Cysts and Tumors of Odontogenic Origin

Clinical Features

This cyst is always associated initially with the crown of an impacted, embedded or unerupted tooth (Fig. 4-1). A dentigerous cyst may also be found enclosing a complex compound odontoma or involving a supernumerary tooth. The most common sites of this cyst are the mandibular and maxillary third molar and maxillary cuspid areas, since these are the most commonly impacted teeth. Most lesions present in second and third decades, with slight male predilection (M:F–3:2). Most dentigerous cysts are solitary. Bilateral and multiple cysts are usually found in association with a number of syndromes including cleidocranial dysplasia and Maroteaux–Lamy syndrome. In the absence of these syndromes, bilateral dentigerous cysts are rare. The dentigerous cyst is potentially capable of becoming an aggressive lesion. Expansion of bone with subsequent facial asymmetry, extreme displacement of teeth, severe root resorption of adjacent teeth and pain are all possible sequelae brought about by continued enlargement of the cyst. Cystic involvement of an unerupted mandibular third molar may result in a ‘hollowing-out’ of the entire ramus extending up to the coronoid process and condyle as well as in expansion of the cortical plate due to the pressure exerted by the lesion. Associated with this reaction may be displacement of the third molar to such an extent that it sometimes comes to lie compressed against the inferior border of the mandible. In the case of a cyst associated with a maxillary cuspid, expansion of the anterior maxilla often occurs and may superficially resemble an acute sinusitis or cellulitis. There is usually no pain or discomfort associated with the cyst unless it becomes secondarily infected.

Radiographic Features

Radiographic examination of the jaw involved by a dentigerous cyst will reveal a radiolucent area associated in some fashion with an unerupted tooth crown (Fig. 4-2A). The impacted or otherwise unerupted tooth crown may be surrounded symmetrically by this radiolucency, although the distinction between a small dentigerous cyst and an enlarged dental follicle or follicular space is quite arbitrary, especially since the small cyst and the enlarged follicle would be histologically identical. While a normal follicular space is 3–4 mm, a dentigerous cyst can be suspected when the space is more than 5 mm. Only when the size of the radiolucency is grossly pathologic can the distinction be made with assurance.

Three radiological variations of the dentigerous cyst may be observed. In the central variety, the crown is enveloped symmetrically. In these instances, pressure is applied to the crown of the tooth and may push it away from its direction of eruption. In this way, mandibular third molars may be found at the lower border of the mandible or in the ascending ramus and a maxillary canine may be forced into the maxillary sinus as far as the floor of the orbit. The lateral type of dentigerous cyst is a radiographic appearance which results from dilatation of the follicle on one aspect of the crown. This type is commonly seen when an impacted mandibular third molar is partially erupted so that its superior aspect is exposed. The so-called circumferential dentigerous cyst results when the follicle expands in a manner in which the entire tooth appears to be enveloped by cyst. The dentigerous cyst is usually a smooth, unilocular lesion, but occasionally one with a multilocular appearance may occur. In actuality, the various compartments are all united by the continuous cystic membrane. Sometimes the radiolucent area is surrounded by a thin sclerotic line representing bony reaction. In cases of apparently multiple dentigerous cysts, care should be taken to rule out the possible occurrence of the odontogenic keratocyst, basal cell nevus, bifid rib syndrome (q.v.).

Histologic Features

There are no characteristic micro-scopic features which can be used reliably to distinguish the dentigerous cyst from the other types of odontogenic cysts. It is usually composed of a thin connective tissue wall with a thin layer of stratified squamous epithelium lining the lumen (Fig. 4-2B). Rete peg formation is generally absent except in cases that are secondarily infected. The connective tissue wall is frequently quite thickened and composed of a very loose fibrous connective tissue or of a sparsely collagenized myxomatous tissue, each of which has been sometimes mistakenly diagnosed as either an odontogenic fibroma or an odontogenic myxoma. A hyperplastic dental follicle is not necessarily associated with inflammation. An additional feature of the connective tissue wall of both normal dental follicles and dentigerous cysts is the presence of varying numbers of islands of odontogenic epithelium (Fig. 4-2C). These are sometimes very sparse and obviously inactive, while at other times they are present in sufficient numbers to be mistaken for an amelo-blastoma. While this latter odontogenic tumor can originate in this situation, care must be taken to differentiate between it and simply odontogenic epithelial rests. Inflammatory cell infiltration of the connective tissue is common although the cause for this is not always apparent. An additional finding, especially in cysts which exhibit inflammation, is the presence of Rushton bodies within the lining epithelium. These are peculiar linear, often curved, hyaline bodies with variable stainability which are of uncertain origin, questionable nature and unknown significance. Even electron microscopic studies, such as those of El-Labban, have only been of partial help in determining that the structures are probably of hematogenous origin, although it is not clear why they have such an intimate relationship to epithelium. The content of the cyst lumen is usually a thin, watery yellow fluid, occasionally blood tinged.

It was reported by Brannon in his excellent clinicopathologic study of 312 cases of odontogenic keratocysts that 8.5% of a series of 1,850 dentigerous cysts were odontogenic keratocysts (q.v.) with the characteristic histologic findings in the epithelium of a parakeratinized, corrugated surface, a remarkable uniformity of a 6- to 10-cell thickness without rete peg formation, and a polarized and palisaded basal layer of cells. This percentage of dentigerous cysts which are odontogenic keratocysts is in close agreement with the findings of Pindborg and his coworkers (7.1%) and Payne (8.5%).

The pluripotentialities of the epithelium in mandibular dentigerous cysts has been further emphasized by Gorlin, who described mucus-secreting cells in the lining stratified squamous epithelium, respiratory epithelial lining, sebaceous cells in the connective tissue wall, and lymphoid follicles with germinal centers.

Treatment

The treatment of the dentigerous cyst is usually dictated by the size of the lesion. Smaller lesions can be surgically removed in their entirety with little difficulty. The larger cysts which involve serious loss of bone and thin the bone dangerously are often treated by insertion of a surgical drain or marsupialization. Such a procedure is often necessary because of the potential danger of fracturing the jaw if complete surgical removal were attempted. Recurrence is relatively uncommon.

Potential Complications

Several relatively serious potential complications exist stemming from the dentigerous cyst, besides simply the possibility of recurrence following incomplete surgical removal. These include:

It is of great clinical significance that numerous cases of ameloblastoma have been reported developing in the wall of dentigerous cysts from the lining epithelium or associated epithelial rests (Fig. 4-3). Stanley and Diehl have reviewed a series of 641 cases of ameloblastoma and have found that at least 108 cases of this neoplasm, approximately 17%, were definitely associated with an impacted tooth and/or a follicular or dentigerous cyst. The disposition for neoplastic epithelial proliferation in the form of an ameloblastoma is far more pronounced in the dentigerous cyst than in the other odontogenic cysts. The formation of such a tumor manifests itself as a nodular thickening in the cyst wall, the mural ameloblastoma, but this is seldom obvious clinically. Therefore, it is not only good clinical practice, but also an absolute requisite that all tissue from dentigerous cysts be submitted to a qualified oral pathologist for thorough gross and microscopic examination. In reviewing the histologic changes sought by the oral pathologist which occur in the dentigerous cyst as a premonitory manifestation of ameloblastoma, Vickers and Gorlin have stressed that hyperchromatism of basal cell nuclei, palisading with polarization of basal cells and cytoplasmic vacuolization with intercellular spacing of the lining epithelium, when observed together, are manifestations of impending neoplasia. These findings may occur individually in other rather harmless conditions. The presence of sprouting or budding and protruding of epithelial islands from lining epithelium has been claimed to be evidence of neoplastic transformation, but this in itself was not considered such an indication by Vickers and Gorlin.

The development of epidermoid carcinoma from the lining epithelium of the dentigerous cyst also has been adequately documented in the literature reviewed by Gardner, who reported eight acceptable cases among 25 cases of carcinoma developing in odontogenic cysts of all types combined. Browne and Gough have reported two additional cases of malignant transformation in dental cysts and suggested that keratin metaplasia in long-standing cyst lining appears to precede the development of the carcinomatous change, although there is little evidence that the odontogenic keratocyst is associated with malignant change more commonly than other types of odontogenic cysts. The predisposing factor and mechanism of development of this malignancy are unknown, but its occurrence appears unequivocal (Fig. 4-4).

