CHAPTER 93 Odontogenesis, Odontogenic Cysts, and Odontogenic Tumors
Odontogenic tumors are often intricate admixes of neoplastic and non-neoplastic lesions. Even the “simple” odontogenic lesions have their origin traced back to odontogenesis. But odontogenesis is far from simple. By understanding odontogenesis, the reader’s appreciation for these lesions should be enhanced. In fact, it is the unique interaction of ectomesenchymal tissues with epithelial tissues during odontogenesis that make these cysts and tumors unique. These interactions of the mesenchyme and epithelium occur across short distances and within the confined volume of the jaws. Complications in histologic interpretation include artifacts caused by demineralization, sampling errors, separation of hard and soft tissues at the grossing bench, and general difficulties in sectioning disparate tissue types. Separation of disparate tissue at the grossing bench can make it impossible to analyze the relationship of tissues later under the microscope. Even when these background problems are not encountered, the result is often still a histopathologic hodgepodge. In the end, odontogenic lesions that contain both epithelial and mesenchymal components are often difficult to assess histologically.
A basic understanding of odontogenesis by the surgeon/clinician may help to predict behavior, enlighten the clinician on what information to give the pathologist, and guide proper treatment. Thus odontogenesis and the jaws’ unique status within the body create a wide set of possibilities for clinical, radiographic, and histopathologic differential diagnosis lists. It is the goal of this chapter to review odontogenesis, as well as odontogenic cysts and tumors. It is hoped by the end of this chapter that a better understanding of odontogenic cysts and tumors will lead to a more thorough appreciation of this intricate and complicated set of diseases.
Odontogenesis begins within generally well-defined areas of the stomodeum, then by maturational extension the oral cavity and alveolar processes of the jaws. Unfortunately, simply knowing the location does not necessarily allow the clinician to always positively ascertain a lesion as being odontogenic in origin. Confounding elements include the embryologic nature of Rathke’s pouch, extension of large odontogenic lesions outside the confines of the alveolar processes, and the propensity of products of odontogenesis to “wander.” Thus reports of sinonasal ameloblastomas and craniopharyngiomas of the sella should not be surprising and still be considered odontogenic in origin. Simply put, the only prerequisite is that all odontogenic cysts and tumors must be derived from elements of stomodeal origin.
Histologically the rather unique epithelial portions of odontogenesis often remain distinct enough in cysts and tumors to allow for proper determination of origin. Unfortunately, the mesenchymal components of the dental papilla (as seen in myxomas) and cemental components (as seen in odontogenic fibromas) are impossible to definitively identify histologically as being of odontogenic origin. The only hope in identifying these as odontogenic is if they occur in association with other odontogenic epithelial elements. But generally, these mesenchymal lesions are identified as odontogenic on the basis of their location in the jaws.
Though this section focuses only on odontogenesis, remember that the oral and maxillofacial region is also associated with developmental remnants of salivary glands, seromucous glands, sinonasal epithelium, nasopalatine duct epithelium, and dermal epithelia. Due to these nearby, possibly confounding embryologic tissues, the true origin of any given lesion may be cloudy at best. However, by knowing the specific location, history, and histopathologic features and being additionally armed with knowledge of odontogenesis, the proper designation for any given lesion can almost always be filtered to arrive at a relatively short differential diagnosis list.
The enamel organ is generally divided into the bud stage, cap stage, and bell stage. The bud stage begins as a proliferation of the basilar cells of the stomodeum. This proliferation occurs along the area of the future alveolar mucosa apical to and separated from the vestibular mucosa. In this early stage the ectoderm of the stomodeum is lined by two to three cells. It is during the sixth week that the ectoderm in the region of the future alveolar processes begins to proliferate and form two somewhat horseshoe-shaped epithelial bands. Before being differentiated into the epithelial surfaces of the alveolar processes, each band is called a dental lamina. These dental laminae will eventually form the 20 separate proliferations necessary for the deciduous teeth. These 20 areas of proliferation are each called tooth buds. Each tooth bud then proliferates apically into the underlying ectomesenchymal tissue. Eventually at the bell stage the connection between the overlying stomodeum and the enamel organ will become separated. But the actual process of bud proliferation varies by arch, as well as by tooth type (i.e., deciduous central incisor, deciduous lateral incisor, deciduous canine, deciduous first molar and deciduous second molar). By the end of the eighth week all 20 buds have been produced.
During all phases of morphodifferentiation, histodifferentiation, and apposition the features of the enamel organ and the physiologic support of the enamel organ are changing. But with apposition of the dentin and vascularization near the outer enamel epithelium the enamel organ is further defined with a fourth cell layer termed the stratum intermedium. The cells of the stratum intermedium occupy an ill-defined area of flattened cells between the inner enamel epithelium and the stellate reticulum. Though the area of phenotypic change that defines the stratum intermedium must be present before enamel can be laid down, actually identifying these cells individually is extremely subjective.
