48-year-old female patient presented with a chief complaint of swelling of the left side of the upper jaw for the past 15 days. The patient had a history of occasional yellowish discharge from the gums, but no complaint of pain. On oral examination, a smooth surfaced dome-shaped swelling was noted on the palate in relation to the left maxillary canine. The swelling was soft in consistency and non-tender to palpation. The overlying mucosa appeared stretched.
Subsequently the patient underwent routine blood investigations, was advised radiographic investigations i.e. conventional radiography (IOPA) and orthopantomogram (OPG). The radiographic analysis revealed a well-defined multilocular radiolucent lesion in relation to the left maxillary anterior teeth. This was followed by an incisional biopsy. Histopathological evaluation of the biopsied specimen revealed features consistent with the diagnosis of OKC/KCOT (Figure 1).
Toller in 1967 suggested that OKC can be regarded as a benign neoplasm rather than a cyst, based on its clinical behaviour. OKC/KCOT was defined by the WHO as a “benign uni/multicystic intra-osseous tumour of odontogenic origin with a characteristic lining of parakeratinized stratified squamous epithelium and a potential for aggressive infiltrative behaviour.”
Numerous authors have justified both the cystic and neoplastic behaviour of OKC/KCOT by stating several hypothesis and etiological factors (which contributed to the terminology and reclassification of this lesion in 2005 and 2017) and are listed below:
(i) Behaviour: OKC/KCOT present as large lytic lesions often invading into adjacent structures. A high recurrence rate (3% to 60%) is attributed to the following factors, such as incomplete removal of the cyst lining, fragile lining-connective tissue junction, growth of new KCOTs from satellite cysts, and development of new KCOT in an adjacent area that is interpreted as recurrence. Some studies have reported cases of malignant transformation of the KCOT lining into squamous cell carcinoma.
The 2017 update on the WHO classification of odontogenic tumours has focused on the phenotypic nature of a neoplasm which states that no spontaneous regression is possible. However, the OKC/KCOT is known to completely regress following decompression.
(ii) Histopathology: Basal cell budding into connective tissue, presence of mitotic figures in the supra-basal layers and daughter cysts are the characteristic histopathological findings in OKC/KCOT. Cutaneous cysts histologically identical to OKC/KCOT have not yet been reclassified as tumors in medical and dermato-pathology communities, has been the recent counter argument put forth.
(iii) Enzyme Histochemistry: Studies done on the enzymology profile of OKC/KCOT found a high activity of oxidative enzymes representing glycolytic, citric acid, and pentose-phosphate shunt mechanisms. They proposed that these enzymes were likely factors contributing to the high recurrence rate of OKC/KCOT.
(iv) Genetic: The most important genetic alteration reported in OKC/KCOT is the Drosophila Patched gene (PTCH) mutation located on chromosome 9q21-23. The germline mutation of PTCH is the underlying cause of nevoid basal cell carcinoma syndrome (NBCCS); which gives rise to numerous manifestations, the chief of which are multiple basal cell carcinomas, OKC/KCOT, skeletal anomalies, and palmar pits.
Eighty-five percent of syndromic OKC/KCOT and 30% of non-syndromic OKC/KCOT are associated with the PTCH gene. Another pathway called the sonic hedgehog (SHH) signalling pathway is responsible for regulating important factors. Proteins such as Smoothened (coded by the SMO gene) and glioma-associated oncogene GLI1 are the downstream signalling molecules of the SHH/PTCH pathway are also over-expressed in OKC/KCOT. Thus, perturbation of the SHH/PTCH pathway is an important event involved in the pathogenesis of OKC/KCOT. Syndromic, as well as, sporadic cases of OKC/KCOT have been shown to harbour the mutation.
John M. Wright et al. has argued that the PTCH gene mutations in syndromic patients are predictable due to vertical transmission. In 15-20% of syndromic patients who do not show the PTCH mutation, it can be explained by the phenotypic acquisition through somatic mutation. Thus, the justification for neoplastic pathogenesis in non-syndromic patients who do not show the PTCH mutation remains debated.
A ‘two-hit’ mechanism is proposed resulting in inactivation of tumour suppressor genes. The first hit results in mutation of one allele which has no phenotypic effect, however the second hit and loss of the other allele is known as the ‘loss of heterozygosity'(LOH). In OKC/KCOT, the allelic loss at 9q22 results in dysregulation of cyclin D1 and p53. The neoplastic concept of OKC is further supported by molecular studies that demonstrated LOH and deletion in various other tumour suppressor genes such as p16, MCC, TSLC1, LTAS2 and FHIT. However, Li TJ refuted the role of p53 in the etiopathogenesis in support of neoplastic behaviour of OKC/KCOT stating that the short half-life of the p53 protein gives conflicting results when this protein is detected immunohistochemically. The authors of the recent update on odontogenic tumours mention that LOH has also been demonstrated in odontogenic cysts.
It has been stated that over expression and amplification of oncogenes located at 12q13 loci, including cytokeratin 6B (KRT6B), epidermal growth factor receptor (ERBB3) and glioma-associated oncogene homologue 1 (GLI1), may contribute to the persistent growth characteristics of KCOT. Further, other studies have stated that abnormalities related to cell proliferation markers, such as Ki67 and PCNA and suppression of apoptosis-related markers, such as bcl-2 and Bax were present in OKC/KCOT. It is important to mention that proliferative status is not always directly associated with biological behaviour or a true neoplastic nature. Non-neoplastic proliferative lesions such as glandular odontogenic cysts may demonstrate a high expression of some proliferative markers, when compared to some of the malignant tumours such as low-grade mucoepidermoid carcinoma.
(v) Epigenetics: It has been reported that methylation of P21 gene in OKC/KCOT samples exists in contrast to dental follicles. However, whether epigenetics is really related to odontogenic tumour development requires further research.
The demographics of OKC/KCOT have a typical presentation which occurs in second or third decade, and sometimes a second peak in the fourth or fifth decade is seen. As seen in this case report, the patient was in the fourth decade of life. A male gender predominance is noted in most studies as is seen in this case. The clinical presentation favours the lower jaw and results in a localized swelling that is usually seen as a well-defined unilocular radiolucency on radiographs. This case presented with a localized swelling seen in the upper right canine region. It presented as a well-defined unilocular radiolucency, not associated with any impacted tooth or root resorption. Literature states that one-fourth cases of OKC/KCOT are associated with an impacted tooth and 10-15% show resorption of roots of adjacent teeth.
Even though the behaviour of OKC/KCOT as a neoplasm or a cystic entity remains debatable, more conservative methods such as enucleation, marsupialization, and combination of enucleation with Carnoy’s solution/peripheral ostectomy have shown variable recurrence rates. A large body of evidence has shown that resection is the best treatment modality to prevent recurrence.
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