Finally, the development of a mucoepidermoid carcinoma, a type of salivary gland tumor, is less well documented than the epidermoid carcinoma of this origin, but it also appears to be a potentiality. The inclusion of normal salivary gland tissue in the posterior portion of the body of the mandible has been reported, and undoubtedly, some central salivary gland tumors in this location originate from this source. However, cases of central mucoepidermoid carcinoma (q.v.) have been discovered in association with dentigerous cysts involving impacted mandibular third molars, and considering the frequency with which mucus-secreting cells are found in this lining epithelium indicative of the pluripotentiality of this epithelium, this very distinct possibility must always be considered. These findings comprise most of the medical rationale for removal of impacted third molars with pericoronal radiolucencies; however, impacted teeth with small pericoronal radiolucencies (suggesting the presence of normal dental follicle rather than dentigerous cyst) also may be monitored with serial radiographic examination. Any increase in the size of the lesion should prompt removal and histopathologic examination. Any lesion that appears larger than a normal dental follicle indicates removal and histopathologic examination.

Clinical Features

Shear (1992) had recorded a 0.8% frequency. It is likely that they occur more frequent clinically and as some rupture spontaneously, these cysts go unnoticed and are not submitted for histological examination.

These cysts are found in children of different ages, and occasionally in adults if there is delayed eruption. Deciduous and permanent teeth may be involved, most frequently anterior to the first permanent molar. Clinically, the lesion appears as a circumscribed, fluctuant, often translucent swelling of the alveolar ridge over the site of the erupting tooth. When the circumcoronal cystic cavity contains blood, the swelling appears purple or deep blue; hence the term ‘eruption hematoma’. It is usually painless unless infected.

Sometimes more than one cyst may be present. There is often a brief history of about three to four weeks duration during which they enlarge to approximately 1–1.5 cm.

Radiographic Features

It may show a soft tissue shadow since the cyst is confined within it and there is usually no bone involvement.

Histologic Features

The superficial aspect is covered by the keratinized stratified squamous epithelium of the overlying gingiva. This is separated from the cyst by a strip of dense connective tissue of varying thickness which usually shows a mild chronic inflammatory cell infiltrate. Inflammatory cell infiltration is common. The follicular connective tissue is more densely cellular, less collagenous and has a basophilic hue, presumably because of a higher content of acid mucopolysaccharide in the ground substance. Odontogenic epithe-lial cell nests may be present in the connective tissue.

In noninflamed areas, the epithelial lining of the cysts is characteristically of reduced enamel epithelial origin, consisting of two or three cell layers of squamous epithelium with a few foci where it may be a little thicker. The adjacent corium is hyperemic and is the seat of a chronic inflammatory cell infiltrate (Fig. 4-5).

Treatment

No treatment is necessary as the cyst often ruptures spontaneously. Surgically exposing the crown of the tooth may aid the eruption process.

Clinical Features

The largest and most detailed series of cases of odontogenic keratocyst has been published by Brannon, and his data are probably most representative of this lesion. The cyst may occur at any age, from the very young to the very elderly, although Brannon found it to be exceedingly rare under the age of 10 years, there being only two such patients in his series of 283 persons. The peak incidence is in the second and third decades of life, with a gradual decline thereafter. The data of Browne (104 patients) and of Forssell (119 patients) are virtually identical. In all series, there is a predilection for occurrence in males, ranging from 1.44:1 (Brannon), 1.46:1 (Browne) to 1.79:1 (Forssell).

The mandible is invariably affected more frequently than the maxilla: in the series of Brannon, 65% versus 35%, in the series of Browne, 79% versus 21%, and in that of Forssell, 78% versus 22%. In the mandible, the majority of the cysts occur in the ramus-third molar area, followed by the first and second molar area and then the anterior mandible. In the maxilla, the most common site is the third molar area followed by the cuspid region.

Multiple odontogenic keratocysts occur with some frequency. Lesions found in children are often reflective of multiple odontogenic keratocysts as a component of the nevoid basal cell carcinoma syndrome. However, at other times, these multiple cysts are independent of the syndrome. A rather remarkable parallelism between the odontogenic keratocyst and the ameloblastoma with respect to mean age of occurrence, predilection for site of occurrence, radiographic findings and recurrence rate has also been pointed out by Browne.

There are no characteristic clinical manifestations of the keratocyst, although about 50% of the patients in Brannon’s series were symptomatic prior to seeking treatment. Among the more common features are pain, soft-tissue swelling and expansion of bone, drainage and various neurologic manifestations such as paresthesia of the lip or teeth. The maxillary OKC tends to be secondarily infected with greater frequency than the mandibular ones, due to its vicinity to the maxillary sinus.

Radiographic Features

Radiographically most OKCs are unilocular, presenting a well-defined peripheral rim. Scalloping of the border is also a frequent finding and this represents variations in the growth pattern of the cyst. Multilocular radiolucent OKC is also observed, generally representing a central cavity having satellite cysts. When it is multilocular and especially if located in the third mandibular molar area, it may be confused radiographically with an ameloblastoma. Occasionally OKC may mimic a dentigerous cyst and contain the crown of a retained tooth within its lumen. The final diagnosis of any cystic cavity within the jaw bones will be achieved only after biopsy of the surgical specimen. Multilocularity (20%) is often present and tends to be seen more frequently in larger lesions. Most lesions, however, are unilocular, with as many as 40% noted adjacent to the crown of an unerupted tooth (dentigerous cyst position). Approximately 30% of maxillary and 50% of man-dibular lesions produce buccal expansion. Mandibular lingual enlargement is occasionally seen. Proximity to the roots of adjacent normal teeth sometimes causes resorption of these roots, although displacement is more common. Sometimes these cysts displace the neurovascular bundle.

Histologic Features

The odontogenic keratocyst wall is usually rather thin unless there has been superimposed inflammation. The lining epithelium is highly characteristic, and is composed of:

Histologically, these cysts are formed with a stratified squamous epithelium that produces orthokeratin (10%), parakeratin (83%), or both types of keratin (7%). No rete ridges are present; therefore, the epithelium often sloughs from the connective tissue (94% of the time). The epithelium is thin, and mitotic activity is frequent; therefore, OKC grows in a neoplastic fashion and not in response to internal pressure. In the presence of an intense inflammatory process, the adjacent epithelium loses its keratinized surface, may thicken and develop rete processes or may ulcerate.

The connective tissue wall often shows small islands of epithelium similar to the lining epithelium; some of these islands may be small cysts. In at least some cases, the apparent islands of epithelium and small satellite or ‘daughter’ cysts actually represent the ends of folds of the lining epithelium of the main cystic cavity which have been cut in cross-section; the linings of these cysts are very commonly folded. Forssell and his associates have studied this problem using serial sections of cysts and found microcysts in the wall in 20% and epithelial islands in 50% of their cases. In 35% of the cases, apparent microcysts were found to be part of the main cyst by the serial sections while pseudo islands of epithelium were found in 75% of the cases.

The lumen of the keratocyst may be filled with a thin straw colored fluid or with a thicker creamy material. Sometimes the lumen contains a great deal of keratin, while at other times it has little. Cholesterol, as well as hyaline bodies at the sites of inflammation, may also be present. The electrophoretic measurement of fluid from these cysts has been reported by Toller to show that it contains a very low content of soluble protein compared with the patient’s own serum (Fig. 4-6).

Dysplastic and neoplastic transformation of the lining epithelium in the odontogenic keratocyst is an uncommon occurrence but has been reported. Of the 312 keratocysts studied by Brannon, only two exhibited cellular atypia. Occasional other cases have also been described in the literature. Areen and his associates have recently reported a case of epidermoid carcinoma developing in an odontogenic keratocyst, and in reviewing the literature, have emphasized the necessity for careful microscopic examination of all such cysts.

The variant of OKC that produces only orthokeratin acts somewhat differently than other OKCs. These almost always are found in a dentigerous association, usually around the mandibular third molar, and they are much less aggressive. They do not have a hyperchromatic basal layer; in fact, the basal layer is flattened. They are not associated with basal cell nevus syndrome (orthokeratinized odontogenic cyst).