In the tooth root, the dentin forms the huge majority of the root volume, which is then sheathed in a layer of cementum instead of enamel. But the odontoblasts still cannot lay down dentin without induction by epithelium derived from the enamel organ. To accomplish this feat as the reduced enamel epithelium reaches the cementoenamel junction, it becomes reduced to back-to-back inner and outer epithelial cells. This produces a collar of cells that separate from the reduced enamel epithelium. This separated collar is known as Hertwig’s epithelial root sheath. Hertwig’s root sheath as it moves apically to guide root formation will “leave behind” epithelial rests known as rests of Malassez. These rests will reside in the region of the periodontal ligament and provide a basis for several potential odontogenic cysts and tumors.
The periodontal ligament is actually a joint known as a gomphosis joint. Though the cementum cannot be distinguished except by location, the body, for instance, during orthodontic movement will resorb the bone on the lamina dura side of the periodontal ligament and not the cementum on the tooth side of the ligament. The tooth with the periodontal ligament will retain a certain amount of mobility within the joint. The reader is again referred to various texts for a more in-depth coverage of odontogenesis.1–5,5a
There are a number of odontogenic epithelial stages and each may provide a basis for odontogenic cysts or tumors. The four main stages considered are (1) dental lamina, (2) enamel organ, (3) reduced enamel epithelium, and (4) Hertwig’s epithelial root sheath. The rests of Serres and Malassez are considered along with their respective progenitors of the dental lamina and Hertwig’s root sheath. In addition, the stomodeal epithelium gives rise to Rathke’s pouch, which retains odontogenic potential. Shafer and colleagues6 suggest the original basal epithelium of the stomodeum also retains potential. In the adult this basal epithelium is represented by the gingival and alveolar mucosal surfaces.6 This concept seems to be supported when peripheral ameloblastomas appear to develop directly from overlying gingival epithelium. With that said, most clinicians would consider the adult basal epithelium to be a rare source of odontogenic neoplasia. The rests of Malassez are common sources of inflammatory odontogenic cysts but retain little neoplastic potential. The rests of Serres, the enamel organ, and reduced enamel epithelium are generally considered the stages most likely to become neoplastic. All stages have the potential to form cysts but to variable degrees. Dentigerous cysts with their origin from the reduced enamel epithelium and radicular cysts from rests of Malassez make up the overwhelming majority of odontogenic cysts.
When reading various sources it becomes quickly clear that what a cyst “is” varies by author and that the classification schemata are in disarray as well. The modified classification scheme seen in Box 93-1 is my attempt at organization. The odontogenic cyst of undetermined origin is a new, admittedly descriptive “diagnosis” used by some oral pathologists. Unfortunately the descriptive nature of that term will not be available to look up in other texts or journals. However, it replaces the diagnosis of primordial cyst. The need to use a descriptive term instead of primordial cyst is due to the ambiguous use of primordial cyst both as an odontogenic keratocyst (OKC) and a simple nonkeratinizing cyst that cannot be classified in relation to the tooth. The descriptive role is to provide a pigeonhole in which to place lesions that are histologically ambiguous, not directly associated with a tooth but located in the alveolus and thus presumably odontogenic in origin.
Several classification schemata for odontogenic cysts and oral and maxillofacial cysts exist.7–9 The classification scheme seen here is modified from that of the World Health Organization (WHO). In 1992 WHO published the second edition of Histological Typing of Odontogenic Tumors.10 Unfortunately the most recent WHO treatise on odontogenic tumors is contained within the Pathology and Genetics of Head and Neck Tumors.11 In this change odontogenic cysts are no longer covered within the text. Box 93-1 also contains selected nonodontogenic cysts for completeness and comparison.
By definition a cyst is considered a “pathologic cavity at least partially lined by epithelium.” To be an odontogenic cyst the epithelial lining must be derived from odontogenic epithelium. The best advice to the reader is that all classification schemata are artificial to some extent. The key is to organize them the way that is most useful to you. This modification in Box 93-1 is an attempt at self-clarification and will hopefully be useful for others in either its pure or modified form.
Many odontogenic cysts are surfaced by nonkeratinized epithelium. Histologically the following nonkeratinizing cysts can look identical and cannot be separated except by clinical, historical, and/or radiographic means. These include dentigerous cyst (follicular cyst), eruption cyst, odontogenic cyst of undetermined origin, periapical cyst (apical periodontal cyst), lateralized periradicular cyst, residual cyst, and paradental cyst.
