Oral lesions

INTRODUCTION — Diagnosing and treating mucosal lesions of the mouth and gums may be challenging for many clinicians because of the wide variety of conditions that can present with similar-appearing lesions. Moreover, most clinicians, other than dental professionals, receive inadequate training in the evaluation and management of oral diseases [1]. As an example, in a study including hospital-based internists, over 80 percent of those surveyed felt that it was important to examine older patients' mouths, although less than 20 percent routinely performed such examinations [2]. Further, the majority were not confident in their examination skills.

This review will discuss the presentation and diagnosis of many types of oral lesions, including benign and malignant neoplasms, potentially malignant disorders, infections, ulcerations, hyperpigmentation, as well as normal variants that are important to recognize and identify. Detailed discussion of specific conditions, including oral leukoplakia, cheilitis, oral toxicities associated with chemotherapy, gingivitis, periodontal disease, odontogenic infections, halitosis, and burning mouth syndrome, are discussed separately. Oral cancers are also discussed separately.

●(See "Oral leukoplakia".)

●(See "Cheilitis".)

●(See "Actinic cheilitis".)

●(See "Oral toxicity associated with systemic anticancer therapy".)

●(See "Overview of gingivitis and periodontitis in adults".)

●(See "Gingivitis and periodontitis in children and adolescents".)

●(See "Soft tissue lesions of the oral cavity in children".)

●(See "Epidemiology, pathogenesis, and clinical manifestations of odontogenic infections".)

●(See "Bad breath".)

●(See "Overview of craniofacial pain", section on 'Burning mouth syndrome'.)

●(See "Epidemiology and risk factors for head and neck cancer".)

●(See "Overview of the diagnosis and staging of head and neck cancer".)

●(See "Chemoprevention and screening in oral dysplasia and squamous cell head and neck cancer".)

●(See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

ORAL ANATOMY — The mouth is a complex anatomical space demarcated by specific structures (figure 1A-B) and is comprised of two distinct areas, the vestibule and the oral cavity:

●Vestibule – The vestibule is delineated by the inner aspect of the lips anteriorly, the inner cheek (buccal mucosa) laterally, and the labial and buccal aspects of the teeth and the gingivae of the alveolar processes medially (figure 1C).

●Oral cavity – The oral cavity is demarcated by the inner (oral) gingivae of the maxillary and mandibular alveolar processes anteriorly, the roof (the hard and soft palates) superiorly, and the floor of the mouth and the anterior two-thirds of the tongue inferiorly. The posterior boundary of the oral cavity is defined by the palatoglossal arch.

The majority of the oral mucosa is a stratified, squamous, nonkeratinized mucosa and lines the inner lips, cheeks, much of the soft palate, floor of the mouth, ventral surface of the tongue, and the mucosa of the alveolar processes. Keratinized mucosa lines the remainder of the gingivae, the hard palate, and a portion of the soft palate. Specialized mucosa covers the dorsal and lateral aspects of the tongue.

INITIAL EVALUATION FOR ALL PATIENTS WITH ORAL LESIONS — Although the United States Preventive Screening Task Force (USPSTF) determined that there is insufficient evidence to assess the balance of benefits and harms of screening for oral cancer in adults [3], opportunistic screening (ie, that received by many patients from their primary care or dental providers during regular visits and treatments) may be a feasible and cost-effective option [4,5]. In addition to an oral lesion discovered incidentally on such an examination, patients may present for evaluation of a lesion that they notice themselves.

Although the clinician's examination of the oral lesion is critical in establishing the diagnosis, the historical and descriptive characteristics of the lesion provided by the patient (eg, location, duration, enlargement, associated pain) enhance the clinician's diagnostic accuracy. In addition, while oral lesions may arise independently of an association with another medical condition, they can also occur as a focal manifestation of a systemic condition. Further, the location of the lesion may give critical information as to the diagnosis (eg, some oral lesions only occur on the tongue due to the specialized mucosa not seen elsewhere within the mouth). (See 'Tongue lesions' below.)

To establish an accurate differential diagnosis, we perform a focused clinical history and physical examination on all patients with oral lesions [6-8]:

●Clinical history – For all patients with an oral lesion, we perform a focused clinical history, with attention to:

•Location of the lesion (eg, involvement of tongue only, all oral mucous membranes involved).

•Color and quality of the lesion (eg, hyperpigmented, erythematous, white, bullous, erosive/ulcerated, macular versus papular).

•Duration of time the lesion has been present (if noticed).

•Change in the lesion (eg, change in color, enlargement, waxing and waning of lesion size, periodic recurrence with resolution in-between episodes).

•Associated local symptoms (eg, bleeding, discharge, irritation, discomfort or pain, enlargement of local lymph nodes).

•Systemic signs and symptoms (eg, fever, rash, arthralgias or arthritis, unintentional weight loss).

•Medications, including any recent medication changes and the use of any intraoral (topical) preparations.

•Tobacco use (including smoking and smokeless tobacco products), enquiring about current use and tobacco history. We also enquire about cannabis smoking.

•In addition, we enquire about chewing betel quid, or "paan" (a combination of areca nut, spices, and tobacco that is popular in many parts of Asia).

•Alcohol consumption, including current use and history of alcohol use.

•Medical history, including any known autoimmune disease, malignancy (including history of previous hematopoietic cell transplant), immunosuppression (eg, infection with human immunodeficiency virus [HIV], active cancer treatment, immunosuppressive medication).

•Dental work, including the use of dental appliances (eg, dentures) and the presence of amalgam fillings ("silver" fillings that contain elemental mercury).

●Physical examination – In addition to the clinical history, we perform a careful intraoral and extraoral examination:

•Intraoral examination – We perform both a tactile and visual inspection of the oral cavity using gloved hands under adequate illumination.

Before the examination, we ask patients to remove dental appliances (eg, dentures), although examination with the appliance in place can also provide useful information, particularly when a traumatic lesion is suspected.

The oral lesion is carefully inspected with attention to the location, color, size, and quality (eg, pigmented, ulcerated) and palpated for texture (eg, soft versus indurated) and tenderness.

We then systematically examine all oral structures in a consistent sequence. We use both hands, utilizing gauze to grasp the tongue during the examination in order to adequately visualize the entire oral cavity and vestibule (picture 1).

•Extraoral examination – For all patients with oral lesions, in addition to a thorough intraoral examination, we perform a focused examination of the perioral area, including:

-Visual inspection of the lips and skin of the face and neck

-Observation for any asymmetry, swelling, or masses of the face or neck

-Palpation of head and neck lymph nodes, with particular attention to the anterior and posterior cervical, pre- and postauricular, submandibular, submental, parotid, and buccal lymph nodes

NORMAL VARIANTS OF ORAL MUCOSA — It is important to recognize that several apparent mucosal "abnormalities," such as leukoedema, Fordyce spots, and physiologic pigmentation, are actually normal variants and require no further evaluation or treatment.

Leukoedema — Leukoedema is a benign mucosal change [9], which presents as an asymptomatic, bilateral, grayish-white, semitransparent mucosal alteration that typically disappears if the mucosa is stretched (picture 2). Leukoedema is thought to be caused by accumulation of fluid within epithelial cells of the buccal mucosa.

Leukoedema is a common condition. In a cross-sectional study in the United States, the prevalence of leukoedema was variable (between 1 and 90 percent); it is also more prevalent among African-American individuals [10,11].

Fordyce granules — Fordyce granules or Fordyce spots represent ectopic sebaceous glands. They appear as white to yellow, 1 to 2 mm, discrete papules, symmetrically distributed on the buccal mucosa and vermilion border of the lips (picture 3A-C). They are extremely common, found in up to 90 percent of the adult population [9].

