Читать книгу Shear's Cysts of the Oral and Maxillofacial Regions - Paul M. Speight - Страница 28

Three elements are needed:

 A source of epithelium

 A stimulus for epithelial proliferation

 A mechanism of growth and bone resorption

The cyst develops in three phases:

 Phase of initiation – a source of epithelium and stimulus for proliferation

 Phase of cyst formation – a cyst cavity develops and becomes lined by epithelium

 Phase of growth and enlargement – the cyst enlarges, and growth is accompanied by tissue remodelling and bone resorption

Table 2.1 Sources of the epithelial lining of cysts of the head and neck.

	Source of epithelial lining	Developmental origin
Odontogenic cysts
Radicular cyst	Cell rests of Malassez	Remnants of the epithelial root sheath of Hertwig lie in the periodontal ligament (Figure 3.6)
Dentigerous cyst Eruption cyst Inflammatory collateral cysts	Reduced enamel epithelium	Reduced enamel epithelium forms from the internal and external enamel epithelium and embraces the fully formed crown of an unerupted tooth. This gives rise to the dentigerous (and eruption) cyst (Chapters 5 and 6, Box 5.3, Figures 5.18 and 5.19). The reduced enamel epithelium also forms the junctional or sulcular epithelium during tooth eruption and this gives rise to inflammatory collateral cysts (Chapter 4)
Odontogenic keratocyst Lateral periodontal cyst Botryoid odontogenic cyst Gingival cyst of infants Gingival cyst of adults Glandular odontogenic cyst Calcifying odontogenic cyst Orthokeratinised odontogenic cyst	Cell rests of the dental lamina (‘glands of Serres’)	After tooth formation is complete the dental lamina disintegrates, but residual islands are retained in the gingival mucosa and alveolar bone. Cell rests are particularly common in the posterior mandible, where they may also be found in the gubernacular cord or canal (discussed in detail in Chapters 7, 8, 9, and 12; see Figures 7.12, 8.3, 9.7, and 9.9)
Non‐odontogenic cysts
Nasopalatine duct cyst	Remnants of the nasopalatine duct	The nasopalatine duct is a fetal structure and involutes at about 10 weeks of intrauterine life. Residual epithelial remnants, however, may remain in the incisive canal after birth and in adults (Chapter 13, Figure 13.1, Box 13.1)
Nasolabial cyst	Nasolacrimal duct	The nasolacrimal duct forms after 6 weeks of intrauterine life and drains tears from the lacrimal sac to the lower aspect of the lateral nasal wall. Residual epithelial remnants may persist at the inferior portion of the duct (Chapter 14)
Mid‐palatal raphe cyst (Epstein pearls)	Epithelial inclusions	The palatal shelves fuse at about 7–8 weeks of intrauterine life. The epithelial coverings fuse and then break down into many small islands, many of which form small ‘microcysts’ (Figure 9.7). Most involute before birth, but up to 80% of newborns may have cysts up to 3 months of age (Chapter 9). There is some evidence that inclusions may arise in the bone and give rise to an intraosseous ‘median palatal cyst’ (discussed in Chapter 13)
Surgical ciliated cyst	Remnants of respiratory epithelium	Fragments of sinus epithelium become implanted into a wound following surgery involving the maxillary sinus (Chapter 16)
Cysts of the salivary and minor mucous glands
Mucous retention cysts	Ducts of minor mucous glands	The ducts of minor mucous glands become blocked and dilated, most often as a result of trauma (Figures 15.5, 15.6, and 15.10)
Salivary duct cyst Lymphoepithelial cysts	Intraparotid ducts	The pathogenesis is uncertain, but blockage of ducts associated with sialadenitis may cause cystic dilatation (Figure 15.12)
Intraoral lymphoepithelial cysts	Tonsillar crypt epithelium	The opening of intraoral tonsils may become blocked, causing cystic dilatation of the crypt. Some intraoral lymphoepithelial cysts may be retention cysts arising from a superficial duct of minor salivary glands
Developmental cysts of the head and neck
Intraoral dermoid and epidermoid cysts	Epithelial inclusions	Epithelial remnants are sequestered into the tissues during fusion of facial processes. Oral dermoid and epidermoid cysts are found in the anterior oral cavity at sites of fusion of the mandibular processes (Box 18.1)
Intraoral cysts of foregut origin	Epithelial inclusions	Oral foregut cysts arise from epithelial remnants following fusion of the tuberculum impar (first branchial arch) and the posterior one‐third of the tongue (second to fourth arches) (Box 18.2)
Branchial cleft cysts	Epithelial inclusions	Branchial cleft cysts arise from epithelial remnants that become entrapped or persist due to incomplete obliteration of the branchial clefts or pharyngeal pouches (Box 18.3)
Thyroglossal duct cyst	Remnants of the thyroglossal duct	The thyroid gland develops at about 4 weeks of intrauterine life in the dorsum of the tongue. The developing gland descends downwards into the upper neck forming the thyroglossal duct, which then disintegrates. However, residual epithelial remnants are found in the midline of the upper neck and tongue in about 40% of people (Box 18.4)