These cysts make up the majority of odontogenic cysts. As a group they are known as the common odontogenic cysts. For proper diagnosis of these common odontogenic cysts the clinician must provide sufficient information for the diagnosis to be made. The reader is urged to closely note the necessary or significant features when each of these cysts is specifically discussed later in this section.
The other odontogenic cysts will display histologic features to allow for the proper diagnosis, though history and communication are of course always appropriate and often essential. It is important to note that the presence of a specific type of keratin is not pathognomonic for an OKC and may be seen with other odontogenic cysts.
Cyst expansion occurs because of numerous factors including accumulation of inflammatory cells, fibrin, serum, and desquamated epithelial cells. As these products enter the cystic cavity, it is the accumulation of the intraluminal products that spurs the cystic expansion of the wall.12–14 Alternatively, cyst expansion may be spurred on by the inherent mitotic activity of the cyst wall itself. If this mitotic activity is the major component of the cyst expansion, it may be better to consider the lesion a cystic neoplasm rather than a simple cyst.14–20 This debate lies at the center of how to classify the OKC, as well as the calcifying odontogenic cyst.21 In the case of the OKC, WHO has renamed it the keratocystic odontogenic tumor. Discussion of this entity is in the odontogenic cyst section. In the case of the calcifying odontogenic cyst (the tumor version), the reader is referred to more detailed articles on the epithelial odontogenic ghost cell tumor.
Multilocularity may in itself be a signal that the lesional growth is mitotically or multifocally driven rather than hydraulically driven.22–25 For this reason the potentially multilocular odontogenic cysts, such as the botryoid odontogenic and glandular odontogenic cyst, may arguably have a neoplastic potential as well.22,26–30 However, in the case of the botryoid cyst the possibility of multifocality cannot be ignored. Cell regulation protein studies to determine cell inhibition and division activities may be helpful in future classifications.31,32 In addition, the ability of epithelia to break down elements of the connective tissue wall could be important.33–37
However, even simple cysts like the periradicular cyst derived from rests of Malassez must possess some mitotic activation, or growth would be impossible. Activation is thought to occur as a result of inflammatory production within the periodontal membrane.13,38 In the skin and gingiva it has been shown that inflammation leads to release of inhibitors, which then allow the renewal of mitotic activity.15 Once a solid epithelial sphere has been formed, it is thought that it eventually outgrows its vascular nourishment and the central area degenerates to form a lumen.15,16 Following the formation of the central lumen, transepithelial flow of fluid is sustained by osmotic forces. Thus hydrostatic pressure plays a role in the development of the classic unilocular appearance of most cysts. How the pressure results to produce osteoclastic resorption is less clear.17,39–41
Cysts that are derived from the more neoplastic dental lamina, or are in themselves “cystic neoplasms,” probably occur as a result of self-sustained or unregulated mitotic activity.42 Even in neoplastic cysts, luminal expansion may occur through degenerative effects, debris accumulation, and hydraulic and mitotic activity.43–45
The periapical cyst must be associated with a nonvital tooth. The tooth may be rendered nonvital by trauma, caries, or periodontal space extension. As such, these cysts may be seen at any age, although permanent teeth are more likely to be involved than deciduous teeth.46 They are thought to be derived from rests of Malassez.
Periapical cysts present as a unilocular radiolucency at the apical portion of the tooth. Though well defined, the border varies from corticated to sclerotic to merely well defined. Variations depend on the amount of inflammation present. Long-standing, neglected lesions can get quite large, though most are less than 1 cm in diameter (Fig. 93-1).
This is the classic inflamed “common odontogenic cyst” and as such the luminal lining will consist of nonkeratinized stratified squamous epithelium. This is an inflammatory cyst and inflammation is invariably present if sufficient sampling is performed (Fig. 93-2). Rests of Malassez are possible in the connective tissue. However, odontogenic rests are rarely seen in the cyst wall even though these rests are thought to be the source of the epithelial proliferation. Cholesterol slits, foreign body giant cells, and hemosiderin deposits are common findings. As in all “common odontogenic cysts,” squamous odontogenic tumor-like” proliferations may be seen in long-standing lesions. These epithelial islands will be cytopathologically benign without evidence of dysplasia. If squamous odontogenic cystlike proliferations are noted, they should essentially be ignored and are of no prognostic significance. In endodontically treated teeth, foreign bodies secondary to endodontic therapy are common.47 Bacterial colonies may also be seen in these cysts. Though actinomycetes colonies may portend a tendency for being slow to resolve, their presence should not result in a diagnosis of osteomyelitis. Such colonies are more commonly an incidental rather than a significant finding. Thus, for multiple reasons, the proper diagnosis of periapical cyst requires radiographic or clinical corroboration.
