important in the initiation and early growth of the keratocyst, while cell proliferation was more important as the cyst enlarged. This is in keeping with the observation that keratocysts tend to be unilocular when they are small, while larger cysts and lesions in older individuals are more often multilocular or scalloped (Forssell 1980 ; Stoelinga 2001 ; MacDonald‐Jankowski and Li 2010 ; Boffano et al. 2010 ; see Chapter 7). Interestingly, Kubota's research group (Kubota et al. 2004 ; Oka et al. 2005 ) also showed that the increased pressure stimulated secretion of cytokines, including IL‐1α, suggesting another common mechanism for activation of biological factors that promote tissue remodelling and bone resorption. These data are discussed in detail in Chapter 7.
The Cyst–Tumour Interface
The pathogenesis of the developmental odontogenic cysts is still poorly understood and this has led to much debate regarding the possible neoplastic nature of some of the cysts. This applies mostly to the odontogenic keratocyst, but there is also debate regarding the nature of the calcifying odontogenic cyst and glandular odontogenic cyst. As discussed in Chapter 7, the odontogenic keratocyst in particular has generated an enormous literature that has increased more than fivefold since the last edition of this book. Many papers have explored the expression of various markers in an attempt to show that the keratocyst is a neoplasm. A common suggestion is that expression of proliferation markers at a higher rate than seen in other cyst types is evidence that the lesion is a neoplasm. Of more value are studies exploring aberrant gene expression or activation of oncogenic signalling pathways. However, at the present time there is no clear marker of neoplasia and the definition of a neoplasm has become uncertain. It is not uncommon for the finding of a single genetic mutation to be taken as evidence of neoplasia regardless of the behavioural characteristics of the lesion. It must be pointed out that a single point mutation or genetic aberration may be the cause of developmental anomalies and is not sufficient to designate a lesion as neoplastic.
At the present time, most pathology textbooks still define neoplasia in the terms first used by Willis in 1960, as ‘an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues, and persists in the same excessive manner after cessation of the stimuli that evoked the change’. No cyst described in this book meets these criteria and in terms of clinical behaviour none of the cysts can therefore be described as neoplastic.
Nevertheless, in the 2005 World Health Organization (WHO) classification (Barnes et al. 2005 ), two cysts that had hitherto been regarded as developmental in origin were renamed ‘tumours’, with the clear intention that they should be designated as benign neoplasms. The odontogenic keratocyst was renamed keratocystic odontogenic tumour and the calcifying odontogenic cyst was renamed calcifying cystic odontogenic tumour. With regard to the keratocyst, the designation as a neoplasm was based on its ‘aggressive, infiltrative behaviour’ and the role of the PTCH gene in its pathogenesis. However, keratocysts do not meet the criteria for neoplasia suggested by Willis, since there is no evidence of uncoordinated independent growth. It is ironic that since the lesion was designated as a neoplasm in 2005, there have been almost 50 publications reporting marsupialisation (or decompression) as an effective treatment compared to only 10 papers before 2005. A number of publications have shown that marsupialisation is effective and that it may result in regression of the typical keratocyst lining to an epithelium indistinguishable from that seen in normal oral mucosa. This cannot be regarded as the behaviour of a neoplasm.
A further consideration is the use of the term ‘aggressive’. It is common for authors to assert that the odontogenic keratocyst is aggressive because it has a propensity for recurrence. While there is no doubt that the keratocyst (and a number of other cysts) has a tendency to recur, we do not support the well‐used assertion that ‘recurrence’ and ‘aggressive’ are synonymous. The recurrence rate is almost entirely associated with the pattern of cyst growth and the type of treatment (see Chapter 7) and is similar to that seen in other cysts that have a multilocular growth pattern (botryoid odontogenic cyst, glandular odontogenic cyst). Inadequate removal may lead to residual cyst elements being left in the tissues and these may proliferate to form new cysts. It is also true that occasionally a keratocyst, especially a recurrent lesion, may spill into the soft tissues and cause considerable clinical problems. However, other cysts that are known to be difficult to remove, and may have very high recurrence rates, are not described as aggressive or thought to be neoplastic. For example, inadequately treated ranulas have a recurrence rate of up to about 65% (see Chapter 15) and thyroglossal duct cysts recur in up to 50% of cases if residual ductal elements are not also removed (see Chapter 18). We believe that the term ‘aggressive’ is overused and may be over interpreted to suggest an invasive lesion or a behaviour similar to that associated with truly aggressive lesions such as malignancies. In this context, none of these cysts behaves in a way that can be described as truly aggressive.
A more compelling argument for the neoplastic nature of cysts is the finding of genetic aberrations. A key point in this discussion, as already mentioned, is the finding of PTCH gene alterations and activation of the HH signalling pathway in a range of developmental cysts. The finding of a single point mutation or LOH in the PTCH gene is insufficient to designate the keratocyst as a neoplasm. However, more recent studies (Stojanov et al. 2020 ) have confirmed earlier work that has shown that some keratocysts show biallelic loss of both copies of the PTCH gene (Levanat et al. 1996 ; Sun et al. 2008 ; Pan et al. 2010 ). In their study, Stojanov et al. (2020 ) found that 80% of sporadic keratocysts showed biallelic loss of PTCH1. Biallelic loss of the gene means that both copies have been lost or mutated and meets the ‘two‐hit’ hypothesis of Knudson (Knudson 1971 , 1996 ), which suggests that loss of both copies of a tumour suppressor gene causes neoplasia. However, Knudson's hypothesis related to hereditary cancer (retinoblastoma), and it is now thought that two hits may not always cause neoplasia and that further genetic aberrations may be necessary (Tomlinson et al. 2001 ).
Notwithstanding this argument, the finding of biallelic loss of the PTCH gene in some keratocysts provide some evidence that at least a subset of odontogenic keratocysts may be neoplastic. However, the line of demarcation between aberrant development and neoplasia is blurred and it seems that the keratocyst may sit on a spectrum between a developmental cyst and a benign cystic neoplasm. At the present time it is difficult to make a clinicopathological distinction between cysts showing different genetic changes and there are no defining criteria for which, if any, keratocysts might be neoplastic. Further research is needed to clearly define neoplasia and to determine if there are any behavioural differences between cysts with different genotypes or clinicopathological phenotypes.
These issues and the debate about the neoplastic nature of the odontogenic keratocyst are discussed in detail in Chapter 7.
Other lesions that sit on the cyst–tumour interface include the calcifying odontogenic cyst and the glandular odontogenic cyst. In 2005, the WHO renamed the calcifying odontogenic cyst the calcifying cystic odontogenic tumour, and designated all odontogenic ghost cell lesions as neoplasms (Barnes et al. 2005 ; Prætorius and Ledesma‐Montes 2005 ). However, more than 85% of ghost cell lesions are simple cysts and do not recur, with little evidence of behaviour that would suggest a neoplastic origin (Ledesma‐Montes et al. 2008 ). It has been shown, however, that ghost cell lesions, including calcifying odontogenic cysts, are characterised by mutations in the β‐catenin gene (CTNNB1) and may be driven by activation of the WNT signalling pathway (reviewed by Gomes et al. 2019 ). The presence of this CTNNB1 mutation has led to suggestions that the calcifying odontogenic cyst is a neoplasm. However, this mutation and the resulting intracellular expression