Finally, the highly characteristic nature of the parakeratinized lining epithelium and its relationship to the high recurrence rate have been emphasized by a report dealing with orthokeratinized odontogenic cysts and their recurrence rate. Wright investigated 59 cases of orthokeratinized odontogenic cysts and found that they showed a predilection for occurrence in males, most commonly in the second to fifth decades. These cysts were located predominantly in the posterior mandible, where they most typically appeared as dentigerous cysts. The thin, uniform lining epithelium was covered with orthokeratin and showed a prominent granular layer and a cuboidal to flattened basal layer. Follow-up of 24 of these patients revealed only one case of recurrence. This difference in biologic behavior would further underscore the necessity for very strict application of the definition of the term odontogenic keratocyst in diagnosis of the lesion (Fig. 4-7).

Treatment and Prognosis

The odontogenic keratocyst should be surgically excised. However, clinical experience has shown that complete eradication of the cyst may be difficult because the wall of the cyst is very thin and friable and may easily fragment. In addition, perforation of cortical bone, particularly in lesions involving the ramus, is common and this complicates total removal.

The most important feature of the odontogenic keratocyst is its extraordinary recurrence rate. This has been reported as being between 13 and 60%. A review of 763 cases of odontogenic keratocysts in 13 different reported series of cases has shown the average recurrence rate to be 26%, with the majority occurring within five years of the surgical procedure. Forssell, Forssell and Kahnberg (1988) observed that recurrences were more frequent (63%) with cysts in patients with the nevoid basal cell carcinoma syndrome than with cysts in patients without the syndrome (37%). Keratocysts enucleated in one piece recurred significantly less often than cysts enucleated in several pieces, and the recurrence rate in cases with a clinically observable infection, a fistula or with a perforated bony wall was higher. The size of the cyst did not seem to influence its prognosis after surgery, but those whose radiographic appearance was multilocular had a higher recurrence rate than those with a unilocular appearance.

Browne found no significant differences in recurrence rate following three basic methods of treating the lesions:

Furthermore, recurrence does not appear related to the presence of satellite cysts. On this basis, Browne concluded that recurrence of the keratocyst is due to the nature of the lesion itself, i.e. the presence of additional remnants of dental lamina from which a cyst may develop, and is not related to its method of treatment. Since recurrence may be long delayed in this lesion, follow-up of any case of odontogenic keratocyst with annual radiographs is essential for at least five years after surgery. It is also essential that patients with an odontogenic keratocyst, especially if multiple, be evaluated medically to rule out the possibility of the jaw cyst-basal cell nevus-bifid rib syndrome (q.v.).

Clinical Features

The syndrome is very complex and includes a great variety of possible abnormalities. These may be briefly summarized as follows:

Some of these patients have shown a lack of response to parathormone as judged by the lack of phosphate diuresis which, coupled with shortened fourth metacarpals in some patients, has suggested that there may be some relationship to pseudohypoparathyroidism.

Oral Manifestations

The odontogenic keratocysts are indistinguishable from those previously described by that term which are not associated with this syndrome (Fig. 4-8). Because they often develop early in life, deformity and displacement of developing teeth may occur. However, they may not develop until middle age even though the basal cell skin tumors have occurred early in life.

Treatment and Prognosis

Several cases of ameloblastoma have developed in cysts of this syndrome, thus emphasizing the importance of surgical removal of the cysts and their histologic examination. Whenever a diagnosis of odontogenic keratocyst is received by the dentist, he must be certain to rule out the presence of this syndrome because of the many associated problems which these patients ultimately will face.

Clinical Features

Occasionally these dental lamina cysts in infants become sufficiently large to be clinically obvious as small discrete white swellings of the alveolar ridge, sometimes appearing blanched as though from internal pressure (Fig. 4-9A). These probably correspond to those structures described in the older literature as the ‘predeciduous dentition’. These lesions appear to be asymptomatic and do not seem to produce discomfort in the infants.

Histologic Features

These are true cysts with a thin epithelial lining which lacks rete processes and show a lumen usually filled with desquamated keratin, occasionally containing inflammatory cells (Fig. 4-9B). Interestingly, dystrophic calcification and hyaline bodies of Rushton (q.v.), commonly found in dentigerous cysts, are also sometimes found in this lesion.

Treatment

No treatment is required inasmuch as these lesions almost invariably will disappear by opening onto the surface of the mucosa or through disruption by erupting teeth.

Clinical Features

The gingival cyst may occur at any age but is most common in adults. In the review of the literature by Reeve and Levy, the majority of patients were over 40 years of age. The mean age in the 33 cases reported by Buchner and Hansen was 48 years and that of the 10 cases reported by Wysocki and his associates was 51 years. The location of the lesion closely follows that of the lateral periodontal cyst. Thus, all except one cyst in the series of Wysocki and his coworkers were in the mandibular bicuspid-cuspid incisor area, the one exception being in the maxillary lateral incisor area. The locations in the series of Buchner and Hansen were virtually identical except that they had several cases also in the maxillary arch from cuspid to first molar.

This lesion presents generally as a small, well-circumscribed, painless swelling of the gingiva, sometimes closely resembling a superficial mucocele (Fig. 4-10). The lesion is of the same color as the adjacent normal mucosa and seldom measures over 1 cm in diameter, generally much less. Although this cyst may occur in either the free or attached gingiva, some gingival cysts occur in the gingival papilla itself.

Radiographic Features

The gingival cyst is a soft tissue lesion and does not generally manifest itself on the dental radiograph. If it enlarges to sufficient size, it may cause superficial erosion of the cortical plate of bone, but this is still generally not visible on the radiograph. If a circumscribed, radiolucent cystic lesion of alveolar bone with some swelling of the soft tissue is present, the cyst probably represents a lateral periodontal cyst rather than a gingival cyst.

Histologic Features

The gingival cyst of the adult is a true cyst, since it is a pathologic epithelium lined cavity which usually contains fluid (Fig. 4-10 B). The lining epithelium is generally identical to that found in the lateral periodontal cyst, with the occasional exceptions noted above. The epithelium ranges in thickness from simply one flattened cell to several cells, a thin stratified squamous epithelium. Glycogen-rich clear cells may be present, especially in the focal thickenings or plaques of the lining. Dental lamina rests may also be found in the connective tissue wall and these are commonly composed of the same type of glycogen-rich clear cells. As noted earlier, these lesions may be unicystic or polycystic. Since the cyst lies free in the connective tissue of the gingiva, it may or may not exhibit an associated inflammatory reaction.

In cases of the traumatic or implantation type of gingival cyst, calcification or even ectopic ossification on rare occasions may be associated with the cystic lesion, reminiscent of the ossification occurring after experimental implantation of bladder epithelium into ubcutaneous tissues.

Treatment

Local surgical excision of the lesion in adults is usually recommended, and the lesions do not tend to recur. A neoplastic potential has never been reported.

Clinical Features

The lateral periodontal cyst occurs chiefly in adults, according to the series of 39 cases reported by Wysocki and his associates in which there was a mean age of 50 years and an age range of 22–85 years. In this series, there was a predilection for occurrence in males over females, 67: 28 with 5% unknown. The location of the lesion was extremely limited in this study: 67% of cases were in the mandibular bicuspid/cuspid/incisor area, while 33% were in the maxillary lateral incisor area. Lesions were found at no other sites and this has also been the xperience of most other investigators. No rational explanation has been offered for this localization.

The majority of cases have presented no clinical signs or symptoms and have been discovered during routine radiographic examination of the teeth. Occasionally, when the cyst is located on the labial surface of the root, there may be a slight mass obvious, although the overlying mucosa is normal. Unless otherwise affected, the associated tooth is vital. If the cyst becomes infected, it may resemble a lateral periodontal abscess and even seek to establish drainage.

Radiographic Features

The periapical radiograph discloses the lateral periodontal cyst as a radiolucent area in apposition to the lateral surface of a tooth root (Fig. 4-11A–D). The lesion is usually small, seldom over 1 cm in diameter, and may or may not be well circumscribed. In most cases the border is definitive and is even surrounded sometimes by a thin layer of sclerotic one. The botryoid odontogenic cyst appears similar except that its polycystic nature is often evident through its multilocular pattern on the radiograph (Fig. 4-12).