This cyst is treated with simple enucleation (Fig. 93-3). Enucleation is often accomplished at the time of tooth extraction. Uncounted numbers of these cysts are probably adequately resolved with endodontic therapy. If a radiolucency persists longer than 6 months following endodontic therapy, enucleation and histopathologic review are necessary.48–50
This cyst is simply a variant of the periapical cyst. It is associated with a nonvital tooth, but instead of being at the apex of the tooth the cyst is located lateral to the tooth root(s). This happens because the root canal system of teeth sometimes has exits on the lateral aspect of the root, not just at the apex. Therefore if the path of least resistance is out one of these lateral canals the lesion will be present laterally. Otherwise, the clinical, microscopic, radiographic, and histologic features are identical to the periapical cyst.
The majority of these cysts will be the result of leaving a periapical cyst “behind” following tooth extraction. All of these cysts are inflammatory cysts. Occasionally an inflamed dentigerous cyst is incompletely removed and could also be the source of a residual cyst. The clinical, microscopic, radiographic, and histologic features are identical to the periapical cyst.48,49,51,52
This may or may not be considered by some to be a true cyst. However, because it is an occasionally used diagnosis, a quick summary is included here. This lesion is associated with periodontal disease of a vital tooth. Uncommonly, a deep intrabony periodontal pocket may be sufficiently isolated to allow for hydraulic expansion of the bone (Fig. 93-4). As such, radiographically there will be a radiolucent periradicular lesion (Fig. 93-5). There will also be a periodontal pocket associated with that radiolucency. This diagnosis should be limited to those cases where the clinician indicates the diagnosis as the most likely choice. Otherwise, the clinical, microscopic, radiographic, and histologic features are identical to the periapical cyst.53
The dentigerous cyst by definition must be associated with the crown of an unerupted tooth, developing tooth, or odontoma. The eruption cyst is essentially a subtype of dentigerous cyst that is confined just by the overlying alveolar mucosa. Dentigerous cysts form when fluid accumulates between reduced enamel epithelium and tooth crown.14 As alluded to earlier, the accumulation of fluid may be partially or largely surrounded by connective tissue and epithelium.54,55 Because the third molars and maxillary canines are the teeth most frequently impacted, they are also the most likely to be associated with dentigerous cysts. However, any impacted tooth has an increased risk. There also may be inherent differences in impacted tooth development and how the reduced enamel epithelium is transformed/resorbed.56 They are generally found in the teenage years and early adulthood.57 However, the longer a tooth is impacted, the greater the chance a dentigerous cyst will develop.58
A dentigerous cyst presents as a unilocular radiolucency, which is associated with an unerupted tooth (Fig. 93-6). Dentigerous cysts may also involve odontomas that, by nature, also have “tooth crowns.” The radiolucency is generally well demarcated and well corticated. The border may become sclerotic or display rarifying osteitis if secondary infection is present. Even large cysts that have pushed the associated tooth considerable distances will display evidence of origin from the cementoenamel junction if the film angle is adequate. In large lesions the origin from the cementoenamel junction is best visualized as an area of cortication at the cementoenamel junction. There is considerable overlap between the appearance of small dentigerous cysts and hyperplastic follicles.56
The specimen will present primarily as variably dense fibrocollagenous connective tissue with some areas being loose and myxomatous. Odontogenic epithelial rests are usually scattered within the connective tissue and are most common near the epithelial lining. The luminal lining consists of nonkeratinized stratified squamous epithelium. The presence of mucous prosoplasia within the lumen is not uncommon. Care should be taken to not overinterpret the mucus prosoplasia. Cholesterol slits and their associated multinucleated giant cells may be present in inflamed cysts and are generally associated with the connective tissue wall.47 As mentioned earlier, the lumen may be partially or mostly lined by connective tissue.14 If present in the specimen, crevicular epithelium may make microscopic separation of an inflamed dentigerous cyst from pericoronitis impossible. Thus proper diagnosis requires radiographic or clinical corroboration.