Physiologic oral pigmentation — Physiologic oral pigmentation is commonly seen in individuals with darker skin types and results from increased melanocyte activity and melanin production [12-14]. The pigmentation presents as a brown-gray band on the attached gingiva and is typically bilateral (picture 4). Pigmented patches can also be seen on the hard palate, mouth floor, or buccal mucosa.

WHITE AND RED ORAL LESIONS — White or red oral lesions include benign lesions (eg, morsicatio buccarum and frictional keratosis, white sponge nevus [WSN]), potentially malignant disorders (eg, erythroplakia, leukoplakia, oral lichen planus and other lichenoid lesions, submucous fibrosis, actinic cheilitis, chronic graft-versus-host disease [GVHD], oral lupus erythematosus [OLE]), malignant lesions (eg, squamous cell carcinoma [SCC]), and infections (eg, candidiasis, oral hairy leukoplakia).

Morsicatio buccarum and frictional keratosis — Morsicatio buccarum or morsicatio mucosae oris is a common lesion due to habitual cheek biting or tongue biting that presents as a macerated, white, thickened plaque with whitish fragments of epithelium that can be partially removed. These lesions are typically located in the proximity of the occlusal surfaces of the dentition (picture 5A-B) [9,15].

Frictional keratosis is a white lesion that cannot be removed and typically develops on areas subject to chronic trauma, such as the retromolar pads and the edentulous alveolar ridge underneath ill-fitting dentures (benign alveolar ridge keratosis [BARK]) (picture 6A-B) [16,17].

Although frictional keratosis may mimic leukoplakia in appearance, it has no malignant potential. Biopsy is unnecessary if the appearance and clinical history are consistent with the diagnosis. If biopsied, mucosal acanthosis and hyperparakeratosis without dysplasia will be seen on histopathologic examination [15]. Avoidance of recurrent mucosal trauma is required for resolution of the oral lesion and to prevent recurrence.

Oral candidiasis — Oral candidiasis is a common, opportunistic infection caused by intraoral, commensal yeasts and presents in three main forms [18]:

●Pseudomembranous candidiasis (thrush) – Pseudomembranous candidiasis is the most common form of oral candidiasis (picture 7A-D). It presents with confluent, white patches or plaques that are, in most cases, asymptomatic. Typically, these lesions can be wiped off with a gauze, exposing an erythematous base.

●Hyperplastic candidiasis – Hyperplastic candidiasis is a relatively uncommon form of oral candidiasis (picture 10C). It presents with elevated, white plaques most often located at the labial commissure or on the dorsal aspect of the tongue. In contrast with pseudomembranous oral candidiasis, these hyperplastic lesions cannot be wiped off.

●Erythematous oral candidiasis – Erythematous oral candidiasis includes denture stomatitis, chronic atrophic candidiasis, median rhomboid glossitis, angular cheilitis, and linear gingival erythema:

•Denture stomatitis is typically found in patients using removable prostheses (eg, dentures) and is typically limited to the mucosa beneath a full or partial denture (picture 8).

•Chronic atrophic candidiasis presents with red patches localized mainly to the palate and dorsum of the tongue. The acute form is most often associated with use of antibiotics or inhaled corticosteroids and with HIV infection.

•Median rhomboid glossitis presents as a red, depapillated, somewhat rhomboidal midline lesion on the dorsum of the tongue (picture 9A-B). (See 'Median rhomboid glossitis' below.)

•Angular cheilitis presents as inflammation of the skin and contiguous labial mucosa located at the lateral commissures of the mouth (picture 10E). (See 'Cheilitis' below and "Cheilitis", section on 'Angular cheilitis'.)

•Linear gingival erythema presents as a brightly inflamed and well-defined band of marginal gingiva (picture 10A-B). (See "Overview of gingivitis and periodontitis in adults", section on 'Non-plaque-associated gingivitis and gingival disease' and "Soft tissue lesions of the oral cavity in children", section on 'HIV gingivitis'.)

Oral candidiasis is most commonly seen in infants, older adults who wear dentures, patients treated with antibiotics, and patients with immunodeficiency, such as those treated with chemotherapy or radiation therapy and those with HIV infection [18,19]. Patients with hyposalivation (eg, reduced salivary flow) and those using inhaled glucocorticoids are also at increased risk for Candida infection. (See "Oropharyngeal candidiasis in adults", section on 'Risk factors'.)

The diagnosis of oral candidiasis is generally clinical, based upon the medical history and physical examination, but can be confirmed if necessary by Gram stain, potassium hydroxide preparation, or fungal culture (see "Oropharyngeal candidiasis in adults", section on 'Diagnosis'). Recurrent, recalcitrant, or extensive disease warrants immune status evaluation, including testing for HIV infection.

Topical therapy is usually effective, although relapses in immunosuppressed patients are common. Patients with dentures should be reminded to clean and disinfect their dentures carefully and frequently to reduce the likelihood of developing candidiasis [20].

Treatment for oral candidiasis is reviewed in detail elsewhere. (See "Oropharyngeal candidiasis in adults", section on 'Treatment'.)

Oral hairy leukoplakia — Oral hairy leukoplakia lesions are white, corrugated, painless plaques that, unlike Candida, cannot be scraped from the surface to which they adhere (picture 11). They generally affect the lateral portions of the tongue, although the floor of the mouth, the palate, or the buccal mucosa may also be involved. Oral hairy leukoplakia is an Epstein-Barr virus-induced lesion that occurs almost entirely in patients infected with HIV, although it has also been reported in immunocompetent patients [21]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Oral hairy leukoplakia'.)

Oral squamous cell carcinoma — Oral squamous cell carcinoma (SCC) represents the vast majority of cancers of the oral cavity.

Although some tumors may arise in apparently normal mucosa, in most cases, oral SCC occurs in areas of abnormal mucosa, such as leukoplakia, erythroplakia, or lichen planus. (See 'Oral potentially malignant disorders' below.)

Oral SCC may present as an ulcer, often with indurated margins, or as a mass that does not heal. Symptoms are variable, depending upon lesion location and extension (picture 12A-C). The tongue, particularly the lateral and ventrolateral aspects, is the most common location, followed by the mouth floor and the buccal mucosa [22].

For an oral lesion of ≥3 weeks duration, the acronym RULE has been proposed as a practical clinical prediction rule for early detection of oral SCC [23]:

●Red or red and white lesion

●Ulcer

●Lump

●Especially when in combination or if indurated (firm on palpation)

Any lesions meeting these criteria should be regarded with suspicion and biopsied.

Oral SCC is particularly common in some regions of the world, such as Southeast Asia, and affects males more frequently than females, with a ratio of approximately 2:1 [24-27].

The main modifiable risk factors for oral SCC are:

●Tobacco use (smoked and smokeless)

●Areca nut use

●Alcohol consumption

The combined effect of alcohol and tobacco is greater than multiplicative for oral cavity cancer [28,29]. However, oral cancer has been increasingly observed among subjects without any of the known modifiable risk factors [30].

Although most oropharyngeal SCCs, particularly SCC arising at the tongue base and palatine tonsils, are associated with human papillomavirus (HPV) infection, specifically HPV-16, oral SCC is associated with HPV-16 in less than 10 percent of cases [31-33]. (See "Epidemiology and risk factors for head and neck cancer" and "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

The diagnosis, staging, and management of oral SCC are reviewed separately. (See "Epidemiology and risk factors for head and neck cancer" and "Pathology of head and neck neoplasms", section on 'Squamous cell carcinoma' and "Overview of the diagnosis and staging of head and neck cancer", section on 'Diagnosis and staging evaluation' and "Treatment of stage I and II (early) head and neck cancer: The oral cavity".)