Histologic Features

Histologically, the lateral periodontal cyst is a distinct type of developmental cyst characterized by a thin, nonkeratinized epithelium usually one to five cell layers thick, which resembles the reduced enamel epithelium. Cuboidal or even columnar cells may be found composing the lining. Many of the lining cells have a clear, vacuolated, glycogen-rich cytoplasm (Fig. 4-13). This lining is incomplete and easily sloughs away. Focal thickened plaques of proliferating lining cells often project into the lumen in areas. These are especially prominent in the botryoid odontogenic cyst (Fig. 4-13). Rests of dental lamina are sometimes found in the connective tissue wall and these similarly are frequently composed of glycogen-rich clear cells. These also appear to be more common in the botryoid-type cyst. Papillary infoldings of the lateral periodontal cyst wall are sometimes seen and inflammatory cells may be present, but this is a secondary reaction. The histologic characteristics of these cysts have been detailed by Wysocki and his colleagues as well as by Shear and Pindborg. The connective tissue subjacent to the epithelium exhibits a zone of hyalinization, consisting of a thick fibrous noninflamed cyst wall. A different histologic appearance has been described for this cyst with the name of botryoid odontogenic cyst. This name reflects the gross similarity of the cystic cavities to that of a cluster of grapes.

Treatment and Prognosis

Provided that the lesion is unilocular on radiographic examination the lateral periodontal cyst is treated by surgical enucleation. Attempts should be made to avoid sacrificing the associated tooth, but this may not always be possible. The botryoid variety, a lesion that is radiographically or histologically multilocular, has an increased risk of recurrence or persistence and patients treated for a botryoid odontogenic cyst should be followed periodically. It is especially important that the diagnosis be established because of the similarity in appearance between this cyst and other more serious lesions such as an early ameloblastoma.

Clinical Features

The glandular odontogenic cyst occurs over a wide age range. A slight male predilection was reported. The common site affected was anterior mandible. The lesions showed slow progressive growth, were painless and locally destructive. The mandible seems to be affected more commonly (87.2%) than the maxilla. The age ranges from 10–90 years with the mean of 49.5 years.

Radiographic Features

The lesions appear well defined with a multilocular pattern but without specific diagnostic features.

Histologic Features

Histologically, glandular odontogenic cyst is lined in parts by a nonkeratinized stratified epithelium of varying thickness (Fig. 4-14). The epithelium has a glandular or pseudoglandular structure, with goblet mucous producing cells as well as intraepithelial crypts or microcysts containing mucus. These microcysts may open onto the surface of the epithelium giving a papillary or corrugated appearance. Some cells may also be ciliated. Occasionally the epithelium is thinner, similar to reduced enamel epithelium. Epithelial thickenings or plaques may be present either in this thin epithelium or in the stratified epithelium. Interface between epithelium and connective tissue is flat. The diagnosis of glandular odontogenic cyst should be considered when observing a lateral periodontal multilocular radiolucency. The diagnosis is essentially microscopic.

Treatment

The treatment should be conservative but with a careful dissection of the margins in order to avoid recurrences. Patient should be followed-up periodically in order to assess early recurrences.

Pathogenesis

This cyst is classified as inflammatory, because in the majority of cases it is a consequence to pulpal necrosis following caries, with an associated periapical inflammatory response. Other causes include any event that may result in pulpal necrosis such as tooth fracture and improper restorations, among others. The first line of defense to pulpal necrosis in the periapical area is the formation of a granuloma. A granuloma is a highly vascularized tissue containing a profuse infiltrate of immunologically competent cells, i.e. lymphocytes, macrophages and plasma cells.

The epithelial rests of Malassez, which are pluripotential in nature can differentiate into any type of epithelium, under the proper stimuli. These rests play a central role in the formation of radicular cysts. In the midst of the rich vascular area provided by the periapical granuloma, the rests of Malassez proliferate and eventually form a large mass of cells. With continuous growth, the inner cells of the mass are deprived of nourishment and they undergo liquefaction necrosis. This leads to the formation of a cavity which is located in the center of the granuloma, giving rise to a radicular cyst.

Islands of squamous epithelium which have developed from odontogenic rests of Malassez can also be found in a periapical granuloma without cystic transformation. Endodontists refer to these granulomas as ‘bay cyst’.

Clinical Features

Around 60% of all jaw cysts are radicular or residual cysts. Radicular cysts can occur in the periapical area of any teeth, at any age but are seldom seen associated with the primary dentition. The majority of cases of apical periodontal cysts are asymptomatic. The tooth is seldom painful or even sensitive to percussion. This type of cyst is only infrequently of such a size that it destroys much bone, and even more rarely does it produce expansion of the cortical plates. The apical periodontal cyst is a lesion that represents a chronic inflammatory process and develops only over a prolonged period of time. In some cases, such a cyst of long standing may undergo an acute exacerbation of the inflammatory process and develop rapidly into an abscess (periapical abscess) that may then proceed to a cellulitis or form a draining fistula. The cause of such a sudden flare up is not known, but it may be a result of loss of local or generalized tissue resistance.

Radiographic Features

The radiographic image of the radicular cyst is a peri- or para-apical, round or oval radiolucency of variable size which is generally well delineated and most likely with a marked radiopaque rim. Other lesions, such as granulomas, neoplasms of various origin and some diseases of bone can also present a similar radiolucent periapical appearance. Therefore, a periapical radiolucency cannot be automatically assumed to be a cyst. Several studies have indicated that it is not possible to rely on the radiographic size of a periapical radiolucency to establish the diagnosis of either cyst or granuloma unless the lesion is larger than 2 cm in diameter. Rarely radicular cysts will induce resorption of the root of the affected tooth.

Histologic Features

Microscopically a radicular cyst is limited by a mature collagenous connective tissue wall. Abundant fibroblasts can be identified within the cystic wall. The wall generally presents an inflammatory infiltrate of variable degree. Lymphocytes are generally the most prominent cells in the infiltrate and are characterized by their darkly stained nucleus, which occupies most of the cytoplasm. Plasma cells are also abundant in cysts’ walls and mostly seen in long standing (chronic) cysts. They are characterized by an eccentric nucleus with a cartwheel arrangement of the nuclear chromatin. Plasma cells are considered repertoire of immunoglobulins. Other histological findings within the cystic wall are: erythrocytes and areas of hemorrhage, occasional spicules of dystrophic bone, multinucleated giant cells and cholesterol crystals (Fig. 4-15A).

The cavity of a radicular cyst is generally lined by stratified squamous epithelium. These cysts can be lined by respiratory epithelium, especially if they are in the vicinity of the maxillary sinus. The epithelial lining, many times, is discontinuous, frequently missing over areas of intense inflammation. Rarely radicular cysts may be lined by mucus producing epithelium in either maxillary or mandibular locations. The mucous epithelium is the result of metaplastic transformation of the epithelial rests of Malassez which are pluripotential. In rare instances, carcinoma has been reported developing from the lining epithelium of odontogenic cysts, including the radicular cyst. These have been reviewed by Gardner (1969).

An interesting and peculiar structure, originally described by Rushton and subsequently reported by Molyneux, Medak and Weinmann and Shear, is the hyaline body or Rushton body, often found in great numbers in the epithelium of apical, periodontal or residual cysts (Fig. 4-15 B). These hyaline bodies are tiny linear or arc-shaped bodies, generally associated with the lining epithelium, that appear amorphous in structure, eosinophilic in reaction and brittle in nature, since they evidence fracture in some cases. Their frequency of occurrence in cyst linings ranges between 2.6 and 9.5% of cysts, according to a review by Allison. The etiology, pathogenesis, and significance of these structures are unknown. The lumen of the cyst usually contains a fluid with a low concentration of protein that stains palely eosinophilic. Occasionally the lumen may contain a great deal of cholesterol, and in rare instances, limited amounts of keratin are present.

Treatment

The treatment of the radicular cyst consists of extraction of the involved teeth and careful curettage of the periapical tissue. Under some conditions, root canal therapy may be carried out with apicoectomy of the cystic lesion. The cyst does not recur if surgical removal is thorough. If the cystic sac is badly fragmented, leaving epithelial remnants, or if a periapical granuloma is incompletely removed with epithelial rests remaining, a residual cyst may develop in this area months or even years later. If untreated, the radicular cyst slowly increases in size at the expense of the surrounding bone. The bone undergoes resorption, but seldom is there a remarkable expansion of the cortical plates, as is frequently seen in the case of the dentigerous cyst.

