Etiology

Various etiological and predisposing factors have been propounded for the development of tumors such as infection, irritation, trauma, dietary deficiency, viruses, hormonal changes and genetic factors.

Classification

With the first edition of the WHO classification on tumors, about 30 years ago, the terminology and the diagnostic framework became available, and this modern and logically constructed classification greatly intensified research into the subject, and markedly stimulated the urge to publish new findings. In 2000, the International Agency for Research on Cancer (IARC) in Lyon, France started a new book series, WHO Classification of Tumors. The new WHO Blue Books encompass both histopathological and genetic criteria for tumor classification (Table 1). Clinically it also can be classified based on site, age and gender predilection as given in Tables 2–4.

The common clinical features of benign tumors include: slow growing and well-circumscribed swelling, bony expansion, displacement and abnormal mobility of teeth and absence of lymphadenopathy.

Diagnosis of benign tumors

Classification

Leon Barnes has classified ameloblastoma into four types on the basis of behavioral pattern, anatomical location, radio-graphic appearances and histologic features as follows:

Clinical features

Ameloblastomas may be present over a wide age range but are usually diagnosed in the 4th and 5th decades of life, although they can occur in children or the elderly. About 80% of tumors occur in the mandible, of which some 70% arise in the molar region and ascending ramus, 20% in the premolar region, and 10% in the incisor region. In the maxilla, most of these also occur in the molar region but about 15% involves the antrum.

The tumor is slow growing and in the early stages may be asymptomatic and discovered as an incidental finding. As the tumor enlarges the patient may become aware of a gradually increasing facial deformity and expansion of the jaw bone (Figure 1A, B). The enlargement is usually bony hard, non-tender, and ovoid or fusiform in outline but in advanced cases, egg-shell crackling may be elicited due to thinning of the overlying bone. However, perforation of bone and extension of the tumor into soft tissues are late features. In the maxilla, even large tumors may produce little expansion as the lesion can extend into the sinus and beyond. Teeth in the area of the tumor may become loosened, but pain is seldom a feature.

Radiographically, the ameloblastoma appears most commonly as a multiloculated radiolucency (Figure 2A, B). Roots of teeth involved by the tumor show varying degrees of resorption. As the tumor enlarges it may become associated with an unerupted tooth, particularly an impacted third molar, and the appearances may mimic those of a dentigerous cyst. Less frequently, ameloblastomas present as a single unilocular radiolucency indistinguishable from an odontogenic cyst.

MRI findings

Characteristic findings are: multilocularity, mixed solid and cystic components, irregularly thickened walls, papillary projections, and marked enhancement of the walls and septa.

Histopathology

There are six histologic subtypes: follicular, plexiform, acanthomatous, granular cells, basal cell and desmoplastic. These can be found combined or isolated and not related to prognosis of the tumor. The two main patterns are anastomosing epithelial strands and fields or discrete epithelial islands. The former pattern is called the plexiform (Figure 3) type, the others the follicular (Figure 4A). Both may occur within the same lesion. The follicles consist of a central mass of loosely connected, angular cells resembling the stellate reticulum of the normal enamel organ, surrounded by a layer of cuboidal or columnar cells resembling ameloblasts. The nuclei of the latter are situated away from the basal ends of the cells, and this is described as reversed polarity. The follicles are separated by varying amounts of fibrous connective tissue stroma. A variety of changes can occur within the stellate area of the follicles and these include cystic breakdown, squamous metaplasia, and granular cell change. The tumor epithelium in the plexiform type is arranged as a tangled network of anastomosing strands and irregular masses, each of which shows the same cell layers as for the follicular pattern. Thus, each strand or mass is bounded by columnar or cuboidal cells resembling ameloblasts, while the central area is occupied by stellate reticulum-like cells. Microcyst formation is commonly seen.

When extensive squamous metaplasia, often associated with keratin formation, occurs in the central portion of a follicular ameloblastoma, the term ‘acanthomaotus ameloblastoma’ is used (Figure 4B).

Differential diagnosis

Differential diagnosis of ameloblastoma are given in Box 1.