Oral potentially malignant disorders — According to the nomenclature and classification proposed by the World Health Organization Collaborating Centre for Oral Cancer and Precancer working group, oral potentially malignant disorders (OPMDs), previously called oral precancerous or premalignant disorders, include [6,34-36]:

●Leukoplakia

●Proliferative verrucous leukoplakia (PVL)

●Erythroplakia

●Oral lichen planus and other lichenoid lesions

●Oral submucous fibrosis

●Actinic cheilitis

●Oral chronic GVHD

●OLE

●Dyskeratosis congenita

●Palatal lesions in reverse smokers

The overall worldwide prevalence of OPMD has been estimated around 4.5 percent and is highest in South Asian, South American, and Caribbean populations, with males more frequently affected than females [37].

Leukoplakia — Oral leukoplakia is a relatively common OPMD that presents as white patches of the oral mucosa (picture 13A-F) [36]. Although leukoplakia is in itself a benign and asymptomatic condition, some patients will eventually develop SCC. In a meta-analysis including 92 studies and nearly 18,000 patients with oral leukoplakia, the estimated annual malignant transformation rate for leukoplakia was 1.56 percent [38].

Leukoplakia should be differentiated from other white oral lesions that do not carry an increased risk of cancer (algorithm 1).

The evaluation and management of oral leukoplakia is discussed in greater detail elsewhere. (See "Oral leukoplakia".)

Proliferative verrucous leukoplakia — Proliferative verrucous leukoplakia (PVL) is a rare, aggressive form of nonhomogeneous oral leukoplakia characterized by verrucous appearance, multifocality, slow growth, and a rate of malignant transformation of over 70 percent (picture 14) [39-41].

Oral PVL is discussed separately. (See "Oral leukoplakia", section on 'Proliferative verrucous leukoplakia'.)

Erythroplakia — Erythroplakia is an uncommon oral lesion that appears as a fiery red, sharply demarcated patch most commonly located on the floor of the mouth, the ventral tongue, or soft palate (picture 15) [36,42]. It is generally found in older patients who consume tobacco and alcohol and carries a high risk of malignant transformation [43]. In a meta-analysis including 92 studies and nearly 350 patients with oral erythroplakia, the estimated annual rate of malignant transformation for erythroplakia was 2.7 percent [38].

On histopathologic examination, erythroplakia frequently shows dysplasia (of variable grade) and carcinoma in situ. Less frequently, it may show features of invasive SCC.

Surgical excision with clear margins is a common treatment for oral erythroplakia. In one study of 84 patients with erythroplakia treated with carbon dioxide (CO₂) laser excision, the recurrence rate was approximately 17 percent [44]. In this study, the lesion size was the main predictor of recurrence, with lesions greater than 80 mm² having a fivefold increased risk of recurrence compared with smaller lesions. Unfortunately, there are no data available to assess the effectiveness of surgical treatment in reducing oral cancer incidence in patients with erythroplakia. These patients are generally managed similarly to those with leukoplakia. (See "Oral leukoplakia", section on 'Management'.)

Oral submucous fibrosis — Oral submucous fibrosis (OSMF) is a chronic, progressive, premalignant condition characterized by submucosal fibrosis involving all of the oral submucosa [23,45]. OSMF occurs only among individuals who chew areca nuts (including betel quid, also known as "paan") and is seen with high frequency in some Southern Asian populations, especially in those from the Indian subcontinent [46].

Early symptoms of OSMF include burning sensation of the oral mucosa, ulceration, and pain. This is followed by atrophic changes, pallor, and induration of the mucosa, resulting in a mottled, marble-like appearance (picture 16) [47]. Fibrosis may extend posteriorly to involve the soft palate and uvula and may also involve the tongue (picture 17A-B). Patients with advanced disease present with restriction of the mouth opening and difficulty with chewing, speaking, and swallowing. Areas of leukoplakia and erythroplakia may also be visible.

The diagnosis of OSMF can usually be made based upon the classic clinical features and a history of betel quid chewing. The diagnosis can be confirmed by a mucosal biopsy that shows collagen hyalinization, blood vessel obliteration, and extensive fibrosis extending to the superficial muscle layer [45].

Discontinuing consumption of betel products is the mainstay of management, although there is no specific therapy for OSMF. Treatments that have been attempted include intralesional corticosteroids, collagenase, or hyaluronidase injections; surgery; or laser therapy. None have proven efficacy.

Oral lichen planus and lichenoid lesions — The presentation of oral lichen planus may vary from lace-like, white patches (Wickham striae (picture 18A-B)) on the buccal mucosa to erosions on the gingival margin (desquamative gingivitis), tongue, or buccal mucosa (picture 19A-F). (See 'Oral lichen planus' below.)

Oral lichen planus and other lichenoid lesions are also considered potentially malignant conditions, although the magnitude of the associated risk of oral SCC is unclear [48,49]. In a systematic review of 16 observational studies, the rate of transformation ranged from 0 to 3.5 percent [50]. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Oral lichen planus: Management and prognosis".)

Oral lupus erythematosus — Lesions of oral lupus erythematosus (OLE) include white plaques; silvery white, scarred lesions; and punched-out erosions or ulcers with surrounding erythema (picture 20) [51]. The oral mucosa is involved in up to 50 percent of patients with OLE and may occasionally be the only manifestation of the disease [45,48,52-54].

The diagnosis of OLE requires a biopsy and is based upon the histopathologic finding of hyperkeratosis; focal liquefaction of the basal layer; and presence of a dermal, band-like, lichenoid infiltrate [51,55]. Management of OLE is reviewed elsewhere. (See "Overview of cutaneous lupus erythematosus", section on 'Mucosal manifestations'.)

Oral chronic graft-versus-host disease — Oral chronic graft-versus-host disease (GVHD) is a complication of allogenic hematopoietic stem cell transplantation (HSCT). It may present with erythema, lichenoid lesions (hyperkeratotic, white lines and lacy-appearing lesions (picture 21A-B)), ulcerations, mucosal atrophy, and superficial mucoceles. Patients may also have salivary dysfunction, resulting in hyposalivation and xerostomia, and restricted mouth opening due to sclerosis of perioral tissues. The presence of lichenoid lesions is diagnostic of oral chronic GVHD [56]. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

In patients with chronic GVHD, the mouth is the second most commonly involved site after the skin [57,58]. Oral chronic GVHD is associated with an increased risk of oral cancer. In a Japanese nationwide study using data from the Transplant Registry Unified Management Program, of over 17,500 recipients of HSCT, the risk of oral SCC was nearly 16-fold higher than in the general population [59]. Continued clinical surveillance and biopsy of mucosal lesions are indicated for early diagnosis of oral SCC, especially in patients with long-standing disease.

Management of oral chronic GVHD and oral health following hematopoietic cell transplant is reviewed elsewhere. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Oral health' and "Treatment of chronic graft-versus-host disease", section on 'Localized/topical treatments'.)

Actinic cheilitis — Actinic cheilitis, also called solar cheilitis, is a chronic inflammation of the lips (typically affecting the lower lip) due to sun exposure. This is discussed separately. (See "Actinic cheilitis".)

White sponge nevus — White sponge nevus (WSN; also called white sponge nevus of Cannon) is a rare, autosomal dominant disorder that presents during childhood with asymptomatic, diffuse, bilateral, white plaques on the buccal mucosa and tongue (picture 22). Other mucosal surfaces (eg, nasal, vaginal, rectal) can also be involved.

WSN is a rare, autosomal dominant genodermatosis caused by mutations in the keratin 4 (KRT4) or keratin 13 (KRT13) genes [60,61]. Histology shows epithelial thickening, parakeratosis, and extensive vacuolization of the suprabasal keratinocytes [61]. There is no known treatment for WSN, although a beneficial effect of topical tetracycline has been reported in a few patients [62,63].