Pathogenesis

There is no unanimity with regard to pathogenesis. Ackerman, Cohen and Altini (1987) like Craig (1976), favored origin from reduced enamel epithelium but suggested that cyst formation occurs as a result of unilateral expansion of the dental follicle secondary to inflammatory destruction of periodontium and the alveolar bone. Fowler and Brannon (1989) suggested that it may be a variant of the dentigerous cyst or derived from an occluded periodontal pocket. Vedtofte and Praetorius (1989) were satisfied that the cyst was of inflammatory origin, initiated by a pericoronitis at the time of tooth eruption and considered rests of Malassez and reduced enamel epithelium the most likely source of the cyst epithelium.

Clinical Features

In the sample of 2,616 jaw cysts reported by Shear (1992), there were 65 paradental cysts classified over a 32-year period (2.5%). The series of 50 cases reported by Ackerman, Cohen and Altini (1987) represented the 3% of a sample of 1,852 odontogenic cysts observed over a 20-year period. Virtually all the cases in the study by Ackermann, Cohen and Altini occurred between the ages of 10 and 39 with two-thirds of their sample in the third decade; the same as in Craig’s material (cited by Shear, 1992). There was a considerable preponderance of males reported by Ackermann, Cohen and Altini and by Fowler and Brannon but of Vedtofte and Praetorius. There was an equal gender distribution. Ackermann, Cohen and Altini found most of their cyst located distally and distobuccally to the third molar. All the papers emphasized that the involved teeth were vital. Bilateral examples occurred in a number of instances.

Radiographic Features

All authors reported a variable radiographic picture but there are some features which appeared consistently and which seem to be useful in contributing to the diagnosis. These are the non widening of the periodontal ligament space and that the lesion was superimposed on the buccal root face. When there was a distal as well as a buccal radiolucency, the distal element was separate from the distinct distal follicular space (Shear, 1992).

Histologic Features

Histologically, the cysts were lined by a hyperplastic nonkeratinized stratified squamous epithelium. An intense inflammatory cell infiltrate is present associated with the hyperplastic epithelium and in the fibrous capsule adjacent to the epithelium. Histologically the paradental cyst cannot be differentiated from a radicular cyst.

Treatment

Enucleation and extraction of associated molar.

Classification of Odontogenic Tumors

The WHO classification (1992) divides odontogenic tumors into benign and malignant, with major subdivisions in each category (White, 2004) (Table 4-2). The subdivisions for the benign neoplasms are based on types of odontogenic tissue involved in the process and include:

The classic example of odontogenic tumor viz. ameloblastoma is an archetype of a neoplasm where the neoplastic component is epithelial only without contribution from the ectomesenchyme. In the second category, some of the neoplasms are pure epithelial tumors but are capable of inducing dysplastic enamel and dentin formation. Examples include adenomatoid odontogenic tumor, calcifying odontogenic cyst, and odontoameloblastoma. Other tumors in the category exhibit neoplastic cells of both odontogenic epithelium and ectomesenchyme and include ameloblastic fibroma and ameloblastic fibro-odontoma (mixed odontogenic tumors). Yet other entities represent hamartomatous proliferations of both tissues, including compound and complex odontomas. In the third category, odontogenic ectomesenchyme with or without included odontogenic epithelium, the neoplastic cells appears to be of connective tissue origin. Neoplasms include odontogenic fibroma and odontogenic myxoma. Any epithelial component is not considered to be neoplastic.

Ameloblastic carcinoma and odontogenic sarcomas are examples of odontogenic neoplasms which contain a malignant epithelial and connective tissue component as part of the tumor. Calcifying odontogenic cyst has been placed in the odontogenic tumors classification by the WHO because some variants consist of a solid tumor with ameloblastoma like areas, dentinoid, and ghost cells. This form has been designated as dentinogenic ghost cell tumor or odontogenic ghost cell tumor. Benign cementoblastoma has currently been delinked from the WHO classification of odontogenic tumors and is described along with benign osteoblastoma.

Pathogenesis

The earlier workers noted the resemblance between the odontogenic apparatus and the ameloblastoma and suggested that the neoplasm was derived from a portion of this apparatus or from cells potentially capable of forming dental tissue. Malassez described small collections of epithelial cells adjacent to the roots of teeth in the periodontal ligament and suggested that the ‘adamantine epithelioma’ was produced by a proliferation of these cell rests.

Most authorities consider the ameloblastoma to be of varied origin, although the stimulus initiating the process is unknown. Thus the tumor conceivably may be derived from:

Presently, it is thought that it is likely the result of alterations or mutations in the genetic material of cells that embryologically preprogrammed for tooth development. Environmental factors and individual patient variables (e.g. general health status, nutritional status) also likely have a role in modulating the incidence of the disease. This theory is demonstrated by the finding that the average age of occurrence of ameloblastoma in industrialized nations is 10–15 years greater than that seen in developing countries (Kessler HP et al, 2003).

Cahn in 1933 reported a case of ameloblastoma originating in the wall of a dentigerous cyst, and numerous cases have subsequently been reco gnized as developing in this fashion. It should be reiterated that Stanley and Diehl, in reviewing 641 cases of ameloblastoma, found that 108 of these tumors, approximately 17%, were definitely associated with an impacted tooth and/or a follicular (dentigerous) cyst. They also noted a marked reduction in the prevalence of such cases after the age of 30, presumably because of the loss of the ameloblastomatous potential of the odontogenic epithelium in impacted tooth follicles and follicular cysts as patients age. Such a significant finding emphasizes the dangerous potential of the denti gerous cyst and the need for careful microscopic examination of every such lesion. This is discussed in greater detail in the section on the dentigerous cyst. Since a dentigerous cyst may develop in association with an odontoma, as well as with an impacted tooth, it is suggested that these too be examined by the pathologist. There is apparently little tendency for the development of the ameloblastoma in the ordinary apical periodontal or radicular cyst.

Clinical Features

A wide age range of occurrence of the tumor from 10 years through 90 years has been reported. The average age at diagnosis is in the range of 33–39 years, and most cases cluster between ages 20 and 60 years. Only about 10% of cases are reported to arise in children, and less than one third of those occur in children younger than 10 years. No significant sex predilection has been reported. There is conflicting evidence on the incidence rates in different races. Although some reports claim an increased incidence of ameloblastoma in black individuals, a large study identifies Asians as the population with the greatest number of affected patients. Because sizeable numbers of cases are reported in every racial group, race does not seem to be a significant defining demographic characteristic of the disease (Reichart PA et al, 1995).

Ameloblastoma occurs in all areas of the jaws, but the mandible is the most commonly affected area (more than 80% of all cases). Within the mandible, the molar angleramus area is involved three times more commonly than are the premolar and anterior regions combined. Statistics on the location of maxillary ameloblastomas are more variable and more difficult to interpret. Some studies report a low incidence in the anterior maxilla, whereas other studies suggest that the incidence in the anterior maxilla is roughly equivalent to the incidence in the maxillary molar region. When comparing large studies, it appears that maxillary tumors tend to occur in slightly older patients than do mandibular lesions. The incidence of occurrence of ameloblastoma in different sites within the jaws has been shown to vary among racial groups. Asians seem to have fewer tumors involving the ramus than do whites or blacks, whereas blacks have an increased frequency of tumors in the anterior mandible compared with the other two groups (Kessler HP et al, 2003).

Radiographic Features

The ameloblastoma has been described classically as a multilocular cyst like lesion of the jaw. This is especially true in advanced cases of ameloblastoma. Here, the tumor exhibits a compartmented appearance with septa of bone extending into the radiolucent tumor mass (Fig. 4-18A). In many cases, however, the lesion is a unilocular one and presents no characteristic or pathognomonic features (Figs. 4-18B, 4-19). The periphery of the lesion on the radiograph is usually smooth, although this regularity may not be borne out at the time of operation. In the advanced lesion producing jaw expansion, thinning of the cortical plate may be seen on the radiograph (Figs. 4-20, 4-21).

The term ‘cystic ameloblastoma’ is frequently used in referring to certain of these neoplasms. It is important to note that there is no correlation between the term thus used clinically and the appearance of the tumor on the radiograph. The radiographic film does nothing more than indicate the relative presence or absence of calcified tissue, and a variety of lesions may manifest themselves in manner similar to that of the ameloblastoma.

