Odontogenesis, Odontogenic Cysts, and Odontogenic Tumors

Root Development

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 differentiate and 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 the Hertwig epithelial root sheath. As it moves apically to guide root formation, the Hertwig root sheath will “leave behind” epithelial rests known as rests of Malassez. These rests will reside in the region of the periodontal ligament. These rests provide a basis for several potential odontogenic cysts and tumors.

The periodontal ligament is actually a joint known as a gomphosis joint. Although 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.

Classification

When reading various sources it will become 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 88.1 is my attempt at organization. The “odontogenic cyst of undetermined origin” is a new admittedly descriptive “diagnosis,” which is 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 or when the history provided does not allow for categorization of cysts defined by relationship to the tooth. The need to use a descriptive term instead of primordial cyst is due to the ambiguous use of primordial cyst both as a keratocystic odontogenic tumor (KCOT) as well as simply a nonkeratinizing cyst, which 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, or not directly associated with a tooth but are located in the alveolus and thus, presumably, odontogenic in origin.

There are several classification schemata for odontogenic cysts and for oral and maxillofacial cysts. The classification scheme seen here is a modified amalgamation from that of the World Health Organization (WHO). In 1992 that organization published the 2nd edition of Histological Typing of Odontogenic Tumors . Unfortunately the most recent WHO treatise on odontogenic tumors is contained within the Pathology & Genetics of Head and Neck Tumors . In that 2005 change odontogenic cysts were no longer covered within the text, and this also resulted in the reclassification of several cysts to tumors. Box 88.1 also contains selected nonodontogenic cysts for completeness and comparison. But to confuse things even more, the 2017 version of the WHO Classification of Head and Neck Tumours has now reverted back to the 1992 nomenclature. The organization within Box 88.1 will contain a parenthetical WHO 2017 nomenclature. The International Classification of Diseases and Related Health Problems-10 (ICD 10) also has a projected update to International Classification of Diseases and Related Health Problems-11 (ICD 11) projected in 2018. At the time of this writing it is unclear due to the fluidity of nomenclature exactly where the final decisions will occur. An online search of a draft version of ICD 11 ( https://icd.who.int/dev11/l-m/en ) showed that the term KCOT will still be employed and classified under odontogenic tumors but the term calcifying odontogenic cyst (COC) is being utilized but also classified under odontogenic tumors.

By definition, a cyst will be 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 is an attempt at self-clarification and will hopefully be useful for others either in its pure or modified form.

Pathogenesis

Many odontogenic cyst lumina 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 vast 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, although history and communication is 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 a KCOT and may be seen with other odontogenic cysts. However, parakeratin is indeed the most common form of keratin in a KCOT.

Cyst expansion occurs due to a number 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. 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. This debate lies at the center of how to name and classify the KCOT (odontogenic keratocyst) as well as the calcifying cystic odontogenic tumor (CCOT). In the case of the odontogenic keratocyst the term the KCOT will generally be used in this chapter and discussion of the entity will be in the odontogenic tumor section. The CCOT as well as the closely related more solid dentinogenic ghost cell tumor will also be considered under the tumor section.

Multilocularity may in itself be a signal that the lesional growth is mitotically or multifocally driven rather than hydraulically driven. For this reason the potentially multilocular odontogenic cysts, such as the botryoid odontogenic cyst and glandular odontogenic, may arguably have a neoplastic potential as well. 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. In addition, the ability of epithelia to break down elements of the connective tissue wall could be important.

However, even simple cysts like the periradicular cyst derived from rests of Malassez must possess some mitotic activation or growth would be impossible. Activation of the inflammatory cysts is thought to occur as a result of inflammatory production within the periodontal membrane. In the skin and gingiva, it has been shown that inflammation leads to the release of inhibitors, which then allow the renewal of mitotic activity. 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. 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.

Those cysts, which 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. Even in neoplastic cysts, luminal expansion may occur through degenerative effects, debris accumulation, hydraulic forces, as well as mitotic activity.

Periapical Cyst (Radicular Cyst and Periradicular Cyst)

The periapical cyst must be associated with a nonvital tooth. The tooth may be rendered nonvital by trauma, caries, developmental defect, 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. They are thought to be derived from rests of Malassez.

Radiographic Features

These cysts will present as a unilocular radiolucency at the apical portion of the tooth. Although well defined, the border will vary from corticated to sclerotic to merely well defined. The variations will depend on the amount of inflammation present. Long-standing neglected lesions can get quite large, although most are less than 1 cm in diameter ( Fig. 88.1 ).

Microscopic Features

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. 88.2 ). 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 cyst-like 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. Bacterial colonies may also be seen in these cysts. Although 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, owing to the multiple reasons earlier, the proper diagnosis of periapical cyst requires radiographic and/or clinical corroboration.

Treatment

This cyst is treated with simple enucleation ( Fig. 88.3 ). Enucleation is often accomplished at time of tooth extraction. Uncounted numbers of these cysts are probably adequately resolved with endodontic therapy. If a radiolucency persists greater than 6 months following endodontic therapy, enucleation and histopathologic review are necessary.

Lateralized Radicular Cyst (Lateral Radicular Cyst and Lateral Periapical Cyst)

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 through 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.

Residual 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.

Inflammatory Collateral Cyst

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. 88.4 ). As such, radiographically there will be a radiolucent periradicular lesion ( Fig. 88.5 ). 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.

Dentigerous Cyst (Follicular Cyst)

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 only by the overlying alveolar mucosa. Dentigerous cysts form when fluid accumulates between reduced enamel epithelium and tooth crown. As alluded to earlier, the accumulation of fluid may be partially or largely surrounded by connective tissue as well as epithelium. 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. They are generally found in the teenage years and early adulthood. However, the longer a tooth is impacted, the greater the chance of developing a dentigerous cyst.

Radiographic Features

A dentigerous cyst presents as a unilocular radiolucency, which is associated with an unerupted tooth ( Fig. 88.6 ). Dentigerous cysts may also involve odontomas, which by their 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.

Treatment

Dentigerous cysts are usually easily enucleated at the time of tooth extraction. In large lesions, decompression with subsequent enucleation may be appropriate ( Fig. 88.7 ).

Eruption Cyst

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. They may be seen with erupting deciduous or permanent teeth, but the majority of lesions are seen in the first decade. 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, although the normal coral pink color of the surrounding mucosa is common ( Fig. 88.8 ). 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. Clinical follow-up may also serve to confirm the diagnosis as the tooth will erupt within several weeks to months through the cystic expansion.

Paradental Cyst

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. Although the mesial aspect of a mandibular tooth may rarely be involved, there have been no reported occurrences to the lingual. Craig 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. In one series the paradental cyst accounted for 3% of all odontogenic cysts.

Radiographic Features

The lesion will present as a well-defined radiolucency associated with but not surrounding the coronal area of a partially erupted tooth ( Fig. 88.9 ).

Odontogenic Cyst of Undetermined Origin

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, there are several odontogenic cysts that 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.

Definition of the Odontogenic Cyst of Undetermined Origin

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.

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 yet the cyst 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, was called a primordial cyst. 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 KCOT and a large percentage of these primordial cysts had features of what would now be diagnosed as a KCOT. When the odontogenic keratocyst (as it was then known) 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 odontogenic keratocysts too. International journals especially came to use the term “primordial cyst” as a synonym of the odontogenic keratocyst. 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. It is hoped that this will ensure the more aggressive treatment of a KCOT is NOT performed for this innocuous lesion.

Lateral Periodontal Cyst

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 histologically similar lesion known as a botryoid odontogenic cyst. Lateral periodontal cysts are located on the lateral surface of a vital tooth. 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. Demographically the cyst is most common in males by a 2:1 ratio with a peak incidence in the fifth and sixth decades. The gingival cyst of the adult and the botryoid odontogenic cysts are essentially subtypes of lateral periodontal cysts. Other cysts also present interproximally, especially the KCOT, odontogenic cyst of undetermined origin, and the lateralized periapical cyst. 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.

Microscopic Features

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. 88.10 ). 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 classically display cytoplasmic clearing. The clear cells contain glycogen, which can be demonstrated by staining with periodic acid–Schiff with and without diastase digestion. Cells containing glycogen will not retain Schiff positivity after diastase digestion, thus confirming that they contained glycogen. The diagnosis of lateral periodontal cyst must be reserved for lesions displaying the thin epithelium described earlier. The plaque-like thickenings are helpful microscopic features but are not always found. The connective tissue wall may contain dental lamina rests but these are not required for diagnosis.

Botryoid Odontogenic Cyst

The botryoid odontogenic cyst will usually present radiographically as a multilocular lesion and is a special variant of the lateral periodontal cyst. Botryoid refers to the grape-like cluster these lesions may resemble both histologically and radiographically.

Gingival Cyst of the Adult