Oral Medicine and Pathology PDF

26 ORAL MEDICINE AND PATHOLOGY Vivian Petersen Wagner, dds, phd Manoela Domingues Martins, dds, phd T DEFINITIONS AND his chapter aims to review the main diseases affecting the periodontal TERMINOLOGY...

26 ORAL MEDICINE AND PATHOLOGY Vivian Petersen Wagner, dds, phd Manoela Domingues Martins, dds, phd T DEFINITIONS AND his chapter aims to review the main diseases affecting the periodontal TERMINOLOGY tissues from the perspective of oral medicine and pathology. Due Cyst: A pathologic cavity lined by to the great variety of disorders that can occur in the periodontium epithelium and usually containing fluid and jawbones, only the most clinically relevant or prevalent conditions are or semisolid material.1 included. Desquamative gingivitis: A nonspe- cific term describing erythema and ulceration of the free and attached gingiva. It reflects diffuse inflammation Developmental Disorders of the gingiva with sloughing of the surface epithelium. It can be a manifes- EXOSTOSES tation of one or more of vesiculoero- sive mucosal conditions.1 Exostoses are characterized by limited protuberances arising from cortical Granuloma: A reactive nodule bone. The most common types of exostoses in the jaws are the torus palat- consisting of modified macrophages inus and the torus mandibularis (Fig 26-1), which occur in the midline of resembling epithelial cells surrounded hard palate and along the lingual aspect of the mandible, respectively. Other by a rim of mononuclear cells, usually types of exostoses include bilateral hard swellings along the facial aspect of lymphocytes, and often containing the alveolar process or in the lingual aspect of maxillary tuberosities. Most giant cells.1 exostoses are asymptomatic and can be diagnosed by clinical and radiographic Keratosis: Any keratinous growth, such assessment. In edentulous patients, surgical intervention might be necessary as a wart or callus.1 to accommodate dentures.2 Nikolsky sign: Occurs when the appar- ently normal, superficial layer of skin or oral mucosa may be rubbed off with slight trauma. Originally associated Local Soft Tissue Lesions with pemphigus vulgaris, but can be seen in several bullous conditions.1 TRAUMATIC ULCERS Ulcer, ulceration: A lesion on the surface of the skin or mucosa Traumatic ulcers can occur in any site of the oral mucosa. The etiologic characterized by discontinuation of factor can be usually detected during anamnesis (eg, trauma during brush- the epithelium deeper than erosion, ing) or physical examination (eg, denture hooks). Their clinical features exhibits gradual tissue disintegration and location can vary, and both characteristics are directly correlated with and necrosis.1 the cause of the injury (Fig 26-2). Traumatic ulcers regularly present as an exposure of the connective tissue recovered by a yellowish-white necrotic 294  Local Soft Tissue Lesions pseudomembrane with slightly erythematous borders. Biopsies are not indicated to achieve a final diagnosis once the microscopic aspect consists of exposed connective tissue without any particular feature that allows for a specific diagnosis. Other ulcerative conditions might have a similar microscopic appearance. The etiologic factor must be identified and removed (eg, polishing a cutting edge of a broken tooth or prosthesis adjustment). The gradual or complete regression of the lesion confirms the diagnosis of a traumatic ulcer. Ulcers that do not regress or do not heal completely within 10 days should Fig 26-1 Bilateral tori mandibularis. be reevaluated. A new hypothesis should be considered, and a biopsy may be indicated. Other ulcerative lesions caused by thermal and chem- ical agents can also occur. Hot foods, hot dental instru- ments, electrical burns, or cryosurgery can cause thermal lesions. Chemical etiologic factors include acids used during dental procedures, mouthwashes, and medications or recreational drugs (eg, analgesic tablets or cocaine deliberately rubbed into the gingiva). The diagnosis also needs to be established based on clinical history and physical examination, supplemented by the regression of the lesion. FRICTIONAL KERATOSIS This reactive condition is caused by a constant trauma with low intensity (ie, chronic), leading to more kera- Fig 26-2 Traumatic ulcer located in the gingiva caused by tin production by the epithelium. Frictional keratosis trauma during tooth brushing. frequently occurs in the ridge of edentulous areas or in the retromolar area due to constant trauma from mastication (Fig 26-3). To confirm the diagnosis, the dentist should remove the traumatic agent and observe the regression of the lesion. If the clinical differential diagnosis includes leukoplakia, a potentially malignant disorder, a biopsy can be performed. RECURRENT APHTHOUS STOMATITIS The involvement of gingiva and other keratinized mucosa (hard palate and dorsal surface of the tongue) by recurrent aphthous stomatitis (RAS) is rare and usually represents the extension of a large wound that originates in nonke- ratinized areas. However, this condition is among the most prevalent oral mucosa diseases, so it is important to understand. It is considered an immunologic reac- tion that can be triggered by different events, such as hormonal changes, stress, and spicy foods or foods with Fig 26-3 Frictional keratosis in the retromolar area due to citric acid. RAS is more common in younger patients trauma during mastication. 295  26 | ORAL MEDICINE AND PATHOLOGY Fig 26-4 Drug-related gingival lesions in a patient taking cy- Fig 26-5 The patient presented with two reddish macules in closporine. the attached gingiva above the maxillary right central incisor and left lateral incisor (arrowheads). The biopsy revealed an inflammatory infiltrate composed mostly of plasma cells. Modifi- cations to the patient’s diet resulted in regression of the lesions. BOX 26-1 Drugs associated with gingival hyperplasia5 take more time to heal and are usually associated with scar formation. The herpetiform variant demonstrates the Anticonvulsants greatest number of lesions per episode, and patients expe- Ethosuximide rience frequent recurrences. The diagnosis is based on Ethotoin clinical features associated with a history of recurrences Mephenytoin after excluding systemic conditions that may also trigger Methsuximide* Phenobarbital aphthous-like ulcerations. The treatment usually involves Phenytoin the use of topical agents such as corticosteroids and aims Primidone to relieve pain and accelerate repair. It is important to Sodium valproate differentiate RAS from other autoimmune diseases such Vigabatrin as oral lichen planus, pemphigus vulgaris, and bullous Immunosuppressants pemphigoid, in which lesions usually persist for a longer Cyclosporine time and occur mostly in individuals older than 40 years.3 Sirolimus Tacrolimus Calcium channel blockers DRUG-INDUCED GINGIVAL LESIONS Amlodipine Diltiazem Drug-related gingival enlargement is characterized by firm, Felodipine pale to reddish, and enlarged gingival papillae secondary Manidipine to the use of a systemic medication4 (Fig 26-4). Box 26-1 Nicardipine provides a list of medications that have been demonstrated Nifedipine Nimodipine to produce gingival overgrowth.5 The prevalence of gingival Nisoldipine hyperplasia among drugs varies, and the patient’s suscepti- Nitrendipine bility appears to play an important role. Additionally, poor Verapamil oral hygiene exacerbates the symptoms. The treatment should be planned in collaboration with the professional *Alternately spelled mesuximide, methosuximide, or methosuxinimide. who prescribed the drug. Discontinuation and drug substi- tution are the main treatment modalities, usually resulting in cessation of gingival overgrowth. In some circumstances, such as adolescents. There are three clinical variants: regression can also be observed. Systemic and topical agents minor, major, and herpetiform. The minor form is the can be used to increase plaque control when attempting to most common, in which lesions are usually small and ameliorate the gingival hyperplasia. In a significant number heal in a shorter time than other variants. Major lesions of cases, surgical removal of excess gingiva is necessary. 