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basic mechanisms of cytokine‐mediated tissue remodelling are involved in the growth and expansion of all types of cyst. These same biological factors are also responsible for proliferation of the reduced enamel epithelium that merges with the overlying oral epithelium during normal tooth eruption. It is thought that proliferation of the reduced enamel epithelium, in the absence of normal eruption, may be involved in the pathogenesis of the dentigerous cyst, but proliferation of rest cells of dental lamina within follicular tissue may also drive the formation of other lesions that are commonly associated with unerupted teeth. This would include some odontogenic tumours (e.g. ameloblastoma, adenomatoid odontogenic tumour) as well as the odontogenic keratocyst and orthokeratinised odontogenic cyst. The role of these biological factors in the pathogenesis of dentigerous cyst, the odontogenic keratocyst, and the orthokeratinised odontogenic cyst is discussed in Chapters 5, 7, and 12, respectively.

      As well as activation of cytokines and other biological factors, there is good evidence that activation of oncogenic signalling pathways is a common feature in the pathogenesis of odontogenic cysts and tumours (Diniz et al. 2017 ; Bilodeau and Seethala 2019 ). These pathways are involved in the normal development and morphogenesis of the teeth, but aberrant activation may drive pathological processes. The most widely studied pathway is the hedgehog (HH) signalling pathway, which is a fundamental feature of normal development with crucial roles in cell fate, differentiation, and patterning. HH activation through binding of the Sonic hedgehog (SHH) ligand is a fundamental feature of odontogenesis, regulates the development of the dental lamina, and is responsible for tooth morphogenesis and patterning (Diniz et al. 2017 ; Seppala et al. 2017 ; Hovorakova et al. 2018 ; Sasai et al. 2019 ). The pathway is regulated by the PTCH protein, which is a receptor for SHH and under normal conditions controls and regulates epithelial–mesenchymal interactions, cell proliferation, and differentiation. The HH signalling pathway is discussed in detail in Chapter 7 and is illustrated in Figure 7.13.

      Constitutive or aberrant activation of the HH pathway can be caused by reduced expression or loss of the PTCH protein at the cell surface, and this is an important mechanism in the pathogenesis of the odontogenic keratocyst. Loss of PTCH most often results from loss of heterozygosity (LOH) or point mutations in the PTCH gene, and this is seen in up to 80% or more of keratocysts (see Table 7.6). However, although PTCH gene alterations are important in keratocysts, they are not specific, since mutations or LOH of PTCH or activation of the HH signalling pathway may be seen in other odontogenic lesions, including orthokeratinised odontogenic cyst (Vered et al. 2009 ; Diniz et al. 2011 ), glandular odontogenic cyst (Zhang et al. 2010 ), and dentigerous cyst (Levanat et al. 2000 ; Pavelić et al. 2001 ; Barreto et al. 2002 ; Vered et al. 2009 ; Zhang et al. 2010 ). The role of PTCH and the HH signalling pathway in these cysts is discussed in Chapters 5 (dentigerous cyst), 10 (glandular odontogenic cyst), and 12 (orthokeratinised odontogenic cyst). The role of the B‐catenin gene (CTNNB1) and the WNT signalling pathway in calcifying odontogenic cysts is discussed in Chapter 11.

      Overall, it appears that alterations in the PTCH gene or activation of HH signalling are common features of a number of lesions and may represent an initiating event in the formation of developmental odontogenic cysts, possibly in a progenitor epithelial cell, which then gives rise to the entire epithelial lining and drives growth and expansion. It has been suggested that the PTCH gene may act as a gatekeeper gene and that further genetic events result in the formation of different cysts or tumours (Gomes and Gomez 2011 ). This would explain a role for PTCH in a wide range of cyst types, but does not exclude a role for further specific PTCH mutations in keratocysts.

Another unifying feature involved in the pathogenesis of jaw cysts and probably also of soft tissue cysts is the role of hydrostatic pressure. With few exceptions (odontogenic keratocyst, botryoid odontogenic cyst, glandular odontogenic cyst), cysts in the jaws tend to be round or spherical on radiology or imaging, suggesting that they grow slowly in a regular and centripetal manner. It is widely accepted that hydrostatic pressure due to osmosis provides the evenly distributed internal forces that result in this growth pattern. Osmotic pressure across the cyst wall is caused by the accumulation of soluble proteins in the cyst lumen, so that the concentration of molecules inside the cyst is greater than in the adjacent tissues. This causes passage of fluid (water) into the cyst lumen and results in a high intraluminal pressure that drives cyst expansion and growth. The mechanisms of hydrostatic pressure and its role in the radicular cyst are discussed in detail in Chapter 3, but there is good evidence that hydrostatic pressure due to osmosis is involved in the expansion of most, if not all, cyst types. Although the odontogenic keratocyst grows in a multicentric pattern associated with cell proliferation in the wall, there is also evidence of an increased intracystic pressure, suggesting a role for osmosis in its expansion (Toller 1970b ; Kubota et al. 2004 ). Kubota et al. (2004 ) suggested that increased hydrostatic pressure was particularly 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

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