In the majority of odontogenic cysts, the epithelial lining is derived from epithelial remnants of the dental lamina (Table 2.1). Early in the development of the jaws, the surface epithelium thickens and grows downwards into the mesenchyme of the future dental arches to form the dental lamina. This extends around the arch as a band that maps the future sites of tooth bud formation for both primary and secondary dentitions. The teeth develop as a result of complex epithelial–mesenchymal interactions that result in epithelial thickenings or placodes, which then form the enamel organs that pass through the well‐described bud, cap, and bell stages during formation of the fully developed tooth (Nanci 2017 ). The dental lamina remains as a thin band that joins the surface oral epithelium to the enamel organ and only disintegrates at the late bell stage of tooth development. Disintegration of the dental lamina results in the formation of small epithelial islands that lie over unerupted teeth, but also remain in the tissues adjacent to the teeth after eruption. The disintegrating vdental lamina is illustrated in Figure 9.9. The epithelial cell rests of the dental lamina give rise to most of the odontogenic cysts (Table 2.1) as well as to most odontogenic tumours. Dental lamina rests are particularly numerous at the posterior aspect of the dental arches and in the tissues overlying unerupted teeth and in the dental follicle. This accounts for the fact that the angle of the mandible is a common site for many cyst types, and that many cysts (and tumours) may arise in the dental follicle and embrace or surround an unerupted tooth and lie in a dentigerous relationship. This especially affects the mandibular third molars, since these are the most commonly impacted teeth (Brown et al. 1982 ).

Although most types of odontogenic cyst arise from dental lamina, the most common cyst (radicular cyst) takes its origin from the rest cells of Malassez that lie in the periodontal ligament as remnants of Hertwig's root sheath (see Figure 3.6). The second most common cyst, the dentigerous cyst, arises from the reduced enamel epithelium that embraces the fully formed crown of a tooth prior to eruption. In the case of the radicular cyst, the phases of cyst formation and growth are well understood and are driven by inflammation that is initiated by bacterial factors emanating from a non‐vital pulp. This process is described in detail in Chapter 3. In developmental cysts, however, the processes are less clear, but are almost certainly driven by epithelial–mesenchymal interactions that initiate the molecular signalling pathways that underpin normal tooth development, morphogenesis, and eruption. Thus, the mechanisms of formation of developmental cysts can be regarded as the aberrant expression of normal processes.

Normal tooth eruption provides a good model of the epithelial–mesenchymal interactions that regulate tissue remodelling, including cell proliferation and bone resorption, and involve complex cascades and networks of cytokines, chemokines, and growth factors (Wise et al. 2002 ; Nel et al. 2015 ; Bastos et al. 2021 ). These biological factors are discussed in detail in the context of the radicular cyst (Table 3.2), where the cascade is started by bacterial infection, but the same factors are involved in normal development and tooth eruption and contribute to the pathogenesis of developmental cysts. For example, Il‐1α is a pivotal pro‐inflammatory cytokine that can be activated by bacterial endotoxins, but it also has an important role as a paracrine signalling molecule in the dental follicle where, along with other factors (e.g. parathyroid hormone–related protein) it mediates tissue remodelling and bone resorption during tooth eruption via its role as an activator of osteoclasts.

These 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.