296  Local Soft Tissue Lesions a b c d Fig 26-6 (a) Focal fibrous hyperplasia. (b) Pyogenic granuloma. (c) Peripheral giant cell granuloma. (d) Peripheral ossifying fibroma. PLASMA CELL GINGIVITIS reactive hyperplastic lesions of the gingiva are currently recognized: fibrous hyperplasia, pyogenic granuloma, Plasma cell gingivitis is a rare and distinct type of gingival peripheral giant cell granuloma, and peripheral ossify- alteration characterized by a sharply demarcated bright ing fibroma.6 All four types are mainly characterized by erythematous area in the free and attached gingiva (Fig slow-growing nodular masses arising from the dental 26-5). Plasma cell gingivitis is considered a hypersensi- papilla (Fig 26-6). Edentulous areas may also be affected. tive allergic reaction, and several substances have been Some clinical features, such as surface and color, may associated with this condition, such as cinnamon oil, vary between lesions; however, these characteristics may mint, peppers, and herbal toothpastes, among others. The also overlap. The final diagnosis can only be established inflammatory infiltrate is composed mainly of plasma through histopathologic investigation. The main differ- cells, and investigation of the clonality of these cells ences among these lesions are presented in Table 26-1. might be necessary to rule out a plasma cell neoplasm The main clinical diagnosis hypothesis can be in atypical cases. Possible allergens should be identified constructed based on clinical aspects and patients’ and eliminated. history. Nevertheless, the final diagnosis will be estab- lished according to the microscopic features (Fig 26-7). NONNEOPLASTIC PROLIFERATIVE All lesions need to be completely excised. Strategies such LESIONS as root surface instrumentation and curettage can be performed to prevent recurrence of the lesions by elimi- Nonneoplastic proliferative lesions are especially rele- nating possible sources of irritation. vant because they affect the gingiva more frequently or exclusively. Several inflammatory stimuli can be present GIANT CELL FIBROMA in the periodontal region, such as local irritation from calculus, trauma, food impaction, and restorations with Giant cell fibroma also occurs with greater frequency in irregular margins, among others. Four forms of localized the gingiva. However, this condition is not as common 297  26 | ORAL MEDICINE AND PATHOLOGY TABLE 26-1 Clinical and histopathologic features of the most frequent nonneoplastic proliferative lesions Pyogenic Peripheral Peripheral Focal fibrous hyperplasia granuloma giant cell granuloma ossifying fibroma Surface Smooth Smooth or lobulated Smooth or lobulated Smooth Color Same as mucosa Pink to fiery red Red to reddish-blue Same as mucosa to red Ulceration Usually absent, unless Usually present, bleeds Usually present, bleeds Usually absent, unless secondary trauma easily easily secondary trauma Exclusive in No No Yes Yes the gingiva Peculiarities Frequently associated Frequently develops in Can cause “cupping” Hard mass at physical with ill-fitting complete or pregnant women, may resorption of the adja- examination, might have partial denture exhibit rapid growth cent alveolar bone radiopaque image Histopathology Mass of dense collage- Marked proliferation of Proliferation of mesen- Cellular fibroblastic tissue nous connective tissue in endothelial cells that line chymal cells and multinu- and formation of mineral- a scar-like pattern capillary channels and cleated giant cells ized products mixed inflammatory cells a b c d Fig 26-7 (a) Focal fibrous hyperplasia. (b) Pyogenic granuloma. (c) Peripheral giant cell granuloma. (d) Peripheral ossifying fibroma. 298  Infectious Diseases a b Fig 26-8 Primary herpetic gingivostomatitis in a teenaged patient. The area demonstrated gingival erythema and multiple erosive areas or ulcers in the palate (a) and labial mucosa (b). as localized reactive hyperplastic lesions. Moreover, giant The virus uses the sensory neurons axons to “travel back,” cell fibroma does not seem to be associated with chronic and the manifestation usually occurs at the site of primary irritation. The diagnosis of giant cell fibroma also relies on inoculation. The most common affected site is the outer the histopathologic examination, which reveals numerous edge of the vermilion border. Nevertheless, oral mucosal large, stellate fibroblasts that may contain multiple nuclei. involvement can also occur, mostly in the attached gingiva and hard palate. As in primary infection, the manifesta- tion initiates with fluid-filled vesicles that rapidly collapse, Infectious Diseases leaving erythematous or ulcerated lesions. Patients usually report prodromal signs and symptoms such as burning, itching, or pain. VIRAL INFECTIONS The diagnosis of both primary and recurrent forms Herpetic is generally based on clinical history and features but The oral infection by herpes simplex virus (HSV) can be can also be supplemented by laboratory confirmation. divided into primary infection and secondary or recurrent Patients should be advised to avoid contact with active infection. The infection is usually caused by type 1 HSV lesions (vesicles) in order to prevent spread to other sites (HSV-1) that is transmitted in saliva. The primary infec- (autoinoculation) or infection of other individuals. In a tion is asymptomatic in the majority of patients or causes primary infection, the treatment is usually symptomatic, insignificant signs and symptoms. However, in a subset of involving the prescription of analgesics and antipyretics patients, an acute manifestation known as herpetic gingi- (in cases of fever). In addition, local hygiene measures vostomatitis can occur. Most cases arise between the ages with gauze soaked in serum, hydration, liquid diet, and of 6 months to 5 years, directly related to the first contact rest should be recommended. In recurrent lesions, anti- with the virus. The onset is abrupt and accompanied by viral medications are more effective if initiated in the general malaise, high fever, and regional lymphadenopa- prodromal period. thy. Different mucosa sites, such as tongue, buccal mucosa, palate, and lips, can be affected and demonstrate numer- Human papillomavirus ous vesicles that collapse rapidly, resulting in erosive areas Human papillomaviruses (HPVs) include a large group or ulcers. The gingival involvement is extremely common of DNA viruses that are capable of infecting the skin in primary infection and is characterized by erythema, and mucosa of animal species. Based on their oncogenic edema, and pain (Fig 26-8). potential, HPV types are categorized as low risk or high After the primary infection, either asymptomatic or risk. Among the high-risk HPV types, HPV-16 is the most symptomatic, the virus is transported retrograde by frequently associated with cervical cancer and oropharyn- neurons to the trigeminal ganglion, where latency is geal cancer. The incidence of HPV-positive oropharyngeal established. Different stimuli such as acute sun exposure, cancer has been increasing significantly in the past 30 stress, and low immunity can trigger virus reactivation. years. The tonsils and base of the tongue represent the 299  26 | ORAL MEDICINE AND PATHOLOGY BOX 26-2 Predisposing factors to oral candidiasis Systemic factors Local factors Physiologic factors Dentures (acidic and anaerobic conditions) Extreme ages (children and elderly) Reduced vertical dimension (saliva accumulation Endocrine disorders and a moist environment) Diabetes, hypothyroidism Xerostomia Nutritional factors Sjögren syndrome, radiotherapy, or drug-induced Deficiency of vitamin B12, iron, or folate xerostomia Immunosuppression Medications (changes in normal microbiota) AIDS, drug-induced immunosuppression (trans- Broad-spectrum antibiotics, corticosteroids planted patients) (systemic or inhaled) sites most commonly affected by HPV-positive carcino- Other viral infections mas. Compared with conventional oral squamous cell Infection by varicella zoster virus (varicella or chicken- carcinoma (SCC; associated with tobacco and alcohol), pox) and enteroviruses (hand-foot-and-mouth disease these tumors are frequently diagnosed with a smaller and herpangina) can also cause oral lesions. These situ- size. Yet, nodal metastasis (cystic type in most cases) ations are more common in children. Varicella is well is commonly present at diagnosis. The 3-year survival known by its skin lesions; however, oral mucosa involve- rates