Dentigerous cysts appear to retain the ability to transform into true neoplasms. One study reported that 17% of ameloblastomas were associated with an existing dentigerous cyst.59 This figure varies by study, however.60–62 Both squamous cell carcinomas and mucoepidermoid carcinomas have been reported.63–67
The eruption cyst is a form of dentigerous cyst that is found in the soft tissue overlying an erupting tooth. Because by definition it must be associated with an erupting tooth, eruption cysts occur only during the ages of tooth development.7 They may be seen with erupting deciduous or permanent teeth, but the majority of lesions are seen in the first decade.68 The lesion will present as a soft tissue swelling of the alveolar ridge overlying an area of age-appropriate tooth development. Some eruption cysts will have a slightly blue hue color, though the normal coral pink color of the surrounding mucosa is common (Fig. 93-8). Unlike dentigerous cysts, it is not uncommon for an eruption cyst to be associated with deciduous teeth. Eruption cysts may be seen in newborns with an incidence of 2 per 1000 births reported.69 Clinical follow-up may also serve to confirm the diagnosis because the tooth will erupt within several weeks to months through the cystic expansion.70–74
The paradental cyst is considered by some to be a variant of the dentigerous cyst. This is because the various forms of paradental cyst all originate from the cementoenamel junction just like the dentigerous cyst. However, the paradental cysts are almost uniformly inflamed, so they are generally classified as inflammatory cysts rather than as developmental cysts. Paradental cysts occur on the buccal or distal aspect of an erupted mandibular molar. Though the mesial aspect of a mandibular tooth may rarely be involved, there have been no reported occurrences to the lingual. Craig75 reported the occasional presence of developmental enamel projections near the furcation of some teeth. This is particularly true of the subcomponent of paradental cysts known as infected buccal bifurcation cysts. How big a role these projections play in pathogenesis remains debatable.76–81 In one series the paradental cyst accounted for 3% of all odontogenic cysts.82
It is with great regret that another diagnosis is added to the list of odontogenic cysts, but there appears to be no good alternative. On occasion the clinician and pathologist may come upon a lesion that is not classifiable by histologic, radiographic, or clinical features. As mentioned earlier, several odontogenic cysts have identical microscopic features. Odontogenic cysts with identical or potentially identical histologic features are referred to as the common odontogenic cysts. These “common” cysts are separated on the basis of clinical features alone.
The problem in diagnosis comes when a cyst is not associated with the crown of a tooth, residually or with the root of a nonvital tooth. Additionally, the cyst is not consistent with a fissural cyst but is at least partially located in the alveolar process. Historically, any cyst that occurred in an area where a tooth should have developed, or where supernumerary teeth could occur, were originally called primordial cysts.83 This term was used to allude to development from the tooth primordium. Unfortunately, this was proposed in 1945 before delineation of the features defining the OKC and a large percentage of these “primordial” cysts had features of what would now be diagnosed as an OKC. When the OKC was defined in the 1950s, some pathologists had already recognized those histologic features in what they termed primordial cysts and thus they began to use the term interchangeably with OKCs. International journals, especially, came to use the term primordial cyst as a synonym of the OKC.45,84 Americans often avoided the term primordial or left the moniker of primordial cyst for those lesions without features of a keratocyst.
The term primordial cyst is avoided to eliminate any confusion between the histopathologist and the clinician. This is intended to ensure that aggressive treatment of an OKC is not performed for this innocuous lesion.
An odontogenic cyst of undetermined origin is a unilocular radiolucent cyst of the jaws with histologic features of common odontogenic cysts but lacking the clinical, histologic, and radiographic features of any defined common odontogenic cyst (Fig. 93-9).
These cysts are thought to be derived from the dental lamina and are thus thought to retain some limited neoplastic growth potential. This limited neoplastic potential is best displayed by the associated lesion known as a botryoid odontogenic cyst. Lateral periodontal cysts are located on the lateral surface of a vital tooth.85,86 This assumes that the tooth has not been rendered nonvital by dental caries or trauma unrelated to cyst formation. The most common location is the mandibular premolar/canine area. If present in the maxilla, the lateral incisor area is the most common location. However, the lateral periodontal cyst may be seen in any area of the alveolar processes. This cyst is seen in the interproximal area between tooth roots and is usually an incidental radiographic finding.87,88 Demographically the cyst is most common in males by a 2 : 1 ratio with a peak incidence in the fifth and sixth decades.89 The gingival cyst of the adult and the botryoid odontogenic cysts are essentially subtypes of lateral periodontal cysts. Other cysts, especially the OKC, odontogenic cyst of undetermined origin, and the lateralized periapical cyst, also present interproximally. Histopathologic features and tooth vitality are important diagnostic considerations to separate these lesions. All of these lesions can be separated histologically and the lateralized periradicular cyst will be associated with a nonvital tooth.
