Odontogenic keratocyst: What is in the name? (2024)

The “cholesteatoma”

Odontogenic keratocyst (OKC) is an enigmatic developmental cyst, which Mikulicz in 1876 first described it as a part of a familial condition affecting the jaws. However in 1926 it was first known as a “cholesteatoma.”[2] Cholesteatoma simply means a cystic or “open” mass of keratin squames with a living “matrix”.[3] To know the history of this mysterious cyst, we should look at the account of cysts of the jaws in general. Cystic swellings of the jaws appear first to have been described in 1654 by Scultetus, and it was not until 1728 that Fauchard suggested that they might be connected with the teeth.[4] Cysts were recognized long before the invention of x-rays in 1896, by John Hunter, who described a dental cyst in 1774.[5] Fauchard's series of articles to describe dental cysts continued. Paget's in 1853 coined the term “dentigerous cyst.”[6]

The “primordial cyst”

The concept of “Primordial cyst” was first mentioned by Robinson[7] in 1945 because the cysts were believed to have a more primordial origin as they arose from remnants of the dental lamina or the enamel organs before enamel formation has had taken place. Forssell and Sainio[8] had a preference for the term “primordial cyst,” and showed that in these lesions (genuine keratocysts) the epithelium was distinctly parakeratotic with cuboidal or columnar palisaded basal cells, and occasionally orthokeratotic.

The “odontogenic keratocyst”

Philipsen in 1956,[9] while still a senior dental student working with Jens J Pindborg in Copenhagen, named and described the “odontogenic keratocyst.” The designation “keratocyst” was used to describe any jaw cyst in which keratin was formed to a large extent. The histopathology of OKC is typical and have been well characterized.[9] It includes: A thin, uniform lining of stratified squamous epithelium with tendency to detach from the underlying connective tissue capsule; a thin corrugated surface layer of parakeratin; a spinous cell layer 8 to 4 cells in thickness, often showing intracellular oedema; a flat epithelial-fibrous tissue junction, usually devoid of epithelial rete ridges; and a relatively thin fibrous capsule that lacks inflammatory cell infiltrate.

Benign neoplasm?

Pindborg and Hansen[10] were the first to point out the aggressive behavior of OKC. Toller[4] as early as 1967 suggested that OKC should be considered as a benign neoplasm rather than a conventional cyst mainly because of their clinical behavior. Ahlfors and others[11] in 1984 suggested OKC to be classified as a true benign cystic epithelial neoplasm and suggested modified treatment schedules.

Shear[12] published his extensive work on the aggressive nature of the odontogenic keratocyst and finally labeled it as a benign cystic neoplasm. Shear aggressively used the term “keratocystoma” in naming this cyst.

Regezi and others[13] have attempted to explain the pathogenetic mechanisms of OKC. They mention the mechanisms that favor growth and expansion of OKCs are high proliferation rate, over expression of antiapoptotic proteins (bcl-2) and expression of matrix metalloproteinase (MMPs 2 and 9). Mutation in PTCH 1 (“patched”) gene has also been considered as responsible for the pathogenesis of this cyst.[12,13,14]

Recurrences

The incidence of recurrence of OKC has varied from 2.5% to 62%.[14] The great degree of variation in these reports are mainly because some series included cysts from patients with Nevoid Basal cell carcinoma syndrome (NBCCS), while other reasons for this variation can be due to duration of the follow-up period and method of treatment used.[14]

In 1976, Brannon[15] proposed three mechanisms for OKC recurrence: Incomplete removal of the cyst lining, growth of a new OKC from satellite cysts (or odontogenic rests left behind after surgery), and development of a new OKC in an adjacent area.

Histopathological features that predict recurrences.

The major features that can be considered to predict recurrences in OKC are

• Higher level of cell proliferative activity in the epithelium

• Budding in the basal layer of the epithelium

• Parakeratinization of the surface layer

• Supraepithelial split of the epithelial lining

• Subepithelial split of the epithelial lining

• Presence of remnants/cell rests as well as daughter cysts.