of HPV-positive oropharyngeal carcinoma are ment may occur and even precede the skin manifestation. significantly higher than HPV-negative oropharyngeal Oral lesions are very common in hand-foot-and-mouth carcinoma.7 disease and herpangina, which are considered two distinct Oral papilloma is the most common HPV-associated manifestations of the same disease. In all these conditions, benign lesion of the oral cavity, and it occurs especially the gingiva does not represent the most common oral in the palate, tongue, and lips. Verruca vulgaris, another site affected. benign HPV-associated lesion, is more common in the skin; however, due to autoinoculation, lesions in the oral FUNGAL INFECTIONS mucosa can also occur. Both lesions are characterized as small nodules with a papillary or verrucous surface. Oral Oral candidiasis papilloma is usually solitary, while patients with verruca Candida species are commensal yeast present at the oral vulgaris usually present with multiple lesions. mucosa that can cause infection in specific circumstances, such as a weakening of the host’s immune defenses or HPV vaccine changes in the local environment (Box 26-2). Candida Three HPV vaccines have been licensed for albicans is the most commonly observed species in health use in the United States. Currently, routine and disease situations. The clinical manifestation of oral vaccination is recommended for (1) girls at age candidiasis is very broad and depends mainly in the type 11 or 12 years (series can be started at age 9 of predisposing factors present.9 Table 26-2 summarizes years) and through age 26 years if not vacci- the clinical aspects and etiology associated with the most nated previously; and (2) boys at age 11 or 12 common types of primary oral candidiasis and Candida- years (series can be started at age 9 years), associated lesions. through age 21 years if not vaccinated previ- The diagnosis of oral candidiasis is usually based on ously and through age 26 years for men who clinical signs and symptoms associated with a compre- have sex with men. Two doses of the vaccine hensive investigation of medical and dental history. It is are recommended for immunocompetent indi- important to identify and correct the underlying predis- viduals starting series at age 9 to 14 years, and posing factors. Treatment with antifungal agents without three doses for individuals starting series at removal of the predisposing factor might result in only older ages and for individuals with immuno- temporary relief, and relapses will probably occur. Topical compromised conditions.8 antifungals are generally the drug of choice for localized 300  Infectious Diseases TABLE 26-2 Most common types of oral candidiasis and Candida-associated lesions Etiology Clinical manifestation Pseudomembranous candi- Infants, elderly, corticosteroid or prolonged Creamy white plaques on the tongue, palate, diasis (oral thrush) broad-spectrum antibiotic therapy, diabetes and buccal mucosa that can be removed by mellitus, AIDS wiping gently, leaving behind an underlying erythematous tissue that may bleed slightly. Denture-related stomatitis Dentures associated with poor oral hygiene, Varies from pinpoint hyperemia, diffuse (erythematous candidiasis) nocturnal denture wear, ill-fitting prostheses, or erythematous, or papillary type. Lesions are low salivary flow asymptomatic and present only in the area supporting the denture. Angular cheilitis Reduced vertical dimension (elderly denture Erythematous or ulcerated fissures affecting patients), vitamin B12 or iron deficiency the commissures of the lip. Median rhomboid glossitis Etiology is poorly understood (smoking and Well-demarcated depapillated area (atrophy) inhalation steroids have been implicated) located in the midline of the dorsum of the tongue anterior to the circumvallate papillae. lesions in patients with normal immune function, while systemic drugs will be indicated for disseminated disease and/or patients with a compromised immune system. Systemic mycoses Histoplasmosis. Histoplasmosis is the most common systemic fungal infection in the United States and is caused by the environmental dimorphic fungus Histo- plasma capsulatum. Human infection occurs once the microorganism is inhaled from the environment, and there is no person-to-person transmission. Usually, infected individuals are asymptomatic; however, the Fig 26-9 Multiple paracoccidioidomycosis lesions in the labial mucosa and alveolar ridge. disease will manifest in 1% of the infected population, which might have different clinical presentations, includ- ing acute pulmonary disease, disseminated disease, or chronic pulmonary histoplasmosis. Histoplasmosis oral Blastomycosis, caused by the fungus Blastomyces lesions are rare but can occur in the disseminated form dermatitidis of the disease. The clinical manifestation is usually indis- Paracoccidioidomycosis, caused by Paracoccidioides tinguishable from a malignancy, appearing as a solitary brasiliensis chronic ulceration. The most classic microscopic aspect Coccidioidomycosis (valley fever), caused by Coccid- is epithelioid granulomas. Special stains, such as the ioides immitis periodic acid–Schiff (PAS) and Grocott-Gomori meth- Cryptococcosis, caused by Cryptococcus neoformans enamine silver (GMS) methods, evidence the small yeasts of Histoplasma capsulatum. The treatment is based on The contamination usually occurs due to fungus inha- systemic antifungals, mainly itraconazole. lation. In paracoccidioidomycosis, gingival involvement is very common and presents as mulberry-like ulcerations Other systemic mycoses. Examples include the following, (Fig 26-9). This condition is endemic in several areas though there are others as well: of Brazil, including the Southeast, Midwest, and South. 301  26 | ORAL MEDICINE AND PATHOLOGY a b Fig 26-10 Desquamative gingivitis diagnosed as LP through a clinical and histopathologic examination. (a) Clinical appearance of maxilla. (b) Clinical appearance of mandible. Autoimmune Diseases characteristics and symptomatology, oral LP is classified as reticular or erosive. The same patient can also present An autoimmune disease is characterized by the recog- with both forms of the disease. Reticular is the more prev- nition and attack of autoantigens by the immune system alent type and is characterized by asymptomatic white lacy (cellular and/or humoral). This response can persist for streaks called Wickham striae, surrounded by erythem- an indeterminate time; therefore, most of these conditions atous borders. The lesions are typically symmetric, bilat- are chronic, with periods of remission and exacerbation. eral, and predominantly found in the buccal mucosa and Currently, autoimmune diseases are manageable but border of the tongue. In the erosive form, patients report incurable. The therapy consists of modulating the immune symptomatology that can range from slight discomfort to response to reduce or control the clinical repercussion. severe pain. In this type of LP, areas of erosion or ulcer- Oral lesions of autoimmune diseases are usually symp- ation are present, showing radiating white striae. Some tomatic. The gingival involvement, termed desquamative patients present with lesions restricted to the gingiva, gingivitis, is frequent and can be very similar between the termed desquamative gingivitis (Fig 26-10), which can different diseases: presence of erythema, desquamation, be either symptomatic or asymptomatic. erosion, and blistering of attached and marginal gingiva. The diagnosis should be confirmed through histo- The main differential diagnosis is between mucocuta- pathologic study. The typical microscopic features include neous autoimmune disorders; however, chemical and epithelial rete ridges with a pointed or “saw-toothed” electric burns and allergic reactions can produce similar shape, “liquefaction degeneration” of the epithelial basal clinical features. A biopsy should be performed to estab- cell layer, presence of degenerating keratinocytes (civatte lish the final diagnosis. This procedure is very important bodies), and presence of a band-like zone of inflam- because the different mucocutaneous autoimmune disor- matory infiltrate, mainly lymphocytes, confined to the ders can have very distinct outcomes. superficial part of the connective tissue. The absence of epithelial dysplasia is also considered an important LICHEN PLANUS feature to confirm the microscopic diagnosis of LP (Fig 26-11). Lichen planus (LP) is an immune-mediated mucocu- Reticular LP usually does not require drug-based treat- taneous condition that can affect the skin, nails, hair, ment once patients have no symptoms. In these situations, and mucous membranes. Oral lesions are common orientation and monitoring is sufficient. For erosive cases, and might represent the first or only manifestation of corticosteroids are frequently recommended to control the disease. Oral LP lesions may persist for years with symptoms such as pain. The choice of drug and route of periods of remission and exacerbation. It is common for administration will depend on the intensity of symptoms periods of exacerbation to be associated with episodes of and periodicity of the episodes. The potential for malig- emotional stress or low immunity. Based on the clinical nant transformation of LP is still controversial. 