Histologic Features

Six histopathologic subtypes of ameloblastoma are recognized: follicular, acanthomatous, granular cell, basal cell, desmoplastic, and plexiform. Most tumors show a predominance of one pattern, but few lesions are found to be composed purely of one histopathologic subtype. Mixtures of the different patterns commonly are observed. Lesions tend to be subclassified according to the predominant pattern that is present. The literature-based retrospective study by Reichart et al (1995) showed that the histologic subtype may have prognostic implications for recurrence. According to their study, the follicular type of ameloblastoma had the highest rate of recurrence at 29.5%. In contradistinction, the acanthomatous type of ameloblastoma showed only a 4.5% recurrence rate. The plexiform subtype was intermediate between the two extremes and showed a 16.7% recurrence rate. Studies have verified that desmoplastic ameloblastoma shows a tendency to recur, and the rate of recurrence is reported within the range of the other histologic subtypes of ameloblastoma.

A moderately to densely collagenized connective tissue characteristically constitute the stroma. The epithelial component of the neoplasm proliferates in what seems to be disconnected islands, strands, and cords within the collagenized fibrous connective tissue stroma. A prominent budding growth pattern often is seen, with small, rounded extensions of epithelium projecting from larger islands, recapitulating the various stages of enamel organ formation (Kessler HP et al 2003). The islands, strands, and cords may vary considerably in size. In high power magnification, the darkly staining periphery is composed of tall columnar cells with hyperchromatic nuclei. The nuclei tend to be round to oval in shape, and the nuclei of adjacent cells are in roughly the same location within the cytoplasm. This produces a characteristic palisading pattern. The palisaded nuclei are oriented away from the basement membrane area of the cell, and a small clear vacuole can be seen between the nucleus and the basement membrane. This peripheral layer of tall columnar cells with hyperchromasia, reverse polarity of the nuclei, and subnuclear vacuole formation mimic the normal embryologic development of the tooth bud at the stage of enamel matrix production. These classic features of ameloblastoma originally were described by Vickers and Gorlin in 1970 (criteria).

Focally in many ameloblastomas, the proliferating epithelium is seen to exert an inductive effect on the surrounding connective tissue stroma. In these areas, a zone of hyalinization of the collagen is present immediately adjacent to the epithelium. Fibroblasts are almost totally absent within the zone of hyalinization. It is theorized that the ameloblastic epithelium, in an attempt to complete its embryologic function and produce enamel matrix, signals the connective tissue to induce dentin formation; however, the fibroblastic cells in the connective tissue are unable to differentiate into odontoblasts, a required step in dentin and enamel formation. The hyalinized zone most likely represents the end result of this blockade in the normal embryologic sequence of odontogenesis (Kessler HP et al, 2003).

The follicular (simple) ameloblastoma is the most commonly encountered variant (Reichart PA et al, 1995), composed of many small discrete islands of tumor composed of a peripheral layer of cuboidal or columnar cells whose nuclei are generally well polarized. These cells strongly resemble ameloblasts or preameloblasts and these enclose a central mass of polyhedral, loosely arranged cells resembling the stellate reticulum. The terms ‘solid’ and ‘cystic’ have often been applied to the ameloblastoma and have variously referred to the clinical or histologic appearance of the tumor. Clinically, some cases exhibit tiny cysts that are grossly evident when the lesion is excised and examined carefully. In such instances, the stellate reticulum like tissue has undergone complete breakdown or cystic degeneration, and in such cases, there is often flattening of the peripheral columnar cells so that they resemble low cuboidal or even squamous cells. Cyst formation is relatively common in this follicular type of ameloblastoma.

In the plexiform ameloblastoma, the ameloblast like tumor cells are arranged in irregular masses, or more frequently, as a network of interconnecting strands of cells. Each of these masses or strands is bounded by a layer of columnar cells, and between these layers may be found stellate reticulum like cells. Sometimes double rows of columnar cells are lined up back to back. However, the stellate reticulum like tissue is much less prominent in the plexiform type than in the follicular type of ameloblastoma. Areas of cystic degeneration of stroma are also common.

In the acanthomatous ameloblastoma, the cells occupying the position of the stellate reticulum undergo squamous metaplasia, sometimes with keratin formation in the central portion of the tumor islands. This usually occurs in the follicular type of ameloblastoma. On occasion, epithelial or keratin pearls may even be observed.

In the granular cell ameloblastoma, there is marked transformation of the cytoplasm, usually of the stellate reticulum like cells, so that it takes on a very coarse, granular, eosinophilic appearance. This often extends to include the peripheral columnar or cuboidal cells as well. Ultrastructural studies, such as that of Tandler and Rossi, have shown that these cytoplasmic granules represent lysosomal aggregates with no recognizable cellular components. Hartman has reported a series of 20 cases of granular cell ameloblastoma and emphasized that this granular cell type appears to be an aggressive lesion with a marked proclivity for recurrence unless appropriate surgical measures are instituted at the first operation. In addition, several cases of this type have been reported as metastasizing. However, all other clinical features of the lesion appear similar to the other forms of ameloblastoma.

The basal cell type of ameloblastoma bears considerable resemblance to the basal cell carcinoma of the skin. It is believed that this is the rarest histologic subtype and the epithelial tumor cells are more primitive and less columnar, are generally arranged in sheets, more so than in the other tumor types (Fig. 4-22).

The desmoplastic ameloblastoma, characteristically, is found in a dense collagen stroma that may appear hyalinized and hypocellular. The desmoplastic ameloblastoma has a greater tendency to grow in thin strands and cords of epithelium rather than in an island like pattern. The epithelial proliferation almost seems to be compressed and fragmented by the dense hyalinized stroma. Central cells are often scant in the epithelial proliferation, and the cells making up the periphery of the strands and cords often are flattened or cuboidal rather than tall columnar in appearance. Reverse polarity of nuclei and subnuclear vacuole formation may be difficult to recognize (Fig. 4-23).

Most desmoplastic ameloblastomas display occasional classic islands of follicular ameloblastoma among the predominant strands and cords. Without these classic islands of ameloblastoma, the diagnosis can be difficult.

The growth pattern of the neoplasm, categorized as conventional or unicystic, is more important than the histopathologic subtype in treatment decision. The desmoplastic ameloblasloma is more important than the histopathologic subtype in treatment decision. Desmoplasia of the stromal connective tissue can be argued to be a maturation stage of the tumor, as similar dense collagenization is seem during maturation of long tumors (Sivapathamundaram et al, 2007). However, these authors failed to explain the off occurrence of these variants in the anterior jaw, unlike in conventional forms.

Unicystic ameloblastoma, the second and far less frequent growth pattern seen in the intraosseous ameloblastoma is the unicystic type. This growth pattern is seen in approximately 6% of ameloblastomas. It tends to occur in a younger population (average age in one large study, 22.1 years) compared with the patient population with conventional ameloblastomas. A high percentage of these lesions are associated with an impacted tooth, and the most commonly cited provisional diagnosis is dentigerous cyst. Cystic areas nearly always are noted grossly at the time of surgery. Recognition of this growth pattern is important, because it is well accepted that the unicystic type has a considerably better overall prognosis and a much reduced incidence of recurrence compared with conventional ameloblastoma (Li TJ et al, 1998).

The unicystic ameloblastoma is characterized by one or more of the following features:

The recurrence rate of this lesion is distinctly lower than that for the characteristic ameloblastoma, thus indicating a less aggressive type of lesion. The epithelium lining the cystic cavity of the neoplasm shows typical cytomorphologic features that are recognizable as ameloblastoma, with a basal cell layer composed of columnar cells displaying hyperchromatic, palisaded nuclei.

Reverse polarity of the nuclei is present, and a subnuclear vacuole is usually noted between the basement membrane and nucleus. A thin overlying layer of stellate reticulum-like cells is seen. A luminal parakeratin layer may or may not be present. When keratinization is present, an abrupt transition from the stellate reticulum-like layer is usually observed. In some instances, the ameloblastic epithelium may be proliferative, with extension of the ameloblastic epithelium into the lumen of the cystic cavity. This feature has been termed intraluminal proliferation, and in many instances, this growth resembles the plexiform type of ameloblastoma. Thus, some lesions have been referred to as plexiform unicystic ameloblastoma (Fig. 4-25).