The lesion presents as a unilocular radiolucency of the alveolus that is usually well corticated. Larger lesions may result in diverged roots.90 Multilocular lesions are a special subset and are classified as botryoid odontogenic cysts (see “Botryoid Odontogenic Cyst” later).27
The cyst lining is composed of nonkeratinized simple to stratified squamous epithelium. The lining is most notable for being only a few cells in thickness (Fig. 93-10). Intermixed within this otherwise thin epithelial lining are nodular epithelial thickenings or plaques. The plaques may display somewhat whorled epithelial cell aggregates. The central cells in the aggregate may display cytoplasmic clearing. The clear cells contain glycogen, which can be digested with diastase. Scattered mucous cells may be seen in some lesions but should not be a dominant feature.90,91 The diagnosis of lateral periodontal cyst must be reserved for lesions displaying the thin epithelium described earlier. The plaquelike thickenings are helpful microscopic features but are not always found. The connective tissue wall may contain dental lamina rests, but they are not required for diagnosis.
These cysts are treated with simple enucleation, though the surgeon is reminded to look for intraoperative multilocularity, which may not have been evident radiographically. If multilocularity is present, the lesion is probably a botryoid odontogenic cyst. In such cases light curettage of the surrounding bone wall is advised. Recurrence of the simple lateral periodontal cyst is not a problem and even the recurrences of botryoid cysts are usually easy to manage.
The botryoid odontogenic cyst will usually present as a multilocular lesion and is a special variant of the lateral periodontal cyst. Botryoid refers to the fact that these lesions may appear like grapelike clusters, both histologically and usually radiographically as well.23,25,27
Like the lateral periodontal cyst, treatment consists of enucleation with bony curettage. The multilocular nature may make this difficult, especially if teeth are to be spared. With full enucleation, light bone curettage recurrence should be uncommon. The slow growth of these lesions suggests that a 10-year radiographics is reasonable, though the small sample size makes this a suggestion at best.
This lesion is essentially the soft tissue equivalent of the lateral periodontal cyst. As with the lateral periodontal cyst, it derives from dental lamina or rests of Serres.92–94 These lesions generally present as an asymptomatic bluish nodule on the facial aspect of the gingiva. The sessile elevation will be centered in the attached gingiva, though extension below the mucogingival line is possible. Unlike the lateral periodontal cyst, there may be a slightly increased incidence in women.95 The mandibular gingiva is most commonly involved and the peak incidence occurs in the fifth and sixth decades.9,96 Other odontogenic cysts may also occur in the gingiva. Histologically distinctive odontogenic cysts that are appropriately diagnosed histopathologically should not be descriptively called gingival cysts. The possibility of some cysts of the gingivae arising from traumatically implanted surface epithelium does exist. Whether it is best to call these histologically different cysts epithelial inclusion cysts is debatable.95 The term gingival cyst of the adult must be reserved for those lesions with histologically distinct microscopic criteria.
These cysts occur on the alveolar ridge of newborns. They are generally only a few millimeters in diameter and seen only in the first few months of life. Though studies are appropriately devoid of histologic sampling data, some clinical reports estimate these cysts occur in up to 50% of all newborns. The cysts are sessile and vary from normal in color to yellow or white. Similar-appearing inclusion cysts of the palatal midline (Epstein’s pearls) or at the junction of the hard and soft palates (Bohn’s nodules) are differentiated by location. The gingival cyst of the newborn is a soft tissue cyst and does not have an intrabony component (Fig. 93-11).97
Keratinizing Odontogenic Cyst (Orthokeratinizing Odontogenic Cyst, Orthokeratinizing Odontogenic Keratocyst)
Recognition of the keratinizing odontogenic cyst is a rather recent phenomenon. When the OKC was first defined, the definition did not separate these lesions. Over time several reviewers noted and separated keratinizing cysts that did not seem to otherwise conform with the microscopic criteria of the OKC.98–100 The most notable difference in these cysts was the presence of orthokeratin rather than parakeratin, though other features such as lack of tombstoning, corrugation, and hyperchromatism are more important criteria. Wright101 was the first to formally separate this group of cysts and proposed the name of OKC, orthokeratinizing variant. He noted the different histopathologic features and ably reported the lack of recurrences associated with these orthokeratinized cysts. However, the nomenclature of including the term keratocyst has created quite a bit of confusion, at least anecdotally. Historically, older texts and articles described keratinization of various odontogenic cysts and recognized the difference of these cysts from OKCs.47,100
The designation as orthokeratinized OKC (OKC, orthokeratinized variant) has evolved since first being described. Current nomenclature has evolved to avoid confusion with the “standard” OKC. It is also worth noting that some OKCs can contain orthokeratin, and the original series of “orthokeratinizing OKCs” described by Wright included 7 of 60 cysts with parakeratin.101 Thus classification based solely on the type of keratin alone is unwise.