Rechristened

Meanwhile, Reichart and Philipsen[16] reclassified the odontogenic tumors in 2002 and renamed OKC as keratinizing cystic odontogenic tumor (KCOT) and placed it under the subheading of “benign neoplasm of odontogenic epithelium with mature, fibrous stroma; odontogenic ectomesenchyme not present.” This classification got the approval by WHO/IARC at the Editorial and Consensus Conference, held at Lyon, France in July 2003 and in the present classification, the OKC has been renamed as “keratocystic odontogenic tumor” (KOT). KOT is now defined as “a benign uni-or multicystic, intraosseous tumor of the odontogenic origin, with a characteristic lining of parakeratinized stratified squamous epithelium and potential for aggressive, infiltrative behavior.”[3] WHO “recommends the term keratocystic odontogenic tumor as it better reflects its neoplastic nature.”[3] Recent molecular studies showing loss of heterozygosity of certain tumor suppressor genes in many odontogenic keratocysts have supported this renaming by WHO.[17]

Genetics

The PTCH gene has been mapped to chromosome 9q22.3-q31 and it probably functions as a tumor suppressor.[3] The PTCH1 is an important molecule in the so-called Hedgehog (Hh) signaling pathway.[14] Normally, PTCH forms a receptor complex with the oncogene SMO (“smoothened”) for the SHH (“sonic hedgehog”) ligand.[18] Studies on NBCCS and sporadic KCOT have provided molecular evidence of a two-hit mechanism in the pathogenesis of these tumors demonstrating allelic loss, at two or more loci, of 9q22[19,20] leading to the overexpression of bcl-1 and TP53 in the NBCCS. This supports the concept that KCOT represents a neoplasm.[20] There is also accumulating evidence that the PTCH gene might be a significant factor in the development of sporadic KCOT. Furthermore, preliminary results have shown over-expression and amplification of genes located in 12q.[21]

The epithelial lining of OKC/KOT expresses higher levels of p53 than any other cyst types. This overexpression is not due to mutation of p53 gene, rather reflects overproduction and/or stabilization of normal p53 protein.[14] Other genes that can be correlated to OKC/KOT are PTCH2 and SUFU. Few authors also have demonstrated loss of heterozygosity in p16, MCC, TSLC1, LTAS2, and FHIT genes.[14] These findings are helpful to explain the aggressive behavior of OKC.

Treatment

OKC is well known for their strong tendency to recur.[11] Much debate has been done and various studies performed, to ascertain ideal treatment modality for OKC/KOT. Mostly these arguments revolve around whether to treat OKC as a cyst or as a benign neoplasm. Whatever modality has been implied, none of these have shown to completely prevent recurrence of the lesion, the problem is still compounded in case of NBCCS and multiple lesions.

Eyre and Zakrezewska[22] in 1985, have stated the following treatment modalities for OKC/KOT-

• Enucleation

  With primary closure

  With packing

  With chemical fixation

  With cryosurgery

• Marsupialization

  Only

  Followed by enucleation

• Resection

The choice of the treatment has always been difficult, since the patient well-being is of prime concern, although not compromising the chances of recurrences. Morgan and his colleagues[23] have categorized surgical treatment methods for KOT as conservative or aggressive. The conservative treatment is “cyst oriented” and thus includes enucleation, with or without curettage or marsupialization. The advantage is preservation of anatomical structures and reduced morbidity to the patient. The aggressive treatment is done considering “neoplastic nature” of KOT and includes peripheral ostectomy, chemical curettage, or enbloc resection. It is mostly recommended for large lesions, recurrent cases and syndromic patients. Decompression has also been used to treat KOTs, which have aggressive behavior and having tendency to recur.[14]

Few authors recommend “site-and size-based” approach for the treatment of KOT. Dammer et al.[24] have suggested conservative approach for small KOTs (maximum 1 cm in diameter) near alveolar process, and radical excision for larger lesions near the base of the skull that has invaded soft tissue. On the contrary, Forsell and coworkers have reported that the size of the lesion does not affect the recurrence rate.[25]

Future modalities

Due to the recent advances and thus determination of molecular basis of this entity, a new novel methodology concentrating on molecular aspects has been devised. The Hh pathway can be blocked at different levels, and Hh inhibitors could serve as attractive antitumor agents.[26] According to some studies, cyclopamine, a plant-based steroidal alkaloid, blocks activation of SHh pathway caused by oncogenic mutation.[27] Other studies also show antagonists of SHh signaling factors could effectively treat KOT.[28]

Source of Support: Nil

Conflict of Interest: None declared.

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