Treatment and Prognosis

There are some differences of opinion about the preferable method of treatment of the ameloblastoma. The only unanimity centers around the fact that complete removal of the neoplasm, regardless of how it is accomplished, will result in a cure of the patient.

The types of treatment that have been used include both radical and conservative surgical excision, curettage, chemical and electrocautery, radiation therapy or a combination of surgery and radiation. The majority of workers today prefer some form of surgical excision. Curettage is least desirable, since it is associated with the highest incidence of recurrence. The basic principles of treatment have been discussed in detail by Gardner and Mehlisch and his colleagues.

Frissell reviewed the reported cases in which radiation therapy was utilized and found that there was considerable variance of opinion as to its benefit. The report of Kimm, supported by study of serial biopsy, on the treatment of the ameloblastoma by radiation indicated that this neoplasm is generally highly radioresistant and that the use of this form of therapy is not warranted. Wide clinical experience has shown the truth of this finding. Regardless of the form of treatment, long-term follow-up of the patient is an absolute necessity.

Treatment decisions for ameloblastoma are based on the individual patient situation and the best judgment of the surgeon. The surgical plan should be influenced strongly by whether the lesion involves the mandible or maxilla. Maxillary lesions behave distinctly differently from mandibular lesions. The higher cancellous bone percentage in the maxilla facilitates the spread of the ameloblastoma, whereas the density of the cortical plates in the mandible tends to limit spread of the neoplasm. Regardless of which jaw is involved, once an ameloblastoma has recurred, retreatment becomes more challenging. Radical retreatment typically is performed even for suspected unicystic lesions during the initial phase of the disease.

Clinical Features

A report by Franklin and Pindborg in 1976 shows that 113 cases of this intraosseous tumor have been described in the literature since Pindborg’s original paper. As the number of reported cases continues to increase, we are rapidly improving our knowledge of this lesion.

This tumor occurs most frequently in middle-age. Of the reported cases, the mean age of occurrence at the time of diagnosis was 40 years of age in both men and women, with a range of 8–92 years. There is no significant difference in occurrence between the gender, since 49% of the cases were in men and 51% in women.

There is a predilection for occurrence of the tumor in the mandible over the maxilla by a ratio of 2 : 1, and the prevalence in the molar region is three times that in the bicuspid region, whereas in other sites in the jaws there is a relatively even distribution. If these two respects, i.e. age and site, the Pindborg tumor is very similar to the ameloblastoma.

Most patients with this lesion are asymptomatic and are aware only of a painless swelling. It is significant, however, that 52% of the reported cases have been definitely associated with an unerupted or impacted tooth.

An extraosseous calcifying epithelial odontogenic tumor is also known to occur but is quite rare, with only eight reported cases, according to the review by Wertheimer and his associates in 1977. This extraosseous lesion has had a mean age of occurrence of 35 years and an approximately equal sex distribution. With the exception of one equivocal lesion on the upper lip, all cases have occurred on the gingiva, five mandibular and two maxillary, and almost invariably in the anterior segment (Fig. 4-26). The extraosseous lesion is histologically identical with the intraosseous one.

Radiographic Features

The tumor may show considerable radiographic variation. In some cases, the lesion appears as either a diffuse or a well-circumscribed unilocular radiolucent area, while in other cases there may appear to be a combined pattern of radiolucency and radiopacity with many small, irregular bony trabeculae traversing the radiolucent area in many directions, producing a multilocular or honeycomb pattern. Scattered flecks of calcification throughout the radiolucency have given rise to the descriptive term of a ‘driven snow’ appearance. In some instances, the lesion is totally radiolucent and is in association with an impacted tooth, thus leading to a mistaken clinical diagnosis of dentigerous cyst (Fig. 4-27).

On CT examination, calcifying epithelial odontogenic tumor in the mandible demonstrates expansion and thinning of buccal and lingual cortical bony plates by a well-defined mass containing scattered radiopaque areas of varying size and signal intensity. MRI reveals predominantly a hypointense lesion on T1-weighted images and a mixed hyperintense lesion on T2-weighted images.

Histologic Features

The calcifying epithelial odontogenic tumor is composed of polyhedral epithelial cells, sometimes closely packed in large sheets but other times consisting chiefly of scattered small islands of cells in a bland fibrous connective tissue stroma (Fig. 4-28). Occasionally, the cells are arranged in cords or rows, mimicking adenocarcinoma.

The tumor cells have a well-outlined cell border with a finely granular eosinophilic cytoplasm, and intercellular bridges are often prominent. The nuclei are frequently pleomorphic, with giant nuclei and multinucleation being quite common but mitotic figures rare. The tumor cells in some lesions are characterized by extreme morphologic variation with severe cellular abnormalities, mimicking those often seen in some highly malignant neoplasms, while other cases of the calcifying epithelial odontogenic tumor are composed of very monomorphic, innocuous-appearing tumor cells; yet, to the best of our knowledge, the biologic behavior does not differ between the two.

A well-recognized form of this neoplasm is the clear-cell variant. In this type, the tumor cells exhibit a clear vacuolated cytoplasm rather than an eosinophilic cytoplasm. The nucleus may remain round or oval in the center of the cells or be flattened against the cell membrane. According to Krolls and Pindborg, who have discussed these histomorphologic variations, most of the clear cells are mucicarmine negative, although a few may show a faint tinge. In some tumors, the clear cells comprise the bulk of the tumor cells while, in others, they consist of only a few scattered foci. In as much as a variety of other types of tumors, both primary (e.g. mucoepidermoid carcinoma) and metastatic (e.g. hypernephroma), may exhibit clear cells, great care must be utilized in their interpretation and diagnosis

This tumor has been investigated under the electron microscope by many researchers including Anderson and his coworkers, who have demonstrated that the tumor cells exhibit the features commonly seen in epidermal cells such as intercellular bridges with desmosomes, intracytoplasmic tonofilaments and well-developed hemidesmosomes.

One of the characteristic microscopic features of this tumor is the presence of a homogeneous, eosinophilic substance which has been variously interpreted as amyloid, comparable glycoprotein, basal lamina, keratin or enamel matrix. In at least some instances, this appears to form intracellularly and then is extruded into the extracellular compartment as a result of cell secretion or degeneration. This homogeneous eosinophilic material may be present in large or very limited quantities. In most cases, it stains metachromatically with crystal violet, positively with Congo red, and fluoresces under ultraviolet light with thioflavin T, all in a fashion similar to amyloid (Fig. 4-29). Ultrastructural studies have shown that this amyloid-like material is composed of at least three different types of fibrils, but that they have a smaller size than the fibers of ‘conventional’ amyloid, although this term is a rapidly expanding one. Some forms of amyloid are now suggested to arise from light chain fragments of immunoglobulin molecules, called immunamyloid, while another form is thought to originate from cells of certain endocrine tumors (e.g. medullary carcinoma of the thyroid) which may be derived from the endocrine polypeptide cells of neural crest origin of the amine precursor uptake and decarboxylation (APUD) system, called APUD-amyloid. On the evidence available at present, the exact nature of the amyloid like substance in the CEOT cannot be definitively assessed.

Another characteristic feature of the Pindborg tumor is the presence of calcification, sometimes in large amounts, and often in the form of Liesegang rings. This calcification actually appears to occur in some instances in globules of the amyloid like material, many of which have coalesced and are transformed from being PAS (periodic acid-Schiff)-negative to PAS-positive during this calcification process. There does not appear to be necessarily a relationship between the amount of amyloid material formed in a given lesion and the amount of calcification occurring.

The source of the epithelial cells comprising this tumor was originally suggested by Pindborg to be the reduced enamel epithelium of the associated unerupted tooth. Today, most investigators believe that the cells originate from the stratum intermedium because of the morphologic similarity of the tumor cells to the normal cells of this layer of the odontogenic apparatus. Unfortunately, this does not explain those cases of tumor apparently occurring without an associated unerupted tooth or those extraosseous cases outside the jaw.

Treatment and Prognosis

There are a variety of alternative surgical treatment methods to successfully manage Pindborg tumors. Small, intrabony lesions with well-defined borders can be treated with enucleation or curettage followed by judicious removal of a thin layer of bone adjacent to the tumor. But some pathologists suggest that maxillary tumors should be treated more aggressively than a similar-sized lesion in the mandible.