The separation of the keratinizing odontogenic cyst is clinically important because the reported recurrence rate of the keratinizing odontogenic cyst is only 2%. The peak incidence of keratinizing odontogenic cysts is in the third, fourth, and fifth decades, with about three fourths of them being in a dentigerous cyst relationship. Other locations are possible, in various relationships to the teeth. Most cysts are asymptomatic, though pain and swelling was reported respectively in 22% and 13% of cases.98,99 The keratinizing odontogenic cyst is not associated with basal cell nevus syndrome (Gorlin-Goltz syndrome).
The epithelial lining will most often be thin with keratinization. However, the thickness will be somewhat variable. Keratin production varies and may only occur on a portion of the cyst wall. Orthokeratin is characteristic but not pathognomonic.102 Most notable are the features that are not present. The features defining an OKC are absent.
Controversy encompasses this lesion and undoubtedly further delineation of features will evolve. The glandular odontogenic cyst is usually asymptomatic and involves the mandible more often than the maxilla.29,103 Large cysts may be destructive and expansile.104,105 The glandular odontogenic cyst involves adults and its pathogenesis is not yet understood.106 This cyst may be either multilocular or unilocular. The cyst is generally well defined and often well corticated.
This cyst is lined by cuboidal epithelium of varying thickness, which may display cilia. Unfortunately, separating this particular microscopic feature from “normal” (and insignificant) mucus prosoplasia is sometimes difficult. The following features are more important in establishing the diagnosis. The cyst lining will be mucicarmine positive. The mucin detected by mucicarmine collects in small pools. Characteristically there are cuboidal cells near the surface, which give a slightly papillary appearance to the lumen.103 The epithelium will also contain spheroid aggregates of cells.108,109 The presence of mucous cells in other odontogenic cysts is not diagnostic for this lesion. This lesion, in this author’s opinion, is “overcalled” and second opinion is often necessary. Standard “common odontogenic cysts” with mucus prosoplasia are often “upgraded” to glandular odontogenic cysts (Fig. 93-13). Glandular odontogenic cysts may be “upgraded” to central mucoepidermoid carcinoma. Great care to properly designate these lesions is necessary to ensure proper patient care.
Recurrence after enucleation has been reported.103 As in any multilocular lesion, nucleation and curettage of bone is recommended. Few cases are available to draw further treatment conclusions, but the overall prognosis is good.30 Suggestions to treat this cyst aggressively appear to be misguided.
The OKC remains an enigma for the clinician and researcher, although knowledge gains in recent years have allowed for an improved understanding of this interesting lesion. The lesion was first described by Philipsen in 1956, but even 5 decades later the debate continues over the pathogenesis, behavior, treatment, and classification of this cystic neoplasm.18–20 One major dilemma is whether to classify it as a cyst or a neoplasm. The current World Health Organization (WHO) nomenclature stresses the neoplastic nature and uses the term keratocystic odontogenic tumor.
Soft tissue extension, extension into adjacent bones, and expansion with associated bony destruction have been reported. These reports have prompted clinicians to question what the most appropriate method of treatment really is. Scharfferter and colleagues110 documented increased mitotic activity within the epithelial lining of the OKC, which seems to support its neoplastic nature.
OKCs occur over a large age range. Lesions are often found during and slightly after odontogenesis of the permanent teeth. Peak incidence is in the second and third decades but may occur at any age. The mandible is more often involved than the maxilla, but treatment of maxillary lesions is often more problematic. OKCs are most common in the mandibular third molar area, but any area of the jaw may be involved. Patients are often symptomatic with swelling, pain, trismus, sensory deficits, and infection being the most common complaints. However, the lesion may also present as an incidental radiographic finding.
Of particular interest to the clinician is the biologic behavior of the OKC. Recurrence rates of up to 62.5% have been reported with enucleation alone. However, modern reports have a much lower recurrence rate when enucleation and careful curettage are performed. Most modern recurrence rates are less than 10%.111,112 Reasons to explain the recurrence rate include daughter or satellite cyst formation113; incomplete removal of the epithelial lining, leaving satellite cysts left behind; collagenase activity of the cyst114; dental lamina rests left in the cyst wall or overlying mucosa; prostaglandin-induced bone resorption115; and increased mitotic activity. A handful of articles have demonstrated that the OKC can proliferate within muscle, and death from intracranial extension of mandibular OKCs has been reported by Jackson and colleagues.84,116,117 Though these case reports should be remembered, the need to aggressively treat all OKCs should be resisted.
