Chapter 78: Odontogenesis and Odontogenic Cysts and Tumors Peter E. Larsen, Arden K. Hegtvedt Cystsand tumorsderived from the odontogenictissuesconstitute anunusually diverse group of lesions. This diversity reflects the complex development of the dental structures, since these lesions all originate through some alteration from the normal pattern of odontogenesis. Some lesions included in this category may in fact not represent neoplasia at all, but are only minor alterations in the normal process of tooth development. Lesions such as cysts are also tumors only in the broadest sense of the word and do not represent true neoplasms. The purpose of this chapter is to review the process of odontogenesis with emphasis on the potential origin of cells that produce the most common odontogenic cysts and tumors. Diagnostic modalities will be discussed with emphasis on the practical approach to development of a differential diagnosis. Common odontogenic cysts and tumors will be presented, and treatment approaches to various odontogenic cysts and tumors outlined. Odontogenesis (Melfi, 1988; Ten Cate, 1989) The primitive oral cavity, also called the stomodeum, is lined with ectoderm. At its deepest portion it contacts the blind superior aspect of the foregut, which is lined with endoderm. The union of these ectodermal and endodermal layers is called the buccopharyngeal membrane. At approximately the twenty-seventh day of development, this membrane ruptures and the stomodeum becomes connected with the foregut. The primitive oral cavity is therefore an ectodermal lined structure beneath which lies the ectomesenchyme. Themesenchymeoftheheadistermedectomesenchymebecauseofitsectodermaloriginfrom neural crest cells. This is distinct from the mesenchyme of the rest of the body, which is of mesodermal origin. Each tooth develops from a tooth bud that forms from the lining of the oral cavity. The tooth bud consists of three separate parts: (1) the enamel organ, which is derived from the oral ectoderm; (2) the dental papilla, which is derived from the ectomesenchyme; and (3) thedentalsac,whichisalsoderivedfromtheectomesenchyme.Theportionofthedeveloping tooth known as the enamel organ produces tooth enamel while the dental papilla produces the tooth pulp and dentin; the dental sac is the precursor of the cementum and periodontal ligament. Tooth development has been broken down into stages primarily based on morphologic changes of the tooth bud. These stages include: (1) the dental lamina stage, (2) the bud stage, (3) the cap stage, and (4) the bell stage. Dental lamina and bud stage About 2 or 3 weeks after the rupture of the buccopharyngeal membrane, when the embryo is about 6 weeks old, the first sign of tooth development is seen. Along the oral ectoderm a ridge of basal cells begin proliferation at a more rapid rate than those cells adjacent to them. This leads to formation of a band of epithelium that runs along the crest of whatwillbethefuturedentalarches.Thisbandofproliferatingepitheliumiscalledthedental lamina. 1 At certain points along the dental lamina, each representing a location of the 10 mandibular and 10 maxillary deciduous teeth, an even more rapid cellular proliferation is seen. This further epithelial downgrowth and proliferation forms invaginations into the underlying ectomesenchymal tissue. These invaginations or buds represent the beginning of tooth development (Fig. 78-1). Cap stage (proliferation) As cellular proliferation continues, unequal growth occurs at various parts of the bud. A shallow depression occurs on the deep surface of the bud. Concomitant to this morphologic change in the developing bud, histologic differentiation occurs within the cells of the enamel organ. The single layer of the cuboidal cells lining the convexity of the enamel organ are known as the outer enamel epithelium and the more columnar cells along the concavity of the organ are called the inner enamel epithelium. As cells within the center of this epithelial enamel organ begin to separate because of an increase in intercellular fluid, they assume a morebranchedorreticularform.Thisareaisnow calledthe stellate reticulum. These changes within the enamel organ produce a figure reminiscent of a cap, hence the name given to this stage of development (Fig. 78-2). While this differentiation is occurring within the enamel organ itself, changes within the associated ectomesenchyme also occur. The portion of the ectomesenchyme that is partiallysurroundedbytheproliferatinginnerenamelepitheliumbeginstocondense,forming the dental papilla. At the same time there is marginal condensation in the ectomesenchyme surrounding the enamel organ and the dental papilla. In this zone a denser and more fibrous layer gradually develops, forming the dental sac. Bell stage (histodifferentiation and morphodifferentiation) The differential growth of the epithelium into the underlying ectomesenchymal tissue continues, changing the form from a cap shape to a bell shape. At this stage, the inner enamel epithelium consists of a single layer of columnar cells that further differentiates into tall columnar cells with oval nuclei that are polarized away from the basal lamina. These cells will become ameloblasts and be responsible for amelogenesis (enamel formation). These preameloblasts exert an organizing influence on the underlying ectomesenchymal cells of the dental papilla, causing them to begin differentiation into odontoblasts, which will be responsible for forming the dentin of the developing tooth (Fig. 78-3). By the time the primary tooth germ has reached the bell stage, other changes are also taking place. Lingual to the enamel organ of this primary tooth germ, the dental lamina is giving rise to the beginning of the enamel organ of the permanent tooth (Fig. 78-4). Concurrently, the dental lamina of the primary tooth begins to disintegrate. As the lamina breaks up, the cells that compose it either disappear or remain as small islands known as the rests of Serres. 