Treatment

The therapeutic approach to the ameloblastoma is still a controversy. There are problems to determine incidence, management or recurrence rate. Not every ameloblastoma has the same destructive potential or recurrence tendency. For unilocular cystic lesions in young patients, curettage or enucleation is effective treatment. Solid lesions show high recurrence rates (50–90%) necessitating tumor excision or partial resection of the jaw bone. There seems to be more consensus in the management of ameloblastomas in children, due to the psychological impact of an aggressive resection, and its relationship with growth and function.

Key points on ameloblastoma are given in Box 2.

Literature review

Ameloblastoma is a tumor with a complex biological character and presents a high recurrence rate even in patients treated with radical therapy. It has been reported that the aggressiveness of ameloblastoma may be related to the histological subtype, in fact.

Reichart et al in a review of the literature, found recurrence rates for plexiform, follicular, acanthomatous and unicystic ameloblastoma respectively of 16.7%, 29.5%, 4.5% and 13.7%. Proliferating cell nuclear antigen (PCNA) is a cell cycle related antigen and has been used for the evaluation of the proliferation ability of this tumor.

Determinants of biological behavior

Histopathology

Based on the character and extent of tumor cell proliferation within the cyst wall, several histologic subtypes of unicystic ameloblastoma are recognized, which include those of simple cystic nature, intraluminal proliferative nodules and infiltrative tumor islands in the cyst walls. The lesion presents as a cyst lined by ameloblastomatous epithelium comprising a basal layer of columnar cells with polarization of their nuclei away from the basal lamina, covered by a loose, vacuolated layer of stellate epithelial cells. The diagnosis is made based on histopathologic examination.

Treatment

This variant is believed to be less aggressive, tends to affect patients at a younger age and its response to enucleation or curettage is more favorable than the classic solid or multicystic ameloblastomas.

Histopathology

The marked histological polymorphism of odontogenic tumors make the final diagnosis difficult and in some cases it must be made based on clinical, radiologic and histopathologic features. Moreover, Wachter et al could not histologically differentiate between OA and ameloblastic fibro-odontoma, and therefore suggest that they are the same entity.

Treatment

Commonly, its clinical presentation mimics an odontoma, and therefore the definite diagnosis is based on the histologic analysis following a simple extirpation and curettage.

Clinical features

It occurs over a wide age range and is about twice as common in the mandible as in the maxilla. The chief sign is cortical expansion and pain is not normally a complaint. Most of the tumors arise in the molar or premolar area and about half are associated with the crown of an unerupted tooth. Although most tumors arise within bone, extraosseous lesions have been reported.

Radiographic features

These tumors show an irregular radiolucent area which may or may not be clearly demarcated from the surrounding normal bone. The radiolucency contains varying amounts of radiopaque bodies due to calcification within the tumor. Radiographic features which have been considered characteristic of CEOT, coronal clustering and ‘driven snow’ patterns, are seen in only a small percentage of cases.

Histopathology

The calcifying epithelial odontogenic tumor consists of sheets of polygonal cells with ample eosinophilic cytoplasm, distinct cell borders, and very conspicuous intercellular bridges. Nuclei are pleomorphic with prominent nucleoli; cells with giant nuclei and multiple nuclei are also present. The epithelial tumor islands as well as the surrounding stroma frequently contain concentrically lamellated calcifications. Stromal deposits of bone and cementum may occur (Figure 5).

Treatment

The treatment for CEOT has ranged from simple enucleation or curettage to radical and extensive resection such as hemimandibulectomy or hemimaxillectomy. The choice should be individualized for each lesion because the radiological and histological features may differ from one lesion to another.

Prognosis

The prognosis of the CEOT is good with infrequent recurrence. Malignant behavior is extremely rare. Although it has not been established in the literature, 5 years should be the absolute minimum follow-up necessary to assess the healing for this type of odontogenic tumor.