302  Autoimmune Diseases PEMPHIGUS VULGARIS Pemphigus vulgaris (PV) is an autoimmune muco- cutaneous disease characterized by the formation of intraepithelial blisters. Exclusive mucosal involvement is frequent, but the skin can also be affected concomi- tantly or exclusively. Mucosal lesions are characterized by flaccid blisters that break easily, resulting in erosions or painful ulcers distributed along the oral cavity. The Nikolsky sign is positive, which is stimulated by an oblique Fig 26-11 Microscopic features of oral LP. Note the inflamma- pressure to the mucosa and/or skin, resulting in new tory infiltrate composed mainly of lymphocytes in a band-like blisters or the easy desquamation of a superficial layer pattern and liquefaction degeneration of the epithelial basal of the epithelium. PV oral lesions are often the first sign cell layer. of the disease and are considered the most difficult to resolve with treatment. Exclusive gingival involvement (desquamative gingivitis) appears to be less frequent in PV compared to LP and mucous membrane pemphigoid (MMP). Direct immunofluorescence of perilesional tissue represents the most reliable and sensitive way to diagnose Oral lesions can be managed with topical corticosteroids. PV. The presence of immunoglobulin G (IgG) antibodies If there is no adequate response, systemic corticosteroids and occasionally components of the complement system or immunosuppressive agents may be used.11 (eg, component complement 3 or C3) are evident in the intercellular spaces between the epithelial cells, resulting SJÖGREN SYNDROME in a “honeycomb” or “chicken wire” pattern. Prolonged treatment associated with immunosuppression is usually Sjögren syndrome is a chronic systemic autoimmune necessary and should be performed by an experienced condition involving the salivary and lacrimal glands, immunosuppressive therapist.10 and it is frequently associated with a diffuse connective tissue disease (collagenosis). The lymphocytic infiltrate MUCOUS MEMBRANE PEMPHIGOID destroys the glandular parenchyma, causing ocular (CICATRICIAL PEMPHIGOID) dryness (xerophthalmia or keratoconjunctivitis sicca) and buccal dryness (xerostomia). The syndrome mainly MMP is characterized by a subepithelial blistering forma- affects women (male:female ratio of 1:9) between 40 and tion that predominantly involves the oral and ocular 60 years of age. Clinicians should be alert to clinical signs mucosae and infrequently the skin. Mucosal lesions start such as dry and shiny mucosa and foaming residual saliva, as vesicles or blisters that rupture, leaving an area of super- which might result in the mucosa becoming adhered to ficial ulceration. Ulcerated lesions are usually painful the mirror or presence of sedimented remains of food. and can persist for weeks or months if left untreated. In Other signs include depapillated tongue and swelling of general, this process is diffusely observed in the mouth, salivary glands. The low salivary flow might also result in but it may be limited to certain locations, especially the dental caries, worsening periodontal disease, candidiasis, gingiva (desquamative gingivitis). The most significant bacterial sialadenitis, or sialolithiasis. Regular monitoring complication of MMP, however, is ocular involvement. is important to prevent these complications. Treatment More severe cases can progress to eyelid and corneal should focus on the relief of symptoms through constant damage and sometimes blindness. The diagnosis should hydration, stimulation of saliva with sugar-free chew- be established through the association of clinical manifes- ing gum or drugs, and artificial saliva. Patients should tations and direct immunofluorescence, revealing linear avoid drugs that can worsen xerostomia and should avoid deposition of IgG, IgA, or C3 along the epithelial base- smoking and drinking alcoholic beverages. Also, patients ment membrane zone. Follow-up by an ophthalmologist should follow up with a rheumatologist once other auto- is imperative to prevent or treat ocular complications. immune connective tissue diseases present or develop. 303  26 | ORAL MEDICINE AND PATHOLOGY Fig 26-12 Physiologic pigmentation of the attached gingiva. Fig 26-13 Clinical features of amalgam tattoo. The patient had a history of endodontic retrofill procedures at the maxillary right central incisor. Pigmented Disorders most affected site (Fig 26-13). The presence of amalgam restorations or endodontic retrofill procedures near the pigmented area should be investigated if an amalgam PHYSIOLOGIC PIGMENTATION tattoo is suspected. In some cases, especially when the Physiologic pigmentation does not represent a true amalgam particles are sufficiently large, radiopaque gran- pathology; instead, it is a variation of normality related ules can be observed on intraoral radiography. In these to race. This condition is very common in patients with cases, the final diagnosis can be established based on clin- dark skin (ie, populations of African, Asian, or Mediter- ical and radiographic findings. If in doubt, a biopsy may ranean origin). The marginal gingiva is the most affected be performed, and microscopic evaluation will permit intraoral site, characterized by bilateral well-demarcated the identification of amalgam particles in the connective brown pigmentation with a band appearance that gener- tissue. ally spares the attached gingiva (Fig 26-12). No treatment is necessary. MELANOTIC MACULE AND NEVUS SMOKER’S MELANOSIS Melanotic macule and nevus represent two forms of localized pigmentation. From a clinical perspective, both Smoking causes pigmentation in light-skinned patients lesions are very similar, characterized by a brown macule, and accentuates brown pigmentation in dark-skinned usually small and well demarcated. The main differences patients. Smoker’s melanosis is observed in approximately between theses lesions are summarized in Table 26-3. 20% of smokers. The intensity of pigmentation is related For both conditions, the clinician may choose between to the duration and number of cigarettes consumed. The monitoring or surgical removal. If changes in size, color, lesions usually involve the anterior facial gingiva. The texture, surface, and/or borders are identified, a biopsy diagnosis is based on clinical features and history. No should be performed and the tissue examined microscop- treatment is necessary, and the pigmentation usually ically to exclude oral melanoma (Fig 26-14). disappears within 3 years of smoking cessation. MELANOMA AMALGAM TATTOO Oral mucosa melanoma is extremely rare, accounting for Implantation of dental amalgam in the oral mucosa less than 1% of all oral malignancies. The most common represents the main cause of exogenous pigmentation location is the palate followed by the gingiva. Clinically, and is known as amalgam tattoo. The gingiva is the early lesions are usually characterized as a brown to 304  Pigmented Disorders TABLE 26-3 Main features of melanotic macule and nevus Melanotic macule Nevus Nature Reactive Neoplastic (benign) Most affected site Lower lip Palate or gingiva Distinct clinical features Usually flat surface Surface can be elevated Microscopic features Increased melanin deposition in the basal and Unencapsulated yet well-demarcated prolifer- parabasal layers. Melanin also seen free or within ation of nevus cells that demonstrate variable melanophages