OKCs may be unilocular or multilocular, multiple, or single. OKCs with calcifications within a cyst wall have been reported, but calcification is rare and OKCs are considered radiolucent lesions. OKCs are highly variable in size (Fig. 93-14). They can appear pericoronally, periradicularly, interradicularly, apically, and even peripherally. In summary, OKCs may occur in all areas of odontogenesis and they may extend significant distances.97 The borders are well defined and often corticated.98,118 Patients involved with Gorlin syndrome are more likely to present with metachronous or synchronous cysts. CT scans may be helpful in assessing large lesions and CTs are often essential in assessing maxillary lesions.119–121
The OKC has a specific microscopic appearance and the mere presence of a keratin lining or keratin within the cyst lumen is not sufficient to assure a diagnosis of OKC. The other features unique to the OKC must also be seen. The stratified squamous epithelium is generally 4 to 10 cells thick. The basal cell nuclei are particularly hyperchromatic, but even the parabasalar cells are more hyperchromatic than the spinous cells seen in other odontogenic cysts. The basal layer consists of cuboidal to columnar cells with a palisaded or “tombstone” appearance. Corrugated surface changes are often seen at the surface. Of perhaps least diagnostic help is the finding that OKCs are surfaced by parakeratinizing stratified squamous epithelium. Again, parakeratin is not pathognomonic for an OKC.
A handful of reports with significant complications have led some clinicians to perform aggressive surgical procedures on all lesions. Debate persists about how to best manage OKC lesions in general. Treatment should center on decreasing the recurrence rate to a rate expected of the modern era and one that reduces patient morbidity. The reader is referred to other articles. After reading many treatises, the following is my opinion.111,112,122–130
Close radiographic follow-up is perhaps the most important modality to prevent complications secondary to recurrence. Recurrences, which often occur in the first 5 years, can take many years to present. Recently at this institution, my colleagues and I saw a recurrence 40 years after initial treatment, though the possibility of a new occurrence could not be eliminated. Establishing a diagnosis is important. Adequate material must be sent to be histologically diagnosed. Common problems are that the inner “layer” of keratin within the lumen is sampled and the diagnostic lining and wall are not submitted. Additionally, the diagnostic histologic features can be lost when inflammation is present.
If the patient has more than one cyst, the possibility of basal cell nevus syndrome is elevated. All cysts should still be examined histopathologically to confirm diagnosis. Clinical work-up to assess for syndrome is always prudent when multiple concurrent or sequential OKCs are diagnosed. Even when OKCs are in teenagers or younger patients are diagnosed with a single lesion, at least a cursory family history and gross clinical assessment for the syndrome should be performed. Some investigators have claimed good success with decompression and subsequent enucleation, while others advocate enucleation, excision of overlying mucosa, peripheral osteotomy, and chemical curettage.125,129
The use of Carnoy’s solution is controversial. Carnoy first reported use of his fixative for the study of nematodes in 1887.131 His goal was to fix the tissue and preserve nuclear detail for microscopic examination. However, fixation of the tissue intraoperatively for future microscopic exam is not really the effect that surgeons desire. Surgeons desire the chemical cauterization effect that the solution produces.
Regardless of the technique, the cyst lining must be entirely removed including satellite cysts and dental lamina rests. Thus careful enucleation is followed by some bone removal. Generally this is removal of daughter cysts and rests accomplished through curettage, peripheral ostectomy with rotary bur, or excision of one anatomic boundary such as periosteum (when bone penetration has occurred).
Recurrent OKCs may need to be treated more aggressively than primary lesions, but in syndrome patients “recurrences” should be considered new occurrences rather than recurrences. Large lesions may leave no other option than resection. However, one should consider decompression to shrink the lesion, followed by enucleation and curettage. In this manner a discontinuity defect or damage to vital structures is reduced or eliminated. If cortical perforation is encountered, frozen sections to assess margins may be necessary. Regardless, patients must be followed on a regular basis for many years following treatment of an OKC. As with most odontogenic lesions, surgery should be dictated by the destruction already caused by the lesion at hand, rather than simply on the histologic diagnosis.
Basal Cell Nevus Syndrome (Gorlin Syndrome, Gorlin-Goltz Syndrome, Nevoid Basal Cell Carcinoma Syndrome)
This complex syndrome is called by many names, and the nomenclature often depends on what portions of the syndrome (e.g., bifid ribs, OKC) are present. In the Gorlin and colleagues132–134 description, no fewer than 37 anomalies have been associated with this syndrome. The reader is referred to the original sources.
OKCs are often the first diagnosis of the syndrome to present in childhood and often aid in establishing a diagnosis. This is especially true in cases in which there are new mutations with no prior familial history.135 Up to 40% of cases may be new mutations, though genetic testing is advancing and there may be large variations in expression in this autosomal dominant disease.134 One patient’s first cyst occurred in the seventh decade. For this reason the syndrome should not be ruled out even in a middle-aged patient, and family history and phenotype may help in all age groups.