History

Adenomatoid odontogenic tumor (AOT) is a relatively uncommon distinct odontogenic neoplasm that was first described by Steensland in 1905. However, a variety of terms have been used to describe this tumor. Unal et al produced a list containing all nomenclatures for AOT reported in the literatures. Various names like adenoameloblastoma, ameloblastic adenomatoid tumor, adamantinoma, epithelioma adamantinum or teratomatous odontoma have been used before to define the lesion currently called AOT.

Definition

Philipsen and Birn (1971), defined it as an odontogenic epithelial tumor with an inductive effect on the odontogenic mesenchyme. The nature of the lesion is uncertain and it may be hamartomatous rather than truly neoplastic.

Classification

Based on the location it can be classified as:

Clinical features

The adenomatoid odontogenic tumor usually presents during the 2nd and 3rd decades of life. The majority of tumors arise in the anterior part of the maxilla (Figure 6A), especially in the canine areas, and there are usually few symptoms apart from a slowly enlarging swelling. Clinical features generally focus on complaints regarding a missing tooth. The lesion usually presents as asymptomatic swelling which is slowly growing and often associated with an unerupted tooth. However, the rare peripheral variant occurs primarily in the gingival tissue of tooth-bearing areas. Unerupted permanent canines are the teeth most often involved in AOT.

Radiographic features

On radiographs it usually appears as a well-defined radiolucency but in some cases calcification within the tumor may produce faint radiopacities (Figure 6B). The lesion is often associated with an unerupted tooth and may simulate a dentigerous cyst (simulating a ‘target’ like appearance).

Histopathology

Lesion is well encapsulated and may be solid or partly cystic; in some cases the tumor is almost entirely cystic. It consists of sheets, strands, and whorled masses of epithelium which in places differentiate into columnar, ameloblast-like cells. The columnar cells form duct or tubule-like structures (hence adenomatoid) with the central spaces containing homogeneous eosinophilic material. These are thought to represent abortive attempts at enamel organ formation. There is very little supporting stroma. Small foci of calcification are scattered throughout the tumor and occasionally tubular dentin and enamel matrix may be seen (Figure 7).

Differential diagnosis

Radiologically, it should be differentiated from dentigerous cyst, which most frequently occurs as a pericoronal radiolucency in the jaws. Dentigerous cyst encloses only the coronal portion of the impacted tooth, whereas AOT shows radiolucency usually surrounding both the coronal and radicular aspects of the involved tooth.

Common neoplastic causes, such as ameloblastoma, CEOT, ameloblastic fibroma and ameloblastic fibro-odontoma are easily differentiated on histology.

Treatment

All variants of AOT are well-encapsulated and show an identical benign behavior. Conservative surgical enucleation or curettage is the treatment of choice with only rare recurrence.

Literature review

The histogenesis of AOT is still uncertain, although recent findings strongly indicate that AOT is derived from a complex system of dental laminae or its remnants. It is often considered as a hamartomatous lesion rather than a true neoplasm.

Clinical features

The calcifying cystic odontogenic tumor occurs over a wide age range but is usually seen below 40 years of age. About 75% are intraosseous and either jaw may be involved. The majority, including those located in the gingival or alveolar soft tissues, arise anteriorly to the first permanent molar tooth. The lesion usually presents as a slowly enlarging but otherwise symptomless swelling. The COC normally appears as a painless, slow-growing tumor, affecting equally the maxilla and mandible, with predilection to the anterior segment (incisor-canine area). It generally affects young adults in the 3rd to 4th decade, without gender predilection.

Radiographically, the lesion appears as a well-defined unilocular or multilocular radiolucent area containing varying amounts of radiopaque, calcified material. It may be associated with the crown of an unerupted tooth (Figure 8).

Histologically, the cyst is lined by epithelium which shows a well-defined basal layer of columnar, ameloblast-like cells and overlying layers of more loosely arranged cells that may resemble stellate reticulum. A characteristic feature is the presence within the lining of masses of swollen and keratinized epithelial cells which are usually referred to as ‘ghost’ cells since the original cell outlines can still be discerned. The ‘ghost’ epithelial cells may calcify. Breakdown of the epithelium may release keratinous debris into the supporting connective tissue resulting in a prominent foreign body, giant cell reaction.

Clinical features

KCOTs comprise approximately 11% of all cysts of the jaws. These occur most commonly in the mandible, especially in the posterior body and ramus regions (Figure 8). They almost always occur within bone, although a small number of cases of peripheral KCOT have been reported. Patients may present with swelling, pain and discharge or may be asymptomatic. Distinctive clinical features include a potential for local destruction and a tendency for multiplicity, especially when the lesion is associated with nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin–Goltz syndrome. In the recent years, published reports have influenced WHO to reclassify the lesion as a tumor.

Several factors form the basis of this decision.

Histopathology

Histologically, these cysts are formed with a stratified squamous epithelium that produces orthokeratin (10%), parakeratin (83%), or both types of keratin (7%). The epithelial lining appears corrugated when viewed under a microscope. A well-polarized hyperchromatic basal layer is observed, and the cells remain basaloid almost to the surface. No rete ridges are present; therefore, the epithelium often sloughs from the connective tissue. The epithelium is thin, and mitotic activity is frequent; therefore, OKCs grow in a neoplastic fashion and not in response to internal pressure. The lumen frequently is filled with a foul-smelling cheese-like material that is not pus but rather collected degenerating keratin (Figure 9A–C).

Radiographic features

Radiographically, KCOT presents predominantly as a unilocular radiolucency with well-developed sclerotic borders. These may also present as a multilocular radiolucency or unilocular radiolucency at varying ratio. The multilocular appearance can be more of a unilocular with scalloped borders lacking true compartment formation. Odontogenic keratocysts of the maxilla are smaller in size compared to the mandible. When they are large, they tend to expand bone. No difference in site distribution is seen between unilocular and multilocular cysts. These lesions can also present as a small and oval radiolucency between teeth simulating a lateral periodontal cyst. They can also appear as a radiolucency simulating a residual apical periodontal cyst (Figure 9D).

Treatment

A review of the literature suggests that recurrence rate is relatively low with aggressive treatment, whereas more conservative methods tend to result in more recurrences.

Recurrence

KCOTs have a high recurrence rate, reportedly between 25% and 60% and when associated with NBCCS, the recurrence rate is about 82%.

History

Paul Broca (1867), defined it as a tumor formed by the overgrowth of transitory/complex dental tissues.

Clinical features

Odontomas are the most common maxillary tumors, and according to different sources in the literature account for 22–67% of all odontogenic maxillary neoplasms. As to their locations, most are found in the areas of the upper incisors and canines, followed by the antero– and posteroinferior regions.

Complex odontomas are more often found in the area of the second and third lower molars. An increased prevalence of these tumors is observed in children and adolescents, with few differences in relation to patient sex. These lesions are normally diagnosed by routine radiological studies in the 2nd and 3rd decades of life. As regards their pathogenesis, odontomas have been associated with antecedents of trauma during primary dentition, as well as with inflammatory and infectious processes, hereditary anomalies (Gardner’s syndrome, Hermann’s syndrome), odontoblastic hyperactivity, or alterations of the genetic components responsible for controlling dental development.

Radiographic features

Odontomas manifest as a dense radiopaque lesion surrounded by a thin radiotransparent halo. Three developmental stages can be identified, based on the radiological features and degree of calcification of the lesion at the time of diagnosis:

Compound odontomas show an irregular radiopaque image with variations in contour and size, composed of multiple radiopacities corresponding to the so-called denticles. In the complex type of lesion radiopacity is not specific; rather, a disorganized, irregular single or multiple mass is identified (Figure 10).

Histology

Complex odontomas consist of a usually well-delineated mass of dental hard tissues in a haphazard arrangement. The bulk of the lesion consists of dentin recognizable by the presence of tubuli. Enamel plays a minor role, usually confined to small rims in cavities in the dentin mass. The stroma consists of mature fibrous connective tissue. Sometimes, odontomas may contain areas identical to the calcifying odontogenic cyst, including ghost cells consisting of tiny teeth that may vary in number from only a few to numerous. These teeth do not resemble normal teeth, but are usually cone shaped.

Prognosis

Odontomas are benign tumors that sometimes produce no symptoms and constitute casual findings of routine radiological studies. However, they usually tend to cause signs and/or symptoms such as delayed eruption. If no signs or symptoms appear then the lesions go undetected. A very infrequent situation in relation to odontomas can be in the form of eruption.

Clinical features

It is characterized by a series of associated manifestations, the most common being maxillary keratocysts and cutaneous basal cell carcinomas, and other less frequent ones which can be present, such as cardiac disturbances such as persistent ductus arteriosus, characteristic facies in the form of mandibular prognathia, frontal and parietal prominence, marked superciliary arches, wide bridged nose and hypertelorism, skeletal (brachymetacarpalism of the fourth and fifth fingers, vertebrae problems, costal synostosis or bifid ribs), skin (dermoid cysts, lipomas), neurological (congenital hydrocephalus, calcification of the cerebral falx, learning difficulties), sight such as blindness, congenital cataracts, strabismus), hormonal (hypogonadism) or associated with other malignant neoplasias. The appearance of pitted depressions, due to the lack of corneous strata in the palms of the hands and soles of the feet, is the only pathognomonic data which has been described in the literature regarding this condition.

Clinical features

The ameloblastic fibroma usually occurs in a younger age group than ameloblastoma and is uncommon in above 21 years of age. It presents as a slowly enlarging painless swelling and arises most frequently in the premolar or molar region of the mandible.

Radiographic features

It is a well-circumscribed lesion and does not require the radical excision that may be necessary to affect cure with the ameloblastoma. Radiographically, the tumor appears as a well-defined, usually unilocular, radiolucency. It may be associated with an unerupted tooth and mimic a dentigerous cyst.

Histopathology

The tumor consists of proliferating strands and clumps of odontogenic epithelium lying in highly cellular fibroblastic tissue resembling the dental papilla of the developing tooth. The epithelial component shows a peripheral layer of cuboidal or columnar cells which encloses a few stellate reticulum-like cells (Figure 11). The appearances are similar to ameloblastoma but the stellate cells are much less abundant and cyst formation is unusual. In some lesions dentin may be present and such tumors may be designated ameloblastic fibrodentinoma. The dentin is usually poorly formed and includes entrapped cells. Tubular dentin is rare.

Literature review

Tumors previously classified as dentinomas are now thought to be examples of the ameloblastic fibrodentinoma. The ameloblastic fibro-odontoma is a tumor which shows further inductive changes leading to the formation of enamel. Although the ameloblastic fibroma and fibrodentinoma are benign neoplasms, it is probable that the ameloblastic fibro-odontoma is a hamartoma. Histologically, it is difficult to distinguish from a developing complex odontome, to which it is probably closely related.

Key points on ameloblastic fibroma are given in Box 3.

Differential diagnosis is given in Box 4.

Clinical features

The cementoblastoma is a rare benign neoplasm most frequently seen in patients below 25 years of age. It usually arises in the molar or premolar area of the mandible and is attached to the root of a tooth. Most cases involve the mandibular first permanent molar. It presents as a slowly enlarging swelling which sometimes gives rise to pain, but the involved tooth is vital. Pain is main symptom, pain is severe and not relieved by NSAIDs.

Radiographic features

Radiographic features show a well-demarcated, mottled, or dense radiopaque mass with a radiolucent margin attached to the root of a tooth which usually shows resorption.

Histologic features

Tumor consists of a mass of calcified cementum-like tissue containing scattered cells lying in lacunae. Around the periphery and in other actively growing parts of the lesion, extensive sheets of uncalcified matrix formed by plump, deeply staining cementoblasts may be seen.

Prognosis

Lesions which are incompletely removed may recur.

Clinical features

Commonly seen in the 3rd decade of life with higher prevalence among women, and occurs mainly in the mandibular molar area. Presents as painless swelling or incidental finding.

Radiographic features

Often multilocular with internal osseous trabeculae arranged in ‘tennis racket’ pattern.

MRI: Prolongation of T1 and T2, reflecting rich myxoid stroma. Gradual contrast enhancement is typically seen on contrast-enhanced images.

Histopathology

Odontogenic myxomas consist of rather monotonous cells with multipolar or bipolar slender cytoplasmic extensions that lie in a myxoid stroma. Nuclei vary from round to fusiform in appearance. Binucleated cells and mitotic figures are present, but scarce. Occasionally, the lesion contains odontogenic epithelial rests. The lesion spreads into the jaw bone without any encapsulation, thereby engulfing neighboring cancellous bone.

Treatment

Excision or partial resection of the jaw bone with high rate of local recurrence due to infiltrative growth pattern enhancement is typically seen on contrast-enhanced images.

Histopathology

These lesions are more collagenous than myxomas but may range from myxofibrous to densely fibrous. Characteristically seen in odontogenic fibromas are few to many islands and strands of bland odontogenic epithelium. Calcific deposits may also be found. A variant (granular cell odontogenic fibroma), in which granular cells are seen in the connective tissue, has been described. The behavior of this tumor does not appear to be different from odontogenic fibroma. Abundant rest proliferation in follicular sacs can occasionally simulate the appearance of odontogenic fibroma or ameloblastic fibroma.

Clinicopathological correlation is important for the diagnosis of these lesions.

Treatment

Ennucleation/excision or partial resection of the jaw bone.

Papillary lesions of oral cavity

Papillary lesions are those that are tumefactive with a cauliflower surface. Some are pedunculated, others are sessile. Some are single, others are multiple or diffusely involve broad areas of the oral mucosa. The vast majority of papillomas are associated with or indeed caused by members of the HPV family, yet there are a few papillary growths that have not been associated with HPV. One lesion in particular, molluscum contagiosum, is caused by a member of the poxvirus group.

Clinical features

Exophytic, papillary mass, measuring less than 1 cm, usually pedunculated and soft in texture.

In the form of white lesion, usually solitary; may be multiple.

Squamous papilloma affects the buccal mucosa, soft palate, uvula, tongue and gingiva.

Histopathology

Epithelial hyperplasia with fibrovascular cores may be seen. The papillary projections may be sharp to blunt (Figure 12). Epithelium may be dysplastic in some lesions from HIV-positive patients.

Diagnosis

Lesions of the condyloma acuminatum, verruca vulgaris, focal epithelial hyperplasia and verrucous carcinoma may mimic lesions of squamous papilloma.

Treatment

Surgical excision is the preferred modality of management.

Clinical features

Papular to nodular and exophytic appearance. The warts may be cauliflower-like, spiked, or raised with a flat surface, perioral skin lesions may be brownish. The oral mucosal lesions are usually white to pink. It can be pedunculated or broad based.

Sites of predilection include the lips, palate, and attached gingiva. The incidence of oral warts due to HPV has dramatically increased in the potent antiretroviral therapy era. Diagnosis can be based on the clinical, microscopic and immunohistochemical demonstration of HPV common antigen.

Histopathology

Histological changes can be in the form of surface hyperkeratosis, granulosis and koilocytosis.

AIDS-associated oral warts may appear dysplastic microscopically.

Differential diagnosis

Treatment

Treatment may involve surgery, laser surgery, or cryotherapy. It should be noted that HPV survives in aerosol. Topical 5-fluorouracil treatment has been used on external lesions, but should be avoided in fair individuals as it can cause hyperpigmentation. It should be noted, however, that this is a specialized treatment and should only be used by those experienced with the use of this topical medication. Lesions tend to recur after treatment.

Clinical features

Presents clinically as exophytic, papillary, keratotic fronds of epithelium or can be a part of the proliferative verrucous leukoplakia spectrum.

Histopathology

Histologic features are in the form of papillary to verruci-form surface projections in which keratin varies in thickness. They can be broad, bosselated epithelial ridges with well-differentiated cellular features and can even mimic an early verrucous carcinoma.

Differential diagnosis

Verrucous carcinoma, papillary squamous cell carcinoma and proliferative verrucous />