in the connective tissue. capacity to produce melanin. Cells tend to be organized in small aggregates known as theques. Lesions are classified as junctional, compound, and intramucosal. Peculiarities Systemic and genetic conditions can cause Melanocytic nevus has other clinical-pathologic lesions clinically and microscopically similar to variants such as congenital nevus, halo nevus, the melanotic macule. spitz nevus, and blue nevus. Benign Malignant Asymmetry Symmetric Asymmetric Border Even Uneven Color Homogeneous Heterogeneous Fig 26-15 Advanced mucosal melanoma. Diameter Small Large Evolving Stable Changes Fig 26-14 ABCDE system used to differentiate benign and malignant pigmented lesions. black macula with irregular borders. Melanomas tend malignant characteristics is to follow the ABCDE system to exhibit an initial radial growth phase followed by a initially developed for skin cancer (see Fig 26-14). All oral vertical growth phase. Thus, advanced lesions usually macules that demonstrate at least some aggressive features evolve to exophytic nodular masses that may or may not should be submitted for microscopic examination. If the be ulcerated (Fig 26-15). When there is bone involvement, diagnosis of melanoma is confirmed, the patient should the radiographic pattern is described as “moth-eaten” be referred to a head and neck surgeon or oncologist for destruction. A useful method to identify if the lesion has treatment. 305  26 | ORAL MEDICINE AND PATHOLOGY TABLE 26-4 Examples of oral lesions characterized by white plaque or macule to be excluded for a diagnosis of leukoplakia Lesion Etiology Clinical features Frictional keratosis Reactive, caused by a chronic irritative agent White asymptomatic homogeneous macule or plaque. Commonly seen in the alveolar ridges. Morsicatio Reactive, caused by chronic habit of biting the White plaques of irregular surface, possibly but mucosa not necessarily associated with areas of erythema. Usually occurs in the occlusion line (buccal mucosa). Burn Reactive, caused by thermal or chemical injury White plaques or macules removable by scraping. Leukoedema Unknown cause (more common in dark-skinned Milky-white alteration affecting the buccal mucosa individuals) bilaterally that disappears when stretched. Nicotine stomatitis Reactive, caused by tobacco smoking (no poten- White to grayish palatal mucosa with slightly tially malignant nature) elevated reddish papules. Pseudomembranous Infectious, caused by the fungus C albicans “Milk curd” or “cottage cheese” appearance; can candidiasis be scraped off, leaving a red base. White sponge nevus Genetically determined skin disorder Bilateral and symmetric thick plaques, with corru- gated or velvety surface in the buccal mucosa (present since birth, childhood, or adolescence). Hairy leukoplakia Infectious, caused by Epstein-Barr virus (EBV) in Plaques with rough surface and vertical fissures in immunosuppressed patients (usually HIV) the lateral border of tongue. Lichen planus Autoimmune condition Bilateral presentation and Wickham striae are usually present. Potentially Malignant Disorders LEUKOPLAKIA Leukoplakia is a clinical term used to designate a predom- inantly white plaque or macule that cannot be character- ized clinically or pathologically as any other disease. The World Health Organization (WHO) currently defines leukoplakia as “a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.”12 Leukoplakia is the most common potentially malignant Fig 26-16 Leukoplakia in the attached gingiva. disorder. The main risk factors are tobacco and alcohol use. Clinically, lesions can be classified into homogeneous and nonhomogeneous based on color and texture. Nonho- mogeneous lesions tend to present more aggressive micro- scopic characteristics and clinical behavior. These lesions are also more common in the lateral border of the tongue and floor of the mouth, and less frequently at the gingiva. The diagnosis of leukoplakia depends on the exclusion of other entities that appear as white oral plaques (Table 26-4). If all other possibilities are excluded, the provisional clinical diagnosis of leukoplakia is established (Fig 26-16). 306  Neoplasms TABLE 26-5 Main clinical and microscopic features of benign and malignant neoplasms Benign neoplasms Malignant neoplasms Clinical features Growth rate Low High Type of growth Expansive Infiltrative Lesion borders Well defined Poorly defined Local and systemic effects Inexpressive Usually severe Recurrences Usually absent Might occur Metastasis Absent Might occur Capsule Usually present Usually absent Microscopic features Degree of cell differentiation Well differentiated Poorly differentiated Cellular and architectural atypia Rare Frequent Mitotic figures Rare Frequent Necrosis and degeneration Absent Present In these cases, an incisional biopsy is mandatory. The Presence of multiple lesions diagnosis of leukoplakia is confirmed when there are no Lesions located in the tongue or floor of the mouth microscopic characteristics of another known lesion. The Lesions larger than 2 cm at the largest diameter histopathologic diagnosis can vary from hyperkeratosis to Nonhomogeneous lesions epithelial dysplasia (characterized by cellular and archi- tectural atypia). The presence of dysplasia represents the LICHEN PLANUS most important risk factor for malignant transformation. Patients should be informed regarding the potentially The malignant transformation potential of oral LP remains malignant nature of the disease and the importance of highly controversial in the literature. Currently, the WHO cessation of tobacco and alcohol use. Periodic follow-ups recognizes LP as a potentially malignant disorder.12 A must also be completed. The treatment of the lesion can systematic review published in 2017 evaluated the rate of be surgical or nonsurgical and can only be performed malignant transformation in 57 studies accounting for a after a previous biopsy has established the final diagnosis. total of nearly 20,000 LP patients. The average malignant Surgical treatment is more common and includes the use transformation rate was 1.1%. There was a greater risk of laser, cryotherapy, and conventional surgery. Nonsurgi- of malignant transformation in smokers, alcoholics, and cal treatment comprises the use of pharmacologic agents patients with hepatitis C, demonstrating that cofactors (topical or systemic), also known as chemoprevention. may contribute to the risk of malignant transformation.14 Recurrence of the lesion is more commonly observed after nonsurgical approaches. The annual malignant transformation rate is approx- Neoplasms imately 2%.13 In addition to the presence of dysplasia, other known risk factors for malignant transformation Neoplasms can be classified as benign or malignant include the following: (Table 26-5). The final diagnosis of neoplasms can only be achieved after microscopic analysis. Thus, a biopsy is mandatory in these situations. This complementary 307  26 | ORAL MEDICINE AND PATHOLOGY Incisional biopsy Excisional biopsy Lesion Lesion a b Fig 26-17 Schematic illustration of incisional (a) and excisional (b) biopsies. TABLE 26-6 Indications for incisional and excisional biopsies Incisional biopsy (removal of part of the lesion) Excisional biopsy (removal of the entire lesion*) Type of lesion Multiple or poorly circumscribed lesions Solitary and well circumscribed lesions Size Extensive lesions Small lesions Nature of lesion Hypothesis of a malignant nature Hypothesis of a reactive† or benign nature *This examination aims to obtain a final diagnosis, but in many situations, the lesion is treated concomitantly by surgical removal. †For reactive lesions, it is essential to eliminate the irritative factor. examination is always indicated when the clinical features MALIGNANT NEOPLASMS are not sufficient to achieve a final diagnosis. In addition, cases in which the clinical course is not consistent with the Squamous cell carcinoma initial diagnosis should also be biopsied. This examination Nearly 95% of all oral malignant tumors are SCCs. The can be classified as incisional or excisional based on the main risk factors for oral SCC are smoking and alcohol. amount of lesional tissue removed (Fig 26-17 and Table Tobacco is a complete carcinogen and acts as a cancer 26-6). For incisional biopsies, the selection of the area is initiator