Lesions designated recurrences, following conservative approaches like intrabony curettage, may in fact represent persistence of disease. Like ameloblastoma, small infiltrative foci of Pindborg tumor may insinuate along bony trabeculae and appear as uninvolved bone radiographically.

Recurrent or persistent tumors, which over an extended time have become larger and more extensive (greater than 4 cm), would require segmental resections such as partial or hemimandibulectomy or hemimaxillectomy.

Early intervention is advocated for the treatment of histopathologically atypical or frankly malignant calcifying epithelial odontogenic tumors before such a lesion could escape the confines of the involved mandible or maxilla. Radical resection of the affected jaw portion and any associated soft tissues with not less than 1 cm in every direction, as might be performed for any other variant of odontogenic carcinoma is adviced. Adjunctive external beam radiation therapy is advocated following determination of local spread to cervical lymph nodes and adjunctive chemotherapy may play some role in control of distant organ metastasis in some patients. Most studies of Pindborg tumor report a local recurrence rate of between 10 and 20% following conservative but complete removal of the lesion. The incidence of malignant transformation to odontogenic carcinoma ex-Pindborg tumor is so extremely low as to be considered distinctly rare; only three such cases being reported.

Histogenesis

Like all other odontogenic tumors, the specific stimulus that triggers proliferation of the progenitor cells of AOT is unknown. Because of its exclusive occurrence within the tooth-bearing areas of the jaws (most often associated closely with an unerupted or impacted tooth) and its cytologic resemblance to the dental lamina and components of the enamel organ, there is no disagreement that the AOT is of odontogenic origin (Rick GM, 2004).

Clinical Features

The mean age of these patients was approximately 18 years, with a range of 5–53 years. However, 73% of the patient were under 20 years of age. There is a marked predilection for occurrence of the tumor in females — 64% contrasted to 36% developing in males. The site of occurrence is greater in the maxilla (65%) than in the mandible (35%). In contrast to the ameloblastoma, this tumor occurs more frequently in the anterior part of the jaws with 76% developing anterior to the cuspid in the maxilla and mandible. Only very rarely does the lesion occur distal to the premolar area. It is of some interest that in at least 74% of the cases, the tumors were associated with an unerupted tooth, and in over two-thirds of the cases, this tooth was the maxillary or mandibular cuspid.

The vast majority of the lesions measured between 1.5 and 3.0 cm, although large lesions, exceeding 7.0 cm, have been reported. A large proportion of these tumors produced an obvious clinical swelling although they were generally asymptomatic. Five tumors reported in the literature have been extraosseous in their occurrence, according to Swinson.

Giansanti and his coworkers have pointed out that the high percentage of these lesions being associated with unerupted teeth and present as dentigerous cysts would strongly suggest that they are related to some late disturbance in odontogenesis. Since none of the associated teeth were described as morphologically defective, the disturbance must occur after odontogenesis is complete.

Adenomatoid odontogenic tumor may occur within the jaw bones or the gingiva. Peripheral lesions present as a painless, gingival colored mass that ranges from 1–1.5 cm in diameter. They are 10 times more prevalent in the maxillary gingiva than in the mandibular gingiva. The female to male ratio for the gingival lesion is 14: 1 (Philipsen HP et al, 1991).

Adenomatoid odontogenic tumor has to be clinically differentiated from central odontogenic cysts and tumors, benign fibro-osseous lesions and benign mesenchymal neoplasms. Gingival lesions cannot be differentiated clinically from gingival fibromas, peripheral cemento-ossifying fibromas, peripheral giant cell lesions, or from other peripheral odontogenic tumors, such as odontogenic fibroma, ameloblastoma, calcifying odontogenic cyst, and calcifying epithelial odontogenic tumor.

Radiographic Features

Central AOTs present as well-demarcated, almost always unilocular radiolucency that generally exhibit a smooth corticated (and sometimes sclerotic) border.

Most lesions are pericoronal or juxtacoronal but the radiolucency may extend apically beyond the cementoenamel junction on at least one side of the root. Rare, multilocular cases have been reported and a scalloped border is observed occasionally. Most cases are between 1 and 3 cm in greatest diameter. About 65% of reported cases also demonstrate faintly detectable radiopaque foci within the radiolucent lesion. Occasionally, a more obvious intralesional radiopacity may be identified, usually eccentrically positioned within the lesion. Divergence of roots and displacement of teeth occurs more frequently than root resorption. Orbital and maxillary sinus encroachment have been reported. Gingival lesions may cause slight erosion of the underlying alveolar bone cortex.

Histologic Features

Treatment and Prognosis

The majority of tumors of this variety have been treated by conservative surgical excision and recurrence, if it ever occurs, is exceedingly rare.

Clinical Features

The age at discovery of the 16 cases evaluated by Goldblatt and his coworkers ranged from 11 to 67 years with 10 cases being between 19 and 31 years of age. There were six males and 10 females in the series.

There is a slight male preponderance, and the mandible is commonly involved. In the maxilla, lesions centered around the incisor-cuspid area, whereas in the mandible, lesions had a predilection for the bicuspid-molar area. However, several cases exhibited multiple site involvement, including both maxillary and mandibular involvement in the same patient.

The lesions were often asymptomatic but presenting manifestations included mobility of involved teeth, pain, tenderness to percussion, and occasionally, abnormal sensations.

Radiographic Features

There are no radiographic features sufficiently characteristic to suggest the diagnosis of this condition. It presents as a semicircular or roughly triangular radiolucent area, with or without a sclerotic border, usually in association with the cervical portion of the tooth root (Fig. 4-31 A, B).

Histologic Features

The squamous odontogenic tumor is composed entirely of islands of mature squamous epitheliumwithout a peripheral palisaded or polarized columnar layer (Fig. 4-31 C, D). This peripheral layer is usually quite flattened or at least cuboidal. The squamous cells are very uniform and exhibit no pleomorphism, nuclear hyperchromatism or mitotic activity. Occasionally, individual cell keratinization is present but no epithelial pearls. Intercellular bridges are usually seen with no difficulty. Three other variable findings are microcyst formation involving only small portions of the epithelial islands, laminar calcifications in the epithelium and globular, hyalin, eosinophilic structures within the islands, which are not amyloid. The fibrous stroma of the tumor is simply mature bundles of collagen fibers and is devoid of any peri-insular inductive effect.

Squamous odontogenic tumor like proliferations have been reported by Wright in the walls of odontogenic cysts, such as dentigerous or apical periodontal cysts. These proliferations may appear histologically nearly identical with those in the squamous odontogenic tumor, but they do not appear to cause any alteration in the usual biologic behavior of the cyst and do not appear to develop into the tumor. Care must be used, however, in differentiating between these proliferations and the tumor itself.

Although squamous odontogenic tumor exhibits a unique microscopic picture, it may be confused with other conditions, including ameloblastoma and squamous cell carcinoma. The acanthomatous and desmoplastic variants of ameloblastoma have been misdiagnosed as squamous odontogenic tumor. Both variants exhibit squamous differentiation within the tumor islands, but there is demonstrable ameloblastic change of the peripheral cells, including columnar shape, polarization of elongated nuclei away from the basement membrane, and a vacuolated or clear cytoplasm. These changes may be less evident in the desmoplastic variant but can be found on careful and thorough examination of the specimen. These changes are not seen in the squamous odontogenic tumor in which the peripheral cell layer is composed of flat to cuboidal cells. The islands and strands of desmoplastic ameloblastoma are often thin and compressed rather than rounded and broad-based, as seen in squamous odontogenic tumor.

Squamous odontogenic tumor may be confused with well-differentiated squamous cell carcinoma; however, the islands in squamous odontogenic tumor are well defined, and the cells lack variation in cell size, shape and nuclear staining and mitotic figures that are characteristically seen in squamous cell carcinoma. Significant keratin formation also is not typical.

Occasionally, dentigerous and apical periodontal (radicular) cysts and periodontal granulation tissue exhibit foci of squamous odontogenic tumor like proliferation. This has been interpreted as a nonneoplastic, reactive process that is secondary to the cyst formation or inflammation. Foci of squamous odontogenic tumor within the connective tissue wall of odontogenic cysts do not seem to alter the prognosis of the primary cystic process.

Treatment

Enucleation, curettage, and local excision are treatment modalities that are most often described in case reports of squamous odontogenic tumor. Clinically aggressive lesions have been treated by en bloc excision.