PIGMENTED LESIONS — Pigmented lesions of the oral mucosa include those that appear typically melanocytic (black or brown) and those that appear other colors (blue or gray). Although we categorize them separately, there is overlap between the groups. Some causes of melanocytic lesions (eg, some types of drug-induced pigmentation and some nevi) may also appear as blue or gray.

Melanocytic lesions

Oral melanotic macules — Melanotic macules or lentigines are the most common mucosal pigmented lesions. They appear as darkly pigmented macules on the lips and oral mucosa, especially at the keratinized sites, such as gingiva and palate (picture 23A-B). They are typically symmetric with sharp borders, occur in adulthood, and are more common in individuals with darker complexions [64]. They typically occur as a single lesion, although more than one can sometimes develop.

Classically, multiple melanotic macules are found in patients with Laugier-Hunziker syndrome or Peutz-Jeghers syndrome (picture 24). These and other disorders characterized by hyperpigmented lesions are reviewed in detail elsewhere. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management" and "Acquired hyperpigmentation disorders", section on 'Laugier-Hunziker syndrome'.)

Drug-induced pigmentation — Drug-induced pigmentation can affect any mucosal site but is more commonly seen on the palate, tongue, and gingivae. Agents most commonly causing oral pigmentation include chlorhexidine mouthwashes, quinacrine, chloroquine, hydroxychloroquine, quinidine, zidovudine, tetracycline, minocycline, clofazimine, chlorpromazine, oral contraceptives, cyclophosphamide, busulfan, bleomycin, and fluorouracil [65,66]. Mucosal hyperpigmentation occurs through different mechanisms, including deposition of the agent on oral mucosal surfaces, stimulation of melanin synthesis, drug or metabolite accumulation, and bacterial metabolism.

Smoker's melanosis — Smoker's melanosis is characterized by irregular, macular hyperpigmentation of the oral mucosa [67]. Lesions consist of brown patches that are most commonly located on the anterior mandibular gingivae in cigarette smokers and on the buccal mucosa in pipe smokers.

The melanosis may be due to the stimulating effect of nicotine on the melanocytes located in the basal layer of the oral mucosa. The intensity of pigmentation is related to the amount and duration of smoking. In those who engage in "reverse smoking" (smoking from the lit end of the cigarette), pigmentation changes are most common on the hard palate (smoker's palate) and are thought to be, in part, caused by repeated thermal injury [68].

Smoker's melanosis gradually disappears over months to years after smoking cessation.

Oral melanoacanthoma — Oral melanoacanthoma is a rare oral lesion that presents as a rapidly enlarging, asymptomatic, pigmented macule (picture 25). It predominantly occurs in individuals with highly pigmented skin and is thought to be a reactive response to local trauma or chronic irritation. On histopathologic examination, it is a benign, mixed lesion composed of keratinocytes and dendritic melanocytes [12,69]. Biopsy is required to exclude mucosal melanoma.

Melanocytic nevi — Oral melanocytic nevi are uncommon lesions that usually present as a solitary, brown or blue, well-circumscribed nodule or macule (picture 26) [69]. Biopsy is required since they can resemble mucosal melanoma.

Melanoma — Melanoma of the oral mucosa is a rare and highly aggressive, malignant neoplasm of the mouth. It most commonly occurs on the hard palate or maxillary alveolus, although any oral mucosa can be involved. (See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment", section on 'Mucosal melanoma of the head and neck'.)

Early mucosal melanoma may present as a pigmented macule or patch that may have some of the characteristics of cutaneous melanoma, such as asymmetry, irregular borders, variegate color, and rapid growth (picture 27). Rarely, oral melanomas can be amelanotic [70]. More advanced lesions can present as raised, nodular or polypoid masses and may be ulcerated or bleeding. Satellite lesions and areas of pre-existing melanosis may be observed around the lesion.

Early oral melanoma must be differentiated from other pigmented lesions of the oral mucosa, either melanocytic (eg, melanotic macule, melanocytic nevi, melanoacanthoma) or nonmelanocytic (eg, amalgam tattoos, drug-associated pigmentation). If there is any concern, a biopsy is needed to exclude the diagnosis of melanoma. (See 'Oral melanotic macules' above and 'Amalgam tattoos' below.)

Nonmelanocytic pigmentation

Amalgam tattoos — Amalgam tattoos are blue-black macules seen within the gingiva at the gingival margin or in the buccal mucosa adjacent to amalgam dental fillings (picture 28A-B). They are caused by the unintentional placement of "silver" dental amalgam in close proximity to or directly into the soft tissues. The most common site for amalgam tattoos is the mandibular arch [71]. Their appearance may mimic oral melanomas; histologic or radiologic visualization of the amalgam particles may be needed to confirm the diagnosis. Similar lesions can be caused by substances other than classic "silver" dental amalgam, such as endodontic materials or graphite.

EROSIVE, ULCERATIVE, AND BULLOUS LESIONS — Erosive, ulcerative, and bullous oral lesions are very common, with a broad differential diagnosis including infectious, autoimmune, and inflammatory processes. The lesions may appear different depending upon the time of evaluation of the lesion; thus, the clinical history is particularly important to elicit.

Aphthous ulcerations — Aphthous ulcerations (aphthae) are painful oral lesions that appear as localized, shallow, round to oval ulcers with a yellowish adherent central exudate (picture 29C). Recurrent aphthous stomatitis (also commonly called canker sores) is the most common cause of mouth ulcers. (See "Recurrent aphthous stomatitis".)

Aphthous ulcerations may occur in the absence of underlying systemic disease but may also be seen in patients with celiac disease, inflammatory bowel disease, Behçet syndrome, acute HIV infection, systemic lupus erythematosus (SLE), and neutropenia (of any etiology); individuals with micronutrient deficiencies; and in patients taking antimetabolites, such as methotrexate. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Mucocutaneous' and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Clinical manifestations and diagnosis of Behçet syndrome" and "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Oropharyngeal findings' and 'Oral lupus erythematosus' below and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations' and "Major side effects of low-dose methotrexate".)

Recurrent aphthous stomatitis — Recurrent aphthous stomatitis is the most common cause of mouth ulcers [72]. It occurs more commonly in adolescents and young adults and is characterized by the recurrent development of discrete, painful ulcers predominantly located on the nonmasticatory mucosal surfaces (picture 29A and picture 29B and picture 29C). Morphologically, ulcers can be minor (<1 cm in diameter), major (>1 cm), or herpetiform (clusters of minute ulcers 1 to 2 mm in diameter that sometimes coalesce into larger ulcers).

Patients with recurrent aphthous stomatitis typically experience several recurrences per year, involving one to several ulcers that last up to 14 days. Trauma to the oral mucosa, such as biting the inside of the cheek or undergoing a dental procedure, may be a precipitating factor for many patients.

The severe variant of recurrent aphthous stomatitis is characterized by the absence of ulcer-free periods and often associated with chronic pain, malnutrition, and weight loss [73].

The diagnosis, clinical presentation, and management of recurrent aphthous stomatitis are discussed in detail elsewhere. (See "Recurrent aphthous stomatitis".)

Oral and genital aphthous ulcerations

Behçet syndrome — Behçet syndrome (or Behçet disease) is an inflammatory, multisystemic disorder with vascular, articular, gastrointestinal, neurologic, urogenital, pulmonary, and cardiac involvement:

●Oral ulcers are the most common feature of Behçet syndrome, affecting up to 100 percent of patients. They are usually the first manifestation of the disease and present clinically and histologically similar to common aphthous ulcers. However, they tend to be more extensive and often multiple (picture 30). Healing of the oral ulcerations is typically spontaneous within one to three weeks; although with recurrent lesions, many patients will have ulcers present almost constantly.

●Genital lesions occur in approximately 75 percent of patients with Behçet syndrome. They are similar in appearance to the oral aphthae.

Recurrent oral ulcers (three times per year) are required for the diagnosis of Behçet syndrome, in addition to two other clinical findings (recurrent genital ulcers, eye lesions, skin lesions, or a positive pathergy test [24 to 48 hours after oblique insertion of a 20 to 25 gauge needle]) (table 1) [74].

Further review of the evaluation, diagnosis, and treatment of Behçet syndrome is reviewed in detail elsewhere. (See "Clinical manifestations and diagnosis of Behçet syndrome" and "Treatment of Behçet syndrome".)

Complex aphthosis — Complex aphthosis is the term used to describe the occurrence of recurrent, large oral ulcers in conjunction with genital lesions in the absence of other criteria for Behçet syndrome [75,76]. (See "Recurrent aphthous stomatitis", section on 'Clinical subtypes'.)

Other — Other syndromes associated with both oral and genital ulcers include:

●MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome, which represents an overlap syndrome of relapsing polychondritis and Behçet syndrome [77]. (See "Clinical manifestations of relapsing polychondritis".)

●PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis) syndrome is a rare entity of unknown etiology usually affecting children [78]. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

●Cyclic neutropenia is a rare, autosomal dominant disorder of bone marrow progenitor cells characterized by recurrent neutropenia, with a cycle period of approximately 21 days. Clinical features include fever, pharyngitis, gingivitis, oral ulcers, and periodontitis. (See "Cyclic neutropenia".)

●Oral and vulvar aphthae have also been associated with Yersinia enterocolitis infection, tuberculosis, and typhoid fever. (See "Yersiniosis: Infection due to Yersinia enterocolitica and Yersinia pseudotuberculosis" and "Pulmonary tuberculosis: Clinical manifestations and complications" and "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)

Infectious ulcerations and vesicles

Herpes simplex virus — Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) can infect any mucocutaneous tissue but most commonly involve the tissues of the oral cavity and perioral area. Herpetic gingivostomatitis is the most common clinical manifestation of primary herpes simplex infection in children and young adults (picture 31) [79]. Usually associated with nonspecific, systemic signs and symptoms (mild fever, malaise, local lymphadenopathy), it is characterized by painful, small ulcers that may coalesce to form larger lesions, affecting the lips and any other oral mucosal site, including the gingivae, palate, or tongue. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Primary infection'.)

Recurrent infection is common. Most patients (>85 percent) develop prodromal symptoms (eg, pain, burning, tingling) approximately 24 hours before the appearance of painful lesions at the lip borders or inside the mouth. Precipitating factors include exposure to sunlight, trauma (including dental treatments), menstruation, and emotional stress. Because the primary HSV infection may be asymptomatic, a recurrence may be the first manifestation of infection.

Recurrences are more frequent and severe in immunocompromised patients. Chronic mucocutaneous herpes simplex infection, characterized by multiple verrucous, erosive, or ulcerated lesions, can be seen in patients with HIV infection and, occasionally, in patients with other types of immunosuppression [80]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Recurrent infection' and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Immunocompromised hosts'.)

The diagnosis of herpetic infection is generally clinical. Available confirmatory investigations include HSV DNA detection by polymerase chain reaction (PCR), rapid direct immunofluorescence assays (DFAs), serologic tests showing immunoglobulin G (IgG)- and immunoglobulin M (IgM)-specific antibody responses [81], and presence of multinucleated giant cells on a Tzanck smear (these are also seen with varicella-zoster virus infection). (See "Office-based dermatologic diagnostic procedures", section on 'Tzanck smear' and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis'.)

The treatment of primary and recurrent HSV-1 infection is discussed in detail separately. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)

Varicella-zoster virus — In patients with primary varicella (chickenpox) infection, oral vesicles and erosions are commonly seen (picture 32A-B).

In patients with herpes zoster (shingles), grouped vesicles or erosions may be seen unilaterally in the affected dermatome, such as the hard palate (picture 32C), the buccal mucosa, tongue, or gingiva. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

Coxsackievirus — Coxsackievirus A causes hand, foot, and mouth disease, an infection that most commonly affects children. Oral lesions typically appear as small aphthae on the tongue and buccal mucosa, often sparing the lips and gingiva (in contrast to HSV). Lesions on the palms and soles appear as oval-shaped, pale papules with a rim of erythema (picture 33A-E). Fever, sore throat, and malaise often precede the onset of lesions. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

HIV infection — A variety of oral manifestations are associated with HIV infection, although successful management with contemporary antiretroviral therapies has significantly reduced their incidence [82-84].

Painful mucocutaneous ulcerations can be seen in the setting of acute HIV infection. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Oropharyngeal findings'.)

In addition, recurrent aphthous ulcers occur in 0.6 to 13.6 percent of patients with HIV infection, the majority of whom have CD4 cell counts below 100 cells per mm³ [85]. Healing of oral ulcers has been reported with antiretroviral therapy [86].

Syphilis — The classic lesion of primary oral syphilis (oral chancre) is a painless ulcer with indurated margins (picture 34D). In secondary syphilis, oral mucous patches (picture 34A-C) can be seen in association with the classic papulosquamous eruption involving the palms and soles and anal condylomata lata. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)

Other infections — Other infections that may also cause oral ulcerations include:

●Invasive fungal infections, such as oral cryptococcosis, histoplasmosis, mucormycosis (zygomycosis), aspergillosis, and penicilliosis, are uncommon and predominantly occur in immunosuppressed patients [87-91].

●Oral ulcerations have been reported secondary to infection with atypical Mycobacterium species, Helicobacter pylori, and Leishmania [92]. (See "Bacteriology and epidemiology of Helicobacter pylori infection" and "Cutaneous leishmaniasis: Clinical manifestations and diagnosis", section on 'Mucosal leishmaniasis'.)

Immune-mediated ulcerations and bullae

Oral lichen planus — The erosive clinical subtype of oral lichen planus is characterized by erosions or frank ulcers (picture 19C, 19E, 19G). Reticular and erythematous lesions are also usually present. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis".)

Oral lupus erythematosus — Up to 50 percent of patients with systemic lupus erythematosus (SLE) have mucous membrane involvement [52-54]. Oral disease can involve the lips or other oral mucosa and may manifest as white plaques, areas of erythema, or punched-out erosions or ulcers with surrounding erythema on the soft or hard palate or buccal mucosa (picture 35A-B). The oral ulcers are typically painless and may be the first sign of SLE. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Mucocutaneous involvement'.)

Mucous membrane pemphigoid — Mucous membrane pemphigoid (MMP) is an autoimmune bullous disease characterized by subepithelial blisters affecting any mucous membrane, although oral mucous membranes are most commonly involved. Desquamative gingivitis (desquamation, erythema, and erosion of gingiva) is a prominent feature (picture 36A-B), but erosive and ulcerative lesions can also be found on the palate (picture 36C) [93,94]. In some patients, there is cutaneous involvement as well. Typical patients are females in their sixties, although men can be affected as well.

The diagnosis is made on routine histopathology and direct immunofluorescence testing of perilesional mucosa, along with the appropriate clinical findings. Further discussion of the evaluation, diagnosis, and treatment of MMP can be found elsewhere. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of mucous membrane pemphigoid' and "Management of mucous membrane pemphigoid".)

Bullous pemphigoid — Bullous pemphigoid is another autoimmune blistering disorder. Cutaneous lesions (bullae or urticarial plaques) commonly occur in the flexural areas, groin, and axillae. Oral involvement, characterized by intact bullae or erosions, occurs in approximately one-third of cases but is rarely the presenting feature.

The diagnosis is made on routine histopathology and direct immunofluorescence testing of lesional and perilesional skin, respectively. Further discussion of the diagnosis and management of bullous pemphigoid can be found elsewhere. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of bullous pemphigoid' and "Management and prognosis of bullous pemphigoid".)

Pemphigus vulgaris — Pemphigus vulgaris is characterized by flaccid, intraepithelial bullae that typically begin in the oral cavity and then may progress to involve the skin, with a predilection for the scalp, face, chest, axillae, and groin (picture 37). The bullae rupture easily, so that the patient often presents with only painful erosions and ulcers but no intact bullae.

The pathogenesis, clinical manifestations, diagnosis, and treatment of pemphigus vulgaris are discussed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus" and "Initial management of pemphigus vulgaris and pemphigus foliaceus" and "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

Paraneoplastic pemphigus — Paraneoplastic pemphigus is a mucocutaneous blistering disorder most often associated with lymphoproliferative disorders [95,96]. Severe, erosive, painful mucositis is the hallmark clinical finding in paraneoplastic pemphigus. In its absence, the diagnosis should not be considered. The painful, erosive stomatitis can involve any oral mucosa but characteristically involves the tongue (picture 38A-C). While cutaneous and pulmonary manifestations can also be present, oral erosions are the initial disease manifestation in almost one-half of patients [97].

The clinical manifestations, diagnosis, and treatment of paraneoplastic pemphigus are discussed in detail separately. (See "Paraneoplastic pemphigus".)

Epidermolysis bullosa acquisita — Epidermolysis bullosa acquisita is a rare, autoimmune mucocutaneous bullous disease that presents with blisters localized predominantly at sites of trauma, which heal with scarring and milia. Erosions and blisters may involve any mucous membrane, including the mouth. Epidermolysis bullosa acquisita is discussed in detail elsewhere. (See "Epidermolysis bullosa acquisita".)

Erythema multiforme — Erythema multiforme is an immune-mediated condition characterized by the acute appearance of distinctive, cutaneous, target-like lesions often accompanied by erosions or bullae involving the oral, genital, and/or ocular mucous membranes. Oral involvement is common, occurring in over 70 percent of patients (picture 39A-B and picture 39C) [98]. In the majority of cases, erythema multiforme is associated with herpes simplex infection, but it also may be associated with other infections (eg, Mycoplasma pneumoniae) or drugs or may be idiopathic. The etiology, clinical presentation, evaluation, and management of erythema multiforme is reviewed in detail elsewhere. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis" and "Erythema multiforme: Management".)

Non-immune-mediated ulcerations and bullae

Inherited epidermolysis bullosa — Epidermolysis bullosa is a group of genetically and clinically heterogeneous, inherited skin fragility disorders with the common finding of epithelial fragility. The most commonly affected sites include areas of trauma and friction. Milder forms do not typically involve the mucosae, while more severe manifestations involve the oral, pharyngeal, and esophageal mucosa. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features".)

Drug-induced ulcerations

Stevens-Johnson syndrome/toxic epidermal necrolysis — Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe mucocutaneous reaction characterized by extensive necrosis and detachment of the epidermis that is most commonly caused by medications. In over 90 percent of patients with SJS/TEN, there is mucosal involvement, which can precede or follow the skin eruption. Lesions of the involved oral mucosa typically appear as painful, hemorrhagic erosions covered with a grayish-white membrane (picture 40A and picture 40B).

The clinical manifestations, diagnosis, and treatment of SJS/TEN are discussed in detail separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

mTOR inhibitor-associated stomatitis — Mammalian (mechanistic) target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a common adverse event, occurring in approximately 30 percent of patients taking everolimus and temsirolimus for the treatment of several types of cancer [99]. mIAS is characterized by discrete, superficial, oval, well-demarcated ulcers with a grayish-white pseudomembrane, usually ≤1 cm in greatest dimension, located on the oral mucosa and tongue. Painful oral ulcerations have also been reported in allogeneic hematopoietic stem cell transplantation recipients treated with sirolimus for the prevention of graft-versus-host disease [100-102]. (See "Oral toxicity associated with systemic anticancer therapy", section on 'Mucositis'.)

Checkpoint inhibitor-associated oral lesions — Oral mucositis, lichenoid lesions, erythema multiforme-like lesions, erosions, and ulcerations have been reported in patients receiving immune checkpoint inhibitor therapy [103,104]. (See "Oral health in cancer survivors".)

Nicorandil-induced ulceration — Nicorandil is a potassium channel activator used in the treatment of angina pectoris and is available only outside of the United States. Its use has been associated with the development of painful skin and mucosal ulcerations in 0.4 to 5 percent of patients [105-108]. The mechanism by which nicorandil induces ulcerations is unknown. Oral ulcers can occur weeks to months after starting treatment, the effect is not dose related, and lesions resolve within a few weeks after withdrawal of the drug [106,109,110].

TONGUE LESIONS

Normal tongue variants — Tongue appearance may vary, with many normal variants of tongue structure and mucosa commonly seen. The clinical history of any change in appearance or associated sensory changes (eg, pain, burning, loss of taste) is important to elicit.

Fissured tongue — Fissured tongue (also called lingua plicata or scrotal tongue) can be a normal tongue variant seen in adults, with deep grooves located on the midline or evenly distributed on the tongue surface (picture 41A-B). Fissured tongue may also be seen in patients with Down syndrome or Melkersson-Rosenthal syndrome (a rare syndrome characterized by the triad of fissured tongue, facial palsy, and granulomatous cheilitis) [111,112]. (See "Down syndrome: Clinical features and diagnosis", section on 'Skin disorders' and "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults", section on 'Melkersson-Rosenthal syndrome'.)

Patients with fissured tongue are generally asymptomatic, although if irritation from entrapped debris occurs, brushing the tongue or using an oral irrigator may be helpful. Fissured tongue may also be a predisposing factor for halitosis. (See "Bad breath".)

Black tongue — Hyperpigmentation of the tongue and oral mucosa is commonly seen in dark-skinned individuals.

Less common causes of tongue hyperpigmentation include drugs (eg, tetracyclines, linezolid, bismuth subsalicylate, tricyclic antidepressants, proton pump inhibitors, interferon), Addison disease (primary adrenal insufficiency (picture 42)), Laugier-Hunziker disease, or pellagra (niacin deficiency) [113-117]. (See "Clinical manifestations of adrenal insufficiency in adults", section on 'Hyperpigmentation' and "Micronutrient deficiencies associated with protein-energy malnutrition in children", section on 'Niacin' and "Acquired hyperpigmentation disorders", section on 'Laugier-Hunziker syndrome'.)

Pigmented fungiform papillae — Fungiform papillae are scattered on the dorsal tongue surface, predominantly on the anterior and lateral aspects, and are usually pink or red in color. Individuals with darker skin tones may have pigmented spots on the dorsal tongue due to melanin deposition on the tips of the fungiform papillae (picture 43) [118]. These spots usually appear during the second or third decade of life and are typically asymptomatic [119-121]. Histologic examination reveals submucosal melanophages within the fungiform papillae in the absence of inflammation.

Atrophic glossitis — Atrophic glossitis is a condition characterized by atrophy of the filiform papillae of the tongue, giving the tongue a smooth, glossy, and erythematous appearance (picture 44A-B). Causes of atrophic glossitis include [122-124]:

●Nutritional deficiencies (iron, vitamin B12, folate) (see "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Findings on examination' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency")

●Oral Candida infection (see 'Oral candidiasis' above)

●Protein-calorie malnutrition in older adults (see "Geriatric nutrition: Nutritional issues in older adults")

●Celiac disease (see "Diagnosis of celiac disease in adults")

●Lichen planus (see "Oral lichen planus: Pathogenesis, clinical features, and diagnosis")

Patients with atrophic glossitis often complain of a burning sensation and increased sensitivity when eating acidic or salty foods. Management is directed at treating the underlying condition.

Black hairy tongue — Black hairy tongue (lingua villosa nigra) is characterized by the elongated filiform papillae (due to a lack of adequate desquamation) and a yellowish to brown discoloration of the tongue surface (due to local and extrinsic factors) (picture 45). This benign condition is associated with smoking, antibiotic use, dehydration, Candida albicans infection, and poor oral hygiene. It is often seen in hospitalized patients who are on a gastrostomy tube (G-tube). The condition is generally asymptomatic. Therapy consists of brushing or scraping that area of the tongue with a soft-bristle toothbrush or a specific tool (tongue cleaner) two to three times per day [125,126].

Geographic tongue — Geographic tongue (benign migratory glossitis) is a recurrent inflammatory disorder of unknown etiology that affects the dorsum of the tongue and, less frequently, other oral mucosae (benign migratory stomatitis) [127]. On the tongue, local loss of filiform papillae leads to depapillated, red patches with circumferential, white, polycyclic borders that give the dorsal tongue the appearance of a map (picture 46A-B). Lesions can change location, pattern, and size very rapidly (migratory), and patients may have numerous exacerbations and remissions over time. Patients are usually asymptomatic, have only mild symptoms, or complain of oral discomfort, burning, and sensitivity to some foods.

The condition has been frequently described in atopic individuals and in association with psoriasis and reactive arthritis. (See "Reactive arthritis".)

The differential diagnosis includes oral candidiasis, lichen planus, systemic lupus erythematosus, herpes simplex virus, and drug reaction [127]. The diagnosis is typically based on the clinical presentation, and biopsy is not necessary. However, biopsy may be reassuring in unclear cases. The histology of involved areas is similar to pustular psoriasis.

No therapy is needed, although for patients with more bothersome symptoms, symptomatic therapy may be tried. Treatments with unproven benefit include systemic acetaminophen, antihistamines, or anxiolytics; anesthetic mouth rinses; and topical treatments, including tacrolimus and corticosteroids [128-130].

Median rhomboid glossitis — Median rhomboid glossitis, also called central papillary atrophy of the tongue, is an uncommon, benign condition presenting as a red, depapillated, somewhat rhomboidal midline lesion on the dorsum of the tongue (picture 9A-C). Some patients may have a "kissing" lesion on the hard palate. In the majority of cases, it is a manifestation of oral candidiasis, although idiopathic cases have also been reported [131,132]. Median rhomboid glossitis predominantly affects older adults. Treatment for asymptomatic lesions is not required, although if bothersome, treatment for oral candidiasis is appropriate. (See "Oropharyngeal candidiasis in adults", section on 'Treatment'.)

Granular cell tumor — A granular cell tumor is a benign neoplasm of neural origin composed of cells with granular cytoplasm. Most often, they present as solitary nodules affecting the dorsum of the tongue (picture 47) but may also occur in the skin, breasts, and gastrointestinal tract [133]. Histologically, granular cell tumors are characterized by sheets or cords of large, polygonal cells with small, round, central nuclei and an eosinophilic, coarse, granular cytoplasm (picture 48). Occasionally, larger, eosinophilic granules surrounded by a clear halo called pustulo-ovoid bodies of Milian can be seen. Treatment is surgical excision [134]. (See "Benign lesions of the esophagus", section on 'Granular cell tumors'.)

MISCELLANEOUS ORAL LESIONS

Cheilitis — Cheilitis is an acute or chronic inflammation of the lips characterized by dryness, scaling, erythema, and fissuring. Eczematous cheilitis (including irritant contact cheilitis (picture 49), allergic contact cheilitis, and atopic cheilitis) is the most common lip condition. Angular cheilitis, also known as perlèche, is another common inflammation affecting the skin and contiguous labial mucosa located at the lateral commissures of the mouth (picture 10E).

The clinical manifestations, diagnosis, and treatment of acute and chronic forms of cheilitis are reviewed in detail separately. (See "Cheilitis".)

Mucoceles — Mucoceles are extremely common, benign, cystic lesions found in the mouth, occurring most frequently in the lower lip mucosa of children or young adults (probably as a result of self-biting) [135]. They are rarely found in the upper lip [136]. They are variable in size, contain a gelatinous fluid, and typically appear as pink/blue, soft papules or nodules (picture 50A-B and picture 51). The variant that occurs in the floor of the mouth (originating from the duct of the sublingual or submandibular gland) is called "ranula."

Mucoceles are lesions of the minor salivary glands or ducts and are epithelium-lined cavities filled with mucus and covered by granulation tissue. They result from damage to a salivary gland or duct with extravasation of mucus into the surrounding tissue. The size of the lesion can vary over time, often as a result of a rupture of the lesion due to lip biting. Occasionally, spontaneous rupture of the mucocele can result in resolution [136], although recurrence is common if the damaged gland is not surgically removed [137].

Diagnosis of mucocele is primarily based upon the clinical presentation (eg, classic appearance and texture of the lesion). Aspiration alone may initially relieve symptoms but is rarely indicated except to aid in diagnosis or for short-term relief of irritation, as recurrence is common. Mucoceles are the most commonly biopsied oral lesions in children [138].

In all patients, particularly children and their parents/caregivers, reassurance as to the benign nature of the condition is an important element of management. Advising the patient to avoid biting or chewing the lesion is essential; minimizing trauma may promote resolution. The application of warm compresses can reduce inflammation when present. If the lesion recurs, does not resolve spontaneously, or becomes bothersome or concerning to the patient, surgical removal of the entire lesion and histologic confirmation of the diagnosis is the standard management [139]. Carbon dioxide (CO₂) laser vaporization has also shown good results with a low rate of recurrence and is an option for clinicians experienced with this modality [140]. Intralesional corticosteroid injections have also been used with success [141].

Torus palatinus — Torus palatinus, a bony overgrowth (exostosis) located on the midline of the hard palate, appears as a bony, hard, nodular, lobular, or spindle-shaped mass covered with normal mucosa (picture 52) [142-144].

It generally develops during childhood and enlarges slowly over many years. Torus palatinus is generally asymptomatic and is typically an incidental finding during routine physical examination. However, if the mass is rapidly growing (over weeks or months), is not located on the midline, or has an atypical appearance, referral for imaging or biopsy may be warranted.

Torus palatinus is very common, with a prevalence of approximately 12 to 27 percent in the general population [145-147].

Surgical removal may be an option if patients develop symptoms or the lesion precludes the proper fitting of dentures or other oral prosthetic devices.

Torus mandibularis (mandibular exostoses) are similar lesions and probably more common than torus palatinus. They are typically found on the lingual aspect of the mandible [148].

Minor salivary gland tumors — Tumors may develop in any of the minor salivary glands. There are approximately 1000 minor glands, each measuring from 1 to 2 mm in size, and are dispersed throughout the oral submucosa. Minor salivary gland tumors may present as a painless, submucosal mass or a mucosal ulceration in the palate, lips, or buccal mucosa. This is reviewed elsewhere. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging", section on 'Clinical presentation'.)

Gingival overgrowth — Gingival overgrowth may develop as a result of inflammation in response to long-standing gingivitis, particularly in children, or due to certain medications. (See "Soft tissue lesions of the oral cavity in children", section on 'Gingival overgrowth'.)

Medications associated with enlargement of gingival tissues include phenytoin, cyclosporine, and calcium channel blockers (most commonly nifedipine, diltiazem, verapamil, and amlodipine, although in case reports, felodipine, nitrendipine, and nicardipine have also been implicated) (picture 53) [149,150]. Management of drug-induced gingival overgrowth is reviewed elsewhere. (See "Overview of gingivitis and periodontitis in adults", section on 'Non-plaque-associated gingivitis and gingival disease'.)

Oral fibroma — Oral fibromas are common, benign soft tissue growths of the oral mucosa that present as smooth, pink or whitish papules or nodules, sessile or pedunculated, on the oral mucosa (picture 54A-B) [151]. They are usually induced by trauma, and thus, they are typically located at sites that are subject to repeated biting or friction from dentures.

Telangiectasias secondary to hereditary hemorrhagic telangiectasia — In patients with hereditary hemorrhagic telangiectasia, mucosal telangiectasias can occur anywhere along the gastrointestinal tract and are frequently visible on the lips, tongue, and oral mucosa (picture 55A-B) [152,153].

Lesions generally develop by the age 30 years and increase in number over time. Bleeding can occur but rarely requires medical intervention. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

Contact stomatitis — Contact stomatitis (contact mucositis involving the oral or perioral tissues) may present with a variety of lesions (eg, erythematous lesions, vesicles, ulcerations, hyperkeratosis) and discomfort (eg, pain, burning, itchiness) (picture 56). Irritant contact stomatitis can be induced by mechanical irritation (ie, ill-fitting dentures or irregular dental fillings), physical trauma, or chemical irritation [154]. Chemical irritants include foods, flavorings, oral hygiene products, dental restoration products, tobacco, and drugs (eg, aspirin). Nicotine stomatitis has been described in e-cigarette users [155].

Hyperkeratotic lesions resembling leukoplakia can occur due to repeated friction from poorly fitting prostheses, cheek sucking, or with the use of oral tobacco. (See 'Morsicatio buccarum and frictional keratosis' above.)

Allergic contact reactions may occur in response to metallic mercury, cinnamon aldehyde, and gold salts, among others agents (table 2). Lip and perioral involvement is seen when the offending agent is eaten (eg, mango off the skin) or applied topically. Food-related reactions may also present with prominent lip swelling. Lichenoid, lace-like, localized buccal mucosal patches may occur secondary to amalgam allergy.

Allergic contact urticaria may be caused by dental materials or natural rubber latex. It presents with rapid development of edema of the lips, tongue, and oral mucosa; anaphylaxis can also occur. Of note, some individuals who are allergic to natural rubber latex may have an associated hypersensitivity to some plant-derived foods, such as avocado, banana, kiwi, chestnut, peach, tomato, white potato, and bell pepper (latex-fruit syndrome). (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis", section on 'Allergic contact urticaria' and "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Latex-fruit syndrome'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Mouth sores (The Basics)" and "Patient education: Leukoplakia (The Basics)")

SUMMARY

●Initial evaluation – In patients presenting with an oral lesion, we perform a careful intraoral and extraoral tactile and visual examination (figure 1A-C). Although the clinician's examination of the oral lesion is critical in establishing the diagnosis, the historical and descriptive characteristics of the lesion provided by the patient (eg, location, duration, enlargement, associated pain) enhance the clinician's diagnostic accuracy. (See 'Initial evaluation for all patients with oral lesions' above.)

●Normal variants of oral mucosa – It is important to recognize that several apparent mucosal "abnormalities," such as leukoedema (picture 2), Fordyce spots (picture 3B-C), and physiologic pigmentation (picture 4), are actually normal variants and require no further evaluation or treatment. (See 'Normal variants of oral mucosa' above.)

●White and red lesions – White or red oral lesions include (see 'White and red oral lesions' above):

•Benign lesions – Morsicatio buccarum (picture 5A-B), frictional keratosis (picture 6B), white sponge nevus (picture 22)

•Benign lesions with malignant potential – Erythroplakia (picture 15), leukoplakia (picture 13A, 13C, 13E), oral lichen planus and other lichenoid lesions (picture 18A-B and picture 19A-C, 19E), submucous fibrosis (picture 16 and picture 17A-B), actinic cheilitis, chronic graft-versus-host disease (picture 21B), oral lupus erythematosus (picture 20)

•Malignant lesions – Squamous cell carcinoma (picture 12A-C)

•Infections – Candidiasis (picture 7C-D, 9A-B, 10A-F), oral hairy leukoplakia (picture 11)

●Pigmented lesions – Pigmented lesions of the oral mucosa include (see 'Pigmented lesions' above):

•Melanocytic lesions (typically black or brown) – Melanotic macules (picture 23A-B), drug-induced pigmentation, smoker's melanosis, oral melanoacanthoma (picture 25), melanocytic nevi (picture 26), oral melanoma (picture 27)

•Blue/black or gray – Amalgam tattoos (picture 28A-B)

●Erosive/ulcerative/bullous lesions – Erosive, ulcerative, and bullous oral lesions are very common, with a broad differential diagnosis including infectious, autoimmune, and inflammatory processes. The lesions may appear different depending upon the time of evaluation of the lesion; thus, the clinical history is particularly important to elicit. Ulcerative conditions include (see 'Erosive, ulcerative, and bullous lesions' above):

•Noninfectious aphthous ulcerations – Recurrent aphthous stomatitis (picture 29A-C), which involves the oral mucosa only; Behçet syndrome (picture 30); and complex aphthosis (may involve the genital mucosa)

•Malignant lesions – Squamous cell carcinoma (picture 12A-C)

•Infections – Herpes simplex virus (picture 31), varicella-zoster virus (picture 32A-C), coxsackievirus (picture 33A-E), syphilis (picture 34A-D), HIV infection

•Immune-mediated ulcerations – Erosive lichen planus (picture 19C, 19E), systemic lupus erythematosus (picture 35B), mucous membrane pemphigoid (picture 36B-C), bullous pemphigoid, pemphigus vulgaris (picture 37), paraneoplastic pemphigus (picture 38A-C), epidermolysis bullosa acquisita, erythema multiforme (picture 39A-C)

•Non-immune-mediated ulcerations – Epidermolysis bullosa (see "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features")

•Drug-induced ulcerations – Stevens-Johnson syndrome/toxic epidermal necrolysis (picture 40A-B), mammalian (mechanistic) target of rapamycin (mTOR) inhibitor-associated stomatitis, and nicorandil-induced ulceration

●Tongue lesions – Tongue lesions include those that are considered normal variants as well as lesions that are abnormal (see 'Tongue lesions' above):

•Normal tongue variants – Fissured tongue (picture 41B), black tongue (picture 42), pigmented fungiform papillae (picture 43) (see 'Normal tongue variants' above)

•Abnormal tongue lesions – Atrophic glossitis (picture 44A-B), black hairy tongue (picture 45), geographic tongue (picture 46A-B), median rhomboid glossitis (picture 9A-C), granular cell tumor (picture 47)

●Miscellaneous lesions – A variety of other lesions can occur in the mouth and oral mucous membranes. These include cheilitis (picture 49), mucoceles (picture 50A-B), torus palatinus (picture 52) and mandibularis, tumors of the minor salivary glands, gingival overgrowth (picture 53), telangiectasias secondary to hereditary hemorrhagic telangiectasia (picture 55A-B), and contact stomatitis (picture 56). (See 'Miscellaneous oral lesions' above and "Cheilitis" and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Adam O Goldstein, MD, MPH, and Beth G Goldstein, MD, who contributed to an earlier version of this topic review.