and promoter. The synergistic effect of both also important and should involve healthy tissue at the habits, however, represents the most alarming risk factor. lesion margin, allowing the analyses of lesional tissues Genetic predisposition plays an important role, especially and its relation to adjacent normal tissues. Central areas in patients not exposed to the usual risk factors. The most of necrosis (in ulcerated cases) must be avoided. frequent locations are tongue (border) and floor of the mouth. The most commonly observed clinical presenta- tion is an ulcer with elevated and hard edges. The lesion BENIGN NEOPLASMS exhibits rapid growth (Fig 26-18) and in more advanced Benign neoplasms are very frequent in the oral mucosa. stages can cause pain, tooth mobility, difficulty swallow- Oral papilloma represents one of the main benign ing (dysphagia), and speech problems. Nodal metastasis neoplasms in this region. Oral fibroma is another frequent can be present at diagnosis and usually occurs in ipsilat- type of benign neoplasm; however, some lesions appear eral lymph nodes in the chin that drain the region of the to have a reactive etiology rather than a true neoplastic primary tumor (Table 26-8). origin. Oral fibroma and other common types of oral Microscopically, oral SCC is characterized by the invasion benign neoplasms are described in Table 26-7. of the epithelial lining into the underlying connective tissue 308  Neoplasms TABLE 26-7 Examples of benign neoplasms that can occur in the oral cavity Neoplasm Cell of origin Most common oral site Other notes Fibroma Fibroblasts Buccal and labial mucosa Might represent a reactive hyperplasic lesion in some cases. Lipoma Adipocytes Buccal mucosa and vestibule The most common benign neoplasm in the body. The lesion floats in liquids due to its fat content. Neurilemoma (schwannoma) Schwann cells Tongue In rare occasions, the tumor can arise centrally within bone (intraosseous). Neurofibroma Schwann cells and perineural Tongue and buccal mucosa Can arise as solitary tumors fibroblasts or be a component of neurofibromatosis. Hemangioma Vascular endothelial cells – Lesion of infancy charac- terized by a rapid growth phase followed by gradual involution. Lymphangioma Lymphatic endothelial cells Tongue Most likely represents a developmental malformation rather than neoplastic. –, not applicable. TABLE 26-8 Differences between reactive and metastatic lymph nodes Neoplastic/metastatic Reactive lymph nodes lymph nodes Pain Yes No Mobility Yes No Texture Smooth and fibroelas- Firm and rough texture tic texture Fig 26-18 Advanced case of oral squamous cell carcinoma at the floor of the mouth and gingiva, leading to mandibular bone destruction. (Fig 26-19). Neoplastic cells demonstrate atypia and loss of After diagnosis, patients should be referred to a head differentiation. Histologic subtypes of oral SCC recognized and neck surgeon for treatment. Surgical resection with by the WHO include basaloid, spindle cell, adenosquamous, safety margins remains the main treatment line for oral cuniculatum, verrucous, lymphoepithelial, papillary, and SCC. In a large number of patients, neck dissection and/ acantholytic. Carcinoma cuniculatum represents a well- or adjuvant radiotherapy are indicated. When chemo- differentiated type that usually occurs on the mucoperios- therapy is used, platinum-based regimens are the most teum. This variant is locally destructive and recurs with high commonly applied. Currently, according to the National frequency, but it rarely if ever metastasizes.12 Cancer Institute, there are seven drugs approved by the 309  26 | ORAL MEDICINE AND PATHOLOGY a b Fig 26-19 Microscopic features of oral SCC. (a) Malignant epithelial cells invading the connective tissue. (b) Epithelial pleomorphic malignant cells. Mitotic figures can also be observed. U.S. Food and Drug Administration (FDA) to treat head of the oropharynx (HR-OC), discriminating it and neck cancer: from oropharyngeal cancer with other causes. The AJCC along with the American College of 1. Bleomycin Pathology states that high-risk HPV testing is 2. Cetuximab recommended for all new oropharyngeal SCC 3. Docetaxel patients through p16 immunohistochemistry 4. Hydroxyurea (IHC). For oral cavity cancer, the most import- 5. Methotrexate ant modifications were in the tumor (T) and 6. Nivolumab lymph node (N) categories. The T category 7. Pembrolizumab now incorporates the depth of invasion (DOI), thereby discerning tumors that are small but The prognosis of oral SCC is considered poor, invasive. To determine the N pathologic cate- especially for patients diagnosed at late stages. The gory, it is now necessary to evaluate if there is 5-year overall survival is around 50%, and this rate extranodal extension (ENE) in metastatic lymph has not been increasing significantly over the years. nodes. These changes were made to signifi- cantly increase the power of the TNM staging TNM staging in predicting patients’ prognoses and therefore The American Joint Committee on Cancer have a major clinical relevance.15 (AJCC) cancer staging is based on the evalua- tion of three categories at the time of diagnosis: Osteosarcoma 1. Tumor (T): Analyzes the size and extent of An osteosarcoma is a malignant bone tumor characterized the primary tumor by the production of bone or osteoid by neoplastic cells. 2. Lymph node (N): Analyzes the degree Genetic predisposition, Paget disease, and previous irra- regional lymph nodes spread diation at the site have been pointed out as risk factors. In 3. Metastasis (M): Analyzes the presence of 90% of cases, the osteosarcoma is located in the metaphy- metastasis sis of the long bones. Osteosarcomas of the jawbones are In 2016, the AJCC released the 8th edition of the very rare. Radiographic aspects of osteosarcomas may Cancer Staging Manual, introducing substantial vary from a fully radiolucent image with irregular ill- modifications from the previous edition. The defined borders (Fig 26-20) to predominantly radiopaque most significant update was a separate staging areas, due to the to greater deposition of osteoid matrix system for high-risk HPV-associated cancer within the lesion. Some peculiar but nonpathognomonic 310  Neoplasms Fig 26-20 Clinical (a) and radiograph- ic (b) features of a mandibular osteo- sarcoma with gingival involvement. a b radiographic findings include a symmetric thickening of the periodontal space due to neoplastic infiltration and the presence of a periosteal reaction characterized by osteophytic bone production on the surface of the lesion, a pattern classically described as “sunburst” or “sunray,” which is more evident in occlusal radiographs. The clinical manifestation varies from a slight swelling to destruction of the cortical bones, dental mobility, mucosal ulceration, pain, and paresthesia. Osteosarcomas of the gnathic bones are usually treated through radical surgery followed by radiotherapy. Lymphomas Oral cavity lymphomas are quite rare. Approximately 2% of extranodal lymphomas arise in the oral cavity. These lesions most often involve the palate or gingiva and can invade subjacent bone. Diffuse large B-cell lymphoma is the most common type. Plasmablastic lymphoma Fig 26-21 Plasmablastic lymphoma arising in the gingiva. represents a rare non-Hodgkin lymphoma with plasma cell immunophenotype; however, this tumor has a predi- lection for extranodal sites, with the oral cavity as the most affected site (Fig 26-21). Epstein-Barr virus (EBV) ulcerations with a grayish-white necrotic base can also infection appears to play an important role in the patho- occur. Frequently, in the myelomonocytic types of leuke- genesis of this tumor, and most patients are HIV positive. mia, malignant cells infiltrate the oral mucosa tissues, resulting in diffuse gingival enlargement. In the gingiva, Leukemic gingival infiltration this event produces firm and reddish generalized gingi- Leukemias are malignant tumors of the body’s blood- val overgrowth that bleeds easily. Association with other forming tissues and are classified according to their clinical systemic symptoms might lead the differential diagnosis behavior (acute/chronic) and histogenesis (lymphocytic/ to a leukemic gingival infiltration. lymphoblastic). Systemic signs and symptoms include fatigue, easy tiring, dyspnea, fever, and easy bruising or Oral metastasis bleeding. These symptoms occur due to a striking decrease The oral cavity is an uncommon site for spread of meta- in normal white and red blood cells counts as well as static tumors. When it occurs, the most common malig- thrombocytopenia. Due to the compromised ability of nant tumor primary sites are the lung and prostate for patients to combat the normal microbial flora, gingival men and breast and genital organs for women. Clinicians 311  26 | ORAL MEDICINE AND PATHOLOGY The 2017 WHO classification of odontogenic lesions is presented in Box 26-3.12 ODONTOGENIC TUMORS Ameloblastic carcinoma This is the malignant counterpart of ameloblastoma and, though it is rare, is the most common type of malignant odontogenic tumor. The tumor can arise de novo or in preexisting ameloblastomas. The posterior part of the jaw is the most affected site, and lesions are characterized by poorly defined or irregularly marginated radiolucencies Fig 26-22 Oral metastasis of kidney cancer. The primary tumor that might cause cortical expansion or perforation and was discovered after the oral lesion was biopsied. infiltration into adjacent structures. The final diagnosis relies on the identification of a histologic pattern of amelo- blastoma associated with cytologic features of malignancy. Radical surgical excision is the primary treatment, and should be alert that, though it is rare, when this event the prognosis is reserved. occurs, the gingiva and jawbones are the most affected sites, particularly the mandible. The clinical presentation Ameloblastoma varies but is usually highly suggestive of an aggressive and Ameloblastomas are common and potentially aggressive destructive lesion. In the jawbones, the most common odontogenic tumors. Recurrent gene mutations associ- symptoms are rapidly progressing swelling, pain, and ated with the mitogen-activated protein kinase (MAPK) paresthesia. In the gingival region, early lesions can mimic signaling pathway have been identified in nearly 90% hyperplastic or reactive lesions and in more advanced of ameloblastomas, suggesting an important role of this cases present extensive tumor growths and/or ulcers (Fig pathway in the pathogenesis of the tumor. Mutations in 26-22). The overall survival rate of patients after diagnosis the BRAF gene have been found in approximately 60% of an oral metastasis is extremely poor; life expectancy is of cases, and RAS mutations have also been detected less around 7 months. frequently. Besides the MAPK pathway, mutations in the SMO gene from the hedgehog pathway have also been identified.12 Odontogenic Cysts and Tumors The tumor occurs in a wide age range with a peak of incidence in younger patients and does not show a predi- Odontogenic lesions are thought to originate from lection for sex or skin color. The posterior region of the remnants of odontogenesis, including the following: mandible is usually affected. Included teeth may or may not be associated with injury. Radiographically, a corti- Epithelial cell rests of Malassez: Remnants of the disin- cated multilocular so-called soap-bubble or honeycomb tegration of the Hertwig epithelial root sheath radiolucency represents the most common presentation Reduced enamel organ epithelium: Remnants of the (Fig 26-23). An incisional biopsy should be taken to estab- enamel organ collapse after complete formation of the lish the diagnosis prior to treatment. The microscopic crown of the tooth evaluation reveals sheets and islands of epithelial cells in Rests of Serres: Remnants of the dental lamina after a fibrous mature stroma. The peripheral cells resemble disintegration preameloblasts, while the cells at the central core resemble Ectomesenchymal remnants of dental papilla or dental the stellate reticulum (Fig 26-24). According to the micro- follicle scopic appearance, tumors can be classified as follicular, plexiform, acanthomatous, granular, and basaloid. This Odontogenic tumors may also originate from the classification has no impact on the patient’s prognosis. epithelial lining of odontogenic cysts, which have origins The treatment consists of wide surgical excision, in the same epithelial remnants previously mentioned.16 including an area of apparently normal bone beyond 312  Odontogenic Cysts and Tumors BOX 26-3 WHO classification of odontogenic and maxillofacial bone tumors12 Odontogenic carcinomas Benign mesenchymal odontogenic tumors Ameloblastic carcinoma Odontogenic fibroma Primary intraosseous carcinoma Odontogenic myxoma/myxofibroma Sclerosing odontogenic carcinoma Cementoblastoma Clear cell odontogenic carcinoma Cementoossifying fibroma Ghost cell odontogenic carcinoma Odontogenic cysts of inflammatory origin Odontogenic carcinosarcoma Radicular cyst Odontogenic sarcoma Inflammatory collateral cyst Benign epithelial odontogenic tumors Odontogenic and nonodontogenic developmental Ameloblastomas cysts – Ameloblastoma, unicystic type Dentigerous cyst – Ameloblastoma, extraosseous/peripheral type Odontogenic keratocyst – Metastasizing (malignant) ameloblastoma Lateral periodontal and botryoid odontogenic cyst Squamous odontogenic tumor Gingival cyst Calcifying epithelial odontogenic tumor Glandular odontogenic cyst Adenomatoid odontogenic tumor Calcifying odontogenic cyst Orthokeratinized odontogenic cyst Benign mixed epithelial and mesenchymal odonto- Nasopalatine cyst genic tumors Ameloblastic fibroma Primordial odontogenic tumor Odontomas – Odontoma, compound type – Odontoma, complex type Dentinogenic ghost cell tumor Fig 26-23 Radiographic aspect of ameloblastoma. Fig 26-24 Microscopic features of ameloblastoma. Observe odontogenic epithelial islands with peripheral columnar to cuboidal cells with hyperchromatic nuclei arranged in a pal- isading pattern with reverse polarity. The central cells are angular and loosely arranged. The stroma is composed of mature connective tissue. This example represents a follicular microscopic variant. radiographic margins. Recurrence rates increase signifi- Unicystic ameloblastoma cantly when conservative approaches are attempted. Unicystic ameloblastoma (UAM) represents a variant of Lifelong follow-up should be considered because late ameloblastoma that occurs as a single cystic cavity. There- recurrences might occur. fore, the radiographic image consists of a well-defined 313  26 | ORAL MEDICINE AND PATHOLOGY a b c Fig 26-25 Histopathologic variants of unicystic ameloblastoma: (a) luminal, (b) intraluminal, and (c) mural. a b c Fig 26-26 A complex odontoma occurring adjacent to the crown of the maxillary left first molar. (a) Radiograph. (b) CBCT scan. (c) CT scan. Odontoma Odontomas are the most common odontogenic tumors. It is believed that they represent tumor-like malformations (hamartomas) rather than a true neoplasia. They are clas- sified into compound and complex. Both are mainly diag- nosed in young patients. Compound odontomas occur mainly in the anterior maxilla, while complex odontomas are found more often in the posterior mandible. Radio- Fig 26-27 Microscopic features of a complex odontoma show- graphically, compound odontomas appear as numerous ing disorganized dental soft and hard tissues. tooth-like structures, and complex odontomas are char- acterized by a disorganized mass of radiopaque calcified tissue (Fig 26-26). Early-stage odontomas might demon- unilocular radiolucency, mimicking a cyst. A conclu- strate a well-defined radiolucent lesion with radiopaque sive diagnosis of UAM can be made only after careful foci. The treatment consists of conservative surgery, and examination of the entire specimen. Unlike conventional the prognosis is excellent. The histopathologic examina- ameloblastoma, the microscopic subtype of UAM has an tion reveals dental soft and hard tissues (pulp, dentin, impact on prognosis. Lesions are classified as luminal, cementum, and enamel matrix) that can be disorganized intraluminal, and mural (Fig 26-25). Mural involvement (complex odontoma; Fig 26-27) or form rudimentary denotes a more aggressive behavior (similar to conven- teeth (compound odontoma). Early-stage odontomas tional ameloblastoma). This variant requires either addi- show variable amounts of odontogenic epithelium and tional surgery or a closer follow-up. mesenchyme with little mineralized product. 314  Odontogenic Cysts and Tumors TABLE 26-9 Main features of other benign odontogenic tumors Tumor Radiographic image Most common site Other notes Adenomatoid odontogenic Well-defined unilocular Anterior maxilla Commonly associated with tumor radiolucent lesion. About impacted canines two-thirds present small foci of radiopacity. Calcifying epithelial Well-defined uni- or multi- Posterior mandible Also known as Pindborg odontogenic tumor locular radiolucent lesion. tumor Two-thirds are mixed radiolu- cent and radiopaque. Ameloblastic fibroma Well-defined uni- or multilocu- Posterior mandible Occurs in young patients lar radiolucent lesion. Odontogenic fibroma Well-defined uni- or multiloc- Maxilla and mandible Peripheral odontogenic ular radiolucent lesion with fibroma is more common than cortical margins. the central Other benign odontogenic tumors the etiologic factor, which can be attempted by conven- Table 26-9 summarizes the main features of other benign tional endodontic treatment. The apex region needs to be odontogenic tumors. reevaluated after a few months to ensure that bone repair is occurring. If the treatment is unsuccessful, endodon- tic retreatment can be performed. Periapical surgery is ODONTOGENIC AND NONODONTOGENIC usually indicated when the two attempts failed or for CYSTS larger lesions. The tissue removed from the periapical Periapical cyst and other apical inflammatory site must be submitted for histopathologic examina- lesions tion. Other cysts and neoplasms can simulate an apical Apical inflammatory lesions occur as a consequence of lesion, which could also justify the failure of previous bacteria or their toxic products in the root canal of a treatments. Histologically, apical granuloma is charac- nonvital tooth. Acute lesions, such as acute apical peri- terized by chronic inflammatory infiltrate surrounded odontitis and dentoalveolar abscess, are usually symp- by a fibrous connective tissue. Radicular cysts are lined tomatic and associated with sensitivity to percussion, by nonkeratinized stratified squamous epithelium with extrusion of the tooth, and tissue swelling. Radiograph- a variable degree of inflammation in the capsule. ically, a thickening of the apical periodontal ligament or an ill-defined radiolucency might be observed. Oral fistula Chronic lesions such as apical granuloma and radicular An oral fistula is a suppurative channel that cyst represent the most prevalent lesions associated with allows for draining of accumulated suppuration pulp necrosis. Both lesions are usually asymptomatic, to the exterior. The presence of oral fistula indi- and the majority are discovered on routine radiographic cates an active inflammatory process; however, examinations, which demonstrates a radiolucency of pain is usually absent (as long as the fistula is variable size at the apex. An overlap of clinical and open). It is important to establish the origin of radiographic features can occur between these lesions; the fistula, which can be performed by introduc- however, a radicular cyst can reach large dimensions and ing a radiopaque and malleable instrument (eg, cause cortical expansion or even rupture (Fig 26-28). gutta-percha) in the fistula channel through its Tooth mobility and root resorption can also occur. The orifice followed by a radiographic examination. treatment of both conditions consists of eliminating 315  26 | ORAL MEDICINE AND PATHOLOGY a b Fig 26-28 Clinical (a), CBCT (b), and radiographic (c) images of a periapi- cal cyst. The maxillary right lateral incisor demonstrated loss of vitality. The lesion growth led to vestibular and palatal cortical rupture. c Gingival cyst of adult and periodontal lateral cyst Gingival cyst of the adult (GCA) and lateral periodontal cyst (LPC) are very rare developmental cysts thought to arise from rests of the dental lamina. The microscopic appearance of both cysts is similar, with the location as the most important piece of information to distinguish these lesions. The GCA arises in soft tissues, while an LPC is an intraosseous lesion (Fig 26-29). This difference GCA results in important clinical and radiographic divergences LPC described in Table 26-10. Enucleation is curative for both lesions, with a low recurrence rate. The botryoid variant of LPC has a greater risk of recurrence. a b Dentigerous and eruption cysts Fig 26-29 Differences in location between (a) GCA, which Dentigerous cyst is associated with the crown of an occurs in the soft tissue, and (b) LPC, which is an intraosseous impacted or partially erupted tooth. The radiographic lesion. aspect is a unicystic well-demarcated radiolucency connected at the cervical portion of the tooth in the cementoenamel junction; however, the 3D relationship with the tooth can vary, leading to different aspects (Figs 26-30 and 26-31). It is important to note that radiographic appearance is not unique; ameloblastoma, odontogenic 316  Odontogenic Cysts and Tumors TABLE 26-10 Differences and similarities between GCA and LPC GCA LPC Location Soft tissue Intraosseous Clinical features Well-defined nodule at the attached gingiva with No clinical features a smooth surface and bluish color Radiographic No radiographic image Well-demarcated unilocular radiolucency seen appearance between the roots of vital teeth Description Cystic space covered by thin nonkeratinized squamous or cuboidal luminal epithelium. Areas with focal plaque-like/nodular thickenings and epithelial cells with clear cytoplasm (glycogen rich) might be seen. Fig 26-30 Different positions of dentigerous cysts: (a) central, (b) lateral, and (c) circumferen- tial. Note that despite the posi- tion, the cyst always begins in the cementoenamel junction. a b c keratocyst, and other lesions can mimic dentigerous cysts. Treatment consists of the extraction of the involved tooth with curettage and enucleation of the cyst. The recurrence rate is very low. The specimen should be evaluated micro- scopically to confirm the diagnosis. The final diagnosis is established based on the correlation of clinical, radio- graphic, and microscopic features. An eruption cyst is an extraosseous variant of a dentig- erous cyst. It is found in the soft tissues overlying an erupt- ing tooth and therefore has no radiographic image and Fig 26-31 Dentigerous cyst in a circumferential configuration causes gingival swelling. Permanent molars and maxillary arising from an impacted canine in an adult patient. incisors are the most affected teeth. If the cyst does not rupture spontaneously, a simple excision of the roof of the cyst allows the affected tooth to erupt normally. 317  26 | ORAL MEDICINE AND PATHOLOGY Fig 26-32 Radiographic view of odontogenic keratocyst. Fig 26-33 Microscopic features of odontogenic keratocyst. Observe a cystic cavity lined with parakeratinized epithelium with fewer layers and columnar basal cells with palisade ar- rangement. Note the corrugated surface and the flat interface between the epithelial and the connective tissues. ramus. The cyst has a tendency toward an anteroposte- rior growth pattern without causing cortical expansion. Radiographically, a uni- or multilocular radiolucent area with well-defined borders is observed (Fig 26-32). Histologic analysis reveals a rather irregular cystic cavity lined by a parakeratinized epithelium with fewer layers and columnar or cubic hyperchromatic basal cells with palisade arrangement. The parakeratinized surface Fig 26-34 Well-defined radiolucent area with a rounded shape located in the midline region of the anterior maxilla. Note that is corrugated, and the interface between the epithelial the maxillary incisors had received endodontic treatment, prob- tissue and the connective tissue is flat (Fig 26-33). The ably due to a misdiagnosis of inflammatory cyst. The vitality test epithelial lining is quite friable, so areas of detachment is important to determine the differential diagnosis. from the fibrous capsule might occur. With regard to the treatment, simple enucleation may increase the chances of relapse, so a peripheral ostectomy or the use of cryotherapy in the surgical bed is recom- Odontogenic keratocyst mended. The likely causes of the high rates of recurrence The odontogenic keratocyst deserves a special consider- are the friable capsule that breaks easily during surgery ation among all developmental odontogenic cyst due to and the presence of satellite cysts in the capsule. unique features, such as the following: