TITLE: STOMATITIS
SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds
DATE: November 29, 1995
RESIDENT PHYSICIAN: Carl Schreiner, M.D.
FACULTY: Francis B. Quinn, Jr., M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.

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"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

Introduction

Otolaryngologists examine the oral cavity on a daily basis and require a broad understanding of oral pathology. Stomatitis is inflammation of the oral mucosa and may be secondary to infection, trauma, systemic diseases or autoimmune mechanisms. This presentation is a brief summary of common benign conditions of the oral mucosa. For organization, the lesions will be categorized as vesiculobullous, ulcerative, red, or white lesions, although considerable overlap exists. Several common tongue lesions will also be discussed.

Vesiculobullous Lesions

Herpes Simplex

Herpes simplex virus Type I (HSV I) manifests as a primary or secondary infection which principally involves the lips and oral mucosa but may also involve the skin,eyes and rarely the central nervous system. The incubation period is around 7 days and the route of spread is by direct contact with infected fluids.

Primary herpetic gingivostomatitis is rare in adults and is usually seen in children from 1 to 3 years of age. Small vesicles appear on any mucosal surface of the oral cavity and are usually accompanied by fever, malaise, headache and cervical adenopathy. The primary infection is often not diagnosed as the symptoms can be mild and the vesicles rupture rapidly and may go unnoticed. The most common sites of involvement include the palate, buccal mucosa, and gingiva. Healing without scarring usually occurs within 2 week sand the virus migrates along the periaxonal sheath of the trigeminal nerve to the trigeminal ganglion and lies dormant until reactivation.

Recurrent lesions affect 30% - 40% of the population and are usually localized to the mucocutaneous junction of the lips and attached gingiva. They represent reactivation of the latent virus in the trigeminal ganglion and are often precipitated by ultraviolet light, stress, fever, or immunosuppression. Painful vesicles appear after a prodrome of tingling or burning and rapidly coalesce to form a superficial ulcer that crusts and heals without scarring in a week to 10 days.

Microscopically, the lesions show ballooning degeneration of basal cell and the formation of intraepithelial vesicles. Infected cells show a glassy, homogenous nucleus, or appear as multinucleated giant cells that are indistinguishable from herpes zoster or chicken pox.

Vesicle formation is the key to differential diagnosis as aphthous ulcers and acute necrotizing gingivitis are not preceded by vesicles.

Treatment is mainly supportive in the nonimmunocompromized and consists of hydration and analgesics. Oral acyclovir may be beneficial if given frequently (100 - 200 mg 5 x day) early in the course of the disease. In immunocompromized patients intravenous acyclovir may be required but prophylactic oral acyclovir has been shown to be more beneficial in these patients.

Herpes Zoster

Herpes zoster represents a reactivation of prior infection of the varicella zoster (chicken pox) virus which travel to sensory ganglia during the primary infection. Fever, pain and tenderness over the involved nerve occurs often several days before the vesicular rash appears and associated lymphadenopathy is common even without secondary infection. The lesions heal spontaneously in several weeks and postherpetic neuralgia is a common complication. The ophthalmic nerve is the most commonly affected branch of the trigeminal nerve and ophthalmological consultation is indicated.

Histologically, the lesions are essentially identical to herpes simplex and treatment is supportive.

Herpangina

Herpangina is a febrile illness of children and young adults characterized by fever, malaise, sore throat and gastrointestinal symptoms followed by the formation of several small vesicles in the oropharynx. The lesions are often limited to the soft palate and usually do not appear until several days after the systemic symptoms begin. The causative agent is a Caxsackie virus and it usually resolves quickly without complications.

The differential diagnosis includes strep throat, measles, and herpetic gingivitis, although herpangina usually does not involve the gingiva. Treatment is supportive and infection provides immunity to reinfection.

Pemphigoid

Pemphigoid is characterized by the formation of tense, subepithelial bullae of the skin and mucous membranes. Two separate entities, benign mucous membrane pemphigoid and bullous pemphigoid, are often described but many think they represent variants of the same disease.

Benign mucous membrane pemphigoid occurs in the 40 to 50 year old age group and affects women twice as often as men. Tense oral bullae form and may persist for days before rupturing, forming large erosions that usually scar with healing. Gentle rubbing of adjacent uninvolved skin may denude the epithelium, producing an ulcer or vesicle (positive Nikolsky's sign). Involvement of the conjunctivae is relatively common and may lead to blindness.

Bullous pemphigoid affects older patients and cutaneous lesions are more common than mucosal lesion. The lesions are similar but may heal with less scarring.

Both lesions are histologically similar and show direct immunofluorescence to lgG in the basement membrane, supporting an autoimmune etiology. Biopsy shows subepithelial clefting with autoimmune etiology. Biopsy shows subepithelial clefting with dissolution of the basement membrane but no degenerative intraepithelial changes.

Treatment is often difficult if multiple sites are involved but potent topical steroids or intralesional steroids can be effective. Systemic steroids may be required for severe cases or ocular involvement. Steroids combined with immunosuppressants (cyclophosphamide, methotrexate) may be needed in refractory cases.

Pemphigus Vulgaris

Pemphigus is a more severe group of potentially fatal diseases characterized by intraepithelial bullae and acantholysis. The disease is more common in Jewish and Italian people and males are more often affected than females. The lesions almost invariably initially involve the oral mucosa and the bullae are so easily ruptured that painful irregular ulcers are often the presenting lesions. The most common sites include the buccal mucosa, palate and gingiva.

Microscopically, the lesions show early intercellular edema and los of intercellular bridges. The lack of cohesion allows cell separation and rounding (acantholysis), and intraepithelial clefting (as opposed to subepithelial in bullous pemphigoid) occurs. The basal cells remain attached to the lamina propria creating a "tombstone" effect and free acantholytic cells assume a spherical form ("Tzanc cells") which are considered pathognomonic for pemphigus vulgaris. Direct immunofluorescence shows antibodies against intercellular bridges. Serum levels of intercellular antibodies have been shown to correlate with the severity of the disease.

Treatment with high dose steroids has greatly reduced the mortality and morbidity of pemphigus but significantly morbidity from steroids has been reported as doses of 100 mg/day are often required for initial control. The dose can be tapered down to 20 mg/day over three months. Intramuscular gold has been with some success and plasmaphoresis is currently under investigation.

Erythema Multiforme

Erythema multiforme is a rapidly progressive, vesiculobullous eruption of unknown etiology that most commonly affects young adults. An allergic reaction to drugs, infection, food or alcohol is suspected resulting in antigen-antibody complex deposition in the vessels of the subdermis. Characteristic ring-like "target lesions" appear on the skin but are rarely seen on the oral mucosa. Diffuse ulceration and crusting of the lips, tongue, and buccal mucosa are more common oral manifestations. The lesions are usually self-limited and heal without scarring in a few weeks.

The histopathology in erythema multiforme is nonspecific and its explosive onset after a precipitating infection or drug is key in differentiating it from other vesiculobullous diseases.

Stevens-Johnson syndrome is a severe from of erythema multiforme with systemic symptoms and involvement of the eyes, gastrointestinal tract, and genitalia. Treatment of severe cases of erythema multiforme and Stevens-Johnson syndrome requires systemic steroids. The prognosis if erythema multiforme is generally good but blindness or death can occur with Stevens- Johnson syndrome.

Ulcerative Lesions

Recurrent Aphthous Ulcers

Aphthous ulcers are extremely common and seem to be more prevalent in upper socioeconomic classes and professionals. The cause is unknown but the best evidence points to an autoimmune mechanism. The "L" form of streptococci in ulcers have been shown to produce a skin hypersensitivity response in guinea pigs. Other theories include HSV or bacterial infections, stress, hormonal alterations, and food allergies. Histologically, aphthous ulcers have no distinguishing features. Clinically, the disease has been divided into three groups based on size, distribution, and severity.

Minor aphthae (cancer sores) measure less than 1 cm and are located on freely-mobile gingiva or mucosa. The lesions are well-demarcated white ulcers with an erythematous halo. They heal without scarring in 7 to 10 days. Treatment is often sought as pain is often in excess of the appearance of the lesion.

Major aphthous ulcers are less common, larger, and more severe. They range from 1 to 3 cm and may persist for up to 6 months. The tongue, soft palate, and anterior facial pillar are often involved. In contrast to minor aphthae, they heal with scarring.

Herpetiform ulcers present as an extremely painful crop of 20 to 200 small ulcers 1 to 3 mm in diameter. They appear similar to herpetic lesions but lack a vesicular stage.

Treatment attempts over the years have been imaginative and largely unsuccessful. Medical treatment has ranged from antibiotics, immunosuppressants and yogurt, to Lactobacillus capsules. An oral suspension of tetracycline taken every 6 hours has shown good results and topical steroids (Lidex, Celestone) may shorten the duration significantly if started early. Systemic steroids are often needed to control mayor aphthae. Peridex and retinoids have also been tried empirically but controlled studies are lacking.

Acute Necrotizing Ulcerative Gingivitis (ANUG)

Also known as "trench mouth" (after World War II) or Vincent's stomatitis, the incidence of ANUG is now increasing with the appearance of AIDS. Ulceration of the interdental papillae with bleeding and pseudomembrane formation occurs with a characteristic fetid odor. Systemic symptoms of fever, malaise and lymphadenopathy may occur. Juveniles and young adults are often affected. The disease is noncommunicable and cultures contain large numbers of fusiform bacilli and spirochetes. The course is often chronic and may lead to bone loss and periodontitis. Treatment consists of superficial scaling, debridement and the