2 Apposition After differentiation of ameloblasts and odontoblasts is complete, apposition of the dental hard tissues begins. Dentinogenesis begins at approximately the fifth month in utero. Dentionformationbeginsasodontoblastselaborateaneosinophilicmateralalongtheinterface between the odontoblasts and ameloblasts. This material is predenting, which upon calcification forms dentin, the principal hard structure of the tooth. This dentin formation begins at the incisal region of the tooth and progresses towards the root. Amelogenesis or enamel formation begins immediately adjacent to the forming dentin and progresses toward the incisal edge. Similar to dentin formation, the first stage of enamel formation is the laying down of enamel as an organic material that subsequently undergoes calcification (Fig. 78-5). Normal amelogenesis relies on prior occurrence of normal dentinogenesis, hence the lack of enamel formation in odontogenic tumors such as ameloblastoma, wherealthough normal-appearing ameloblastsare present, no odontoblastsor dentin formation is present to initiate enamel formation. Root formation After much of the crown formation has occurred, development of the root begins. The outerandinnerenamelepithelialieimmediatelyadjacenttoeachotherwithoutanintervening stellate reticulum at the periphery of the developing tooth. These two layers together form Hertwig's epithelial root sheath, which grows into the surrounding connective tissue. Dentin formation continues towards the root of the tooth and is guided by this rooth sheath (Fig. 78- 6). Root formation typically is complete 2 to 3 years after tooth eruption, at which time the root sheath breaks down and disappears with the exception of occasional epithelial remnants called the rests of Malassez Fig. 78-7). As the dentin grows downward into what will be the root of the tooth, the surrounding dental sac forms a thin calcified layer called cementum around the developing root; the dental sac also develops into connective tissue fibers that will become the periodontal ligament. On a radiograph of an unerupted and incompletely formed tooth, the dental sac is also called the dental follicle. Eruption As amelogenesis occurs, the layer of ameloblastic cells moves progressively closer to the outer enamel epithelium, squeezing the stellate reticulum in between. At the termination of crown development, the ameloblastic layer, the stellate reticulum, and the outer enamel epithelium will all essentially be fused and become known as the reduced enamel epithelium. This reduced enamel epithelium will remain around the developed crown until eruption of the tooth. The Formation of Odontogenic Cysts and Tumors The epithelium associated with odontogenic cysts and tumors is derived from one of the following sources (Fig. 78-8): (1) the reduced enamel epithelium of the tooth crown; (2) epithelialrestsofMalassez,whichareremnantsoftheHertwigrootsheath;(3)epithelialrests 3 of Serres, which are remnants of the dental lamina; and (4) the tooth germ itself, which includes the enamel organ, dental papilla, and dental sac. For example, an increased space between the crown of an unerupted tooth and the surrounding reduced enamel epithelium is frequently an early indication of cyst or tumor formation (Fig. 78-9). In addition, some odontogenic tumors develop partially or entirely from cells of ectomesenchymal origin. The cellular origin for these lesions is either the dental papilla, the follicle, or the periodontal ligament. Classification of Cysts and Tumors of the Jaws Several systems have been devised for classifying cysts and tumors of the jaws. Some of these systems rely on morphologic differences between different lesions, either based on clinical or radiographic parameters, whereas others rely on histologic differences. Other systemscategorizelesionstotallyontheiretiology(Main,1985;Shear,1985).Amodification of the WHO classification (Main, 1985), which divides cysts according to etiology is quite effective (see box on p. 1419). In this classification, the basic division is etiologic. A distinction is drawn between the autonomous development of the majority of cyst varieties and the inflammatory pathogenesis of the most common, the radicular cyst. This is preferable to classification based on histogenesis because opinions differ regarding the histology of several categories of cysts. Box (p. 1419) Classification of jaw cysts A. Developmental 1. Odontogenic a. Follicular cyst b. Odontogenic keratocyst c. Eruption cyst d. Alveolar cyst of infants e. Gingival cyst of adults f. Developmental lateral periodontal cyst 2. Nonodontogenic a. Nasopalatine duct cyst b. Midpalatal cyst of infants c. Nasolabial cyst 4 d. Globulomaxillary cyst, median mandibular cyst, and median alveolar cyst& B. Inflammatory a. Radicular cyst 1) Periapical cyst 2) Inflammatory lateral periodontal cyst C. Nonepithelial&& a. Idiopathic bone cavity (traumatic, solitary, hemorrhagic bone cyst) b. Aneurysmal bone cyst c. Stafne's mandibular lingual cortical defect. & These cysts were previously regarded as developmental nonodontogenic cysts. This is no longer believed to be true and this category is no longer used; it is of historical interest only. && These lesions are often classified as cysts but do not have a distinct epithelial lining. Unlike cysts, odontogenic tumors are most often classified according to their histogenesis. Tumors are either of epithelial, mesenchymal, or unknown origin. Tumors of epithelial origin are further classified into those that have a minimal inductive change on the surrounding connective tissue and those that produce extensive inductive changes within the surrounding connective tissue. Lesions within the last group have in the past been called mixed epithelial mesenchymal tumors (Shafer et al, 1984). This is incorrect because it is now believedthatthe neoplastic portionof the lesionis epithelialinnature andthatthis epithelium produces significant inductive changes within the connective tissue; this leads to the misconception that the connective tissue is also neoplastic. The box on p. 1420 outlines the classification of odontogenic tumors. Box (p. 1420) Classification of odontogenic tumors A. Benign epithelial odontogenic tumors 1. Tumors producing minimal inductive change in the connective tissue a. Ameloblastoma b. Calcifying epithelial odontogenic tumor (Pindborg tumor) c. Odontogenic adenomatoid tumor (adenoameloblastoma, adenomatoidodontogenic tumor) 5 d. Calcifying odontogenic cyst (Gorlin's cyst) 2. Tumors producing extensive inductive change in the connective tissue a. Ameloblastic fibroma b. Ameloblastic fibroodontoma c. Ameloblastic odontoma (odontoameloblastoma) d. Odontoma 1) Compound-composite odontoma 2) Complex odontoma B. Mesenchymal odontogenic tumors 1. Odontogenic fibroma 2. Odontogenic myxoma 3. Cementoma a. Periapical cemental dysplasia b. Cementifying fibroma c. Benign cementoblastoma 4. Dentinoma C. Tumors of unknown origin 1. Melanotic neuroectodermal tumor of infancy D. Malignant odontogenic tumors 1. Primary intraosseous carcinoma 2. Ameloblastic fibrosarcoma 3. Ameloblastic dentinosarcoma 4. Ameloblastic odontosarcoma. 6 Diagnosis Clinical findings The physical signs and symptoms of odontogenic cysts and tumors will depend to a certain extent on the dimensions of the lesion. A small lesion is unlikely to be diagnosed on a routine examination of the mouth because signs will not be demonstrable. Such lesions are only likely to be detected at an early stage as the result of routine radiographic examination. Exceptions are some early lesions that may present in conjunction with a devitalized tooth, which is detectable on clinical examination. Some cystic lesions may become secondarily infected, leading to their diagnosis. Clinical absence of one or more teeth without the history of extraction may also be a clinical indicator of an undiagnosed odontogenic cyst or tumor becausemanyoftheselesionsareassociatedwithimpactedorcongenitallymissingteeth(Fig. 78-10). As the lesion grows, other indirect changes may occur. An enlarging lesion between two teeth can cause the crowns to converge and the roots to diverge (Fig. 78-11). Growth that is nearly undetectable visually may lead to difficulty with denture retention. As the lesion enlarges even further, expansion of the bone may be seen directly. This is usually toward the buccal surface of the alveolar bone because this is the thinnest area and expansion occurs here most easily (Fig. 78-12). Clinically evident expansion is often a late finding, especially in lesions developing within the ramus or angle of the mandible or within the maxillary sinus. Lesions in these areas may become extremely large before expansion is observed clinically (Fig. 78-13). Radiologic examination Radiographic evidence of various odontogenic cysts and tumors varies considerably fromlesiontolesion,withcertainlesionshavingalmostapathognomonicappearancewhereas the only consistent thing about the appearance of other lesions is the total lack of any consistent radiographic presentation. The common lack of of physical findings and the developmentof the majority ofthese lesions within the confines ofbone makes the radiologic investigation and interpretation uniquely important. The radiographic appearance of various lesions will be discussed more completely as each individual lesion is described. There are some general principles that can be applied to the radiographic diagnosis of cysts and tumors of the jaws. This section will address these principles. In order for a radiograph to provide useful information, it must be of good quality. Artifactscausedbyinappropriateplacementoffilmlabels,patientjewelry,movement,orpoor technique can mask the presence of a lesion. Radiographs are also important in treatment planning for surgical removal of odontogenic lesions. Encroachment on vital structures, extent into soft tissue, size of the lesion,andrequirementsforreconstructioncanallbeevaluated.Thiswillbemore completely discussed in the section on treatment of cysts and tumors. 7 Various radiographic modalities are available for use in evaluating cysts and tumors of the jaws. Many lesions are detected on routine intraoral radiographs taken for screening purposesorforevaluatingofotherdentaldiseasesuchascaries.Becauseintraoralradiographs such as the periapical or bite-wing radiograph are most often used, this screening may be the firstopportunitytoevaluateanasymptomaticlesion.Intraoralradiographshavetheadvantage ofprovidingexcellentdetailbecausethefilm-to-objectdistanceissmallandthefilmisplaced intraorally immediately adjacent to the involved bone. This eliminates the overlying osseous structures often seen in routine extraoral head and neck radiographs. The major disadvantage is the lack of availability of these radiographs outside a dental office, their size limitations, and their inability to evaluate the areas that are not accessible to film placement; these are theramus,condyle,andinferiorborderofthemandible.Fig.78-14demonstrateshowa subtle changeonanintraoralradiographcanleadtodiagnosisofalargeintraosseouslesion.Perhaps the most useful intraoral radiograph, one for which there is no good extraoral substitute, is the occlusal radiograph. This is taken with a larger film than the standard periapical or bite- wing. For lesions in the anterior maxillary alveolus and palate, there is no adequate substitute (Fig. 78-15). Extraoral radiographs are often necessary for delineation of the entire lesion. They are useful in showing the extent of the lesion and its effect on adjacent structures. These radiographs also serve as a screening mechanism should multiple lesions be present. The panoramicradiographisthemostusefulexamination.Iteffectivelyshowstheentiremandible including the ramus and condyle, the maxilla and maxillary sinuses, and the dentition. To reproduce this with other types of radiographs may require multiple views. The panoramic radiograph is actually a pantomogram. It makes use of the radiographic technique of tomography in which a collimated radiation source and the film are rotated around the patient's head in opposite directions. This results in blurring of structures on either side of a predetermined focal trough and has the advantage of eliminating much of the surrounding osseous interference that is seen with plain radiographs. However, this advantage is also a source of one of the major problems of the panoramic radiograph, which is that only structures within the focal trough are registered. This area of optimal focus is minimally adjustable and varies from machine to machine. It is possible that a lesion, even a rather large one, be incompletely visualized if it is outside the focal trough (Fig. 78-16). If a lesion is suspected on panoramic radiograph, an additional radiograph should be taken in the sagittal plane to help delineate any lateral and medial expansion that may be present. The panoramic radiograph also has the disadvantage of requiring the patient to remain still and in a sitting position for several seconds. This may not be possible in the debilitated, mentally retarded, or very young patient. Otherextraoralfilmsmaybeusedtoevaluatethelesionfurtherorasasubstitutewhen the panoramic radiograph is not possible. For mandibular lesions, the lateral oblique radiograph will allow the body, angle, ramus, and condyle to be seen. The parasymphysis and symphysis is often difficult to see because of overlying dentition and bone from the contralateral side. The teeth are also difficult to identify because teeth from the ipsilateral maxilla and the contralateral mandible and maxilla may overlie each other. For examination of maxillary cysts and tumors, the Waters view is very helpful as a screening tool. Maxillary lesions are difficult to delineate even on the best plain films; computerized tomography may be necessary. 8 Computerized tomography (CT) is not a cost-effective method of evaluating most routine odontogenic cysts and tumors. There are certain indications for the use of CT scans. For example, CT is helpful in defining the extent of very large lesions, especially if there is significant distortion of normal anatomy, which makes plain radiographs difficult to evaluate. CT can also be used to determine if the lesion is contained entirely within the involved bone, or if it has eroded through the cortex. Although malignant odontogenic tumors are extremely rare, some bening cysts and tumors behave aggressively and tend to have high recurrence rates, especially if they have perforated through cortical bone and into adjacent soft tissue; CT is extremely valuable in treatment planning for the removal of such lesions (Fig. 78-17). Differential diagnosis Once adequate clinical and radiographic examination is complete and before a biopsy has been performed, a differential diagnosis should be formulated. This should take into account information from both the clinical and radiologic examination, but because of the limited clinical findings associated with most odontogenic cysts and tumors, this is primarily a radiographic differential. Much can be learned about the behavior of an odontogenic cyst or tumor by paying closeattentiontotheradiograph.Benign,slow-growinglesionstendtocausetoothmovement, blunting of the roots of teeth, displacement of vital structures such as nerves and vessels, and bony hard expansion with intact cortical bone. These lesions are usually well circumscribed by a radiopaque border (Fig. 78-18). Aggressive, fast-growing, or malignant lesions tend to resorb bone around the roots of teeth and not cause tooth movement. The teeth themselves are of such increased hardness in comparison to the surrounding bone that fast-growing lesions do not have time to cause resorption of the roots before the lesion is detected. Fast- growing and aggressive lesions also tend to resorb cortical bone and spread into soft tissue without significant cortical expansion. They also are poorly delineated radiographically without much cortical bone along the periphery of the lesion (Fig. 78-19). From a radiographic approach, a simplified method of grouping these lesions is by somecommonradiographicfindings.Eachspecificradiographicappearancemaybeassociated with several different lesions, some of which are odontogenic in origin, some of which are not, but significant reduction in the number of different lesions that must be considered in a given differential is possible by grouping lesions according to their radiographic appearance. Other clinical findings such as age, sex, symptoms if any, etc, can be used to further narrow the differential beyond what is possible radiographically. The classic radiographic presentations are radiolucent lesions, radiopaque lesions, and mixed radiopaque/radiolucent lesions. Within the purely radiolucent group, there are several subclassifications according to location and appearance of the lesion. In an attempt to facilitate the development of a differential diagnosis, the most common lesions occurring in the jaws have been categorized according to their radiographic apearance in the box below. This list includes some non- odontogenic processes, which must also be considered in the differential. 9 Biopsy Perhapsthesimplestbiopsytechniqueforintraosseouslesionsofthejawsisaspiration. Although no tissue is obtained with aspiration, it is a biopsy in the broadest sense of the word. Aspiration can yield extremely valuable information about the nature of the lesion, yet it causes little patient discomfort. It may be done as a procedure itself or as a prelude to incisional or excisional biopsy. A radiolucent lesion that yields straw-colored fluid on aspiration is most likely to be a cystic lesion. If pus is aspirated, an inflammatory or infectious process should be considered. White keratin-containing fluid is indicative of an odontogenic keratocyst, whereas air may indicate a traumatic bone cavty. The inability to aspirate (vacuum within the syringe) is usually indicative of a solid process such as a neoplasm. Blood on aspiration could represent several lesions, the most important of which is the vascular malformation. The most common presentation of high-flow vascular lesions of the jaws is exsanguination or near-exsanguinating hemorrhage associated with a simple procedure such as biopsy of an innocuous asymptomatic radiolucency. For this reason, all radiolucent lesions should be aspirated before a biopsy is performed. Whether to perform an incisional or excisional biopsy initially is not always clear. Most odnotogenic cysts and tumors are benign and definitive treatment may be as simple as obtaining an excisional biopsy. However, there are some lesions that are more aggressive and require extensive curettage or marginal resection and it is desirable to know this before the onset of surgery. Indications for excisional biopsy include small, radiographically benign lesions that are readily accessible and can be removed without encroachment on adjacent structures. In cases where the access is more invasive than the surgical removal of the lesion itself, complete excision at the initial biopsy is preferred, even if the lesion is relatively large. This would include lesions in the mandibular condyle and lesions in very young patients for whom a general anesthetic is required for any surgical intervention, even for incisional biopsy. Incisional biopsy is indicated in very large lesions and in lesions suspected of aggressive behavior so that a definitive diagnosis can be made before treatment is instituted. Clinical, Radiographic, and Histoogic Features of Common Odontogenic Cysts The more classic description of a cyst is that it is an epithelial-lined sac filled with fluid or semifluid material (Killey and Kay, 1966). All odontogenic cysts fit this description, but certain nonepithelial cysts commonly included with odontogenic cysts do not. Because of this, a broader definition has been accepted. A cyst is a pathologic cavity having fluid, semifluid, or gaseous contents that are not created by the accumulation of pus; frequently, but not always, it is lined by epithelium (Kramer, 1974). For the purpose of discussion and to simplify development of a differential diagnosis, this section will present a brief overview of each common cyst, its clinical and radiographic presentation, and recommended treatment. Because the histopathology of jaw cysts is confusing and the terminology is not always used consistently by general pathologists, these lesions are frequently misdiagnosed or incorrectly named, which can lead to improper treatment. Lesions that are frequently misdiagnosed will have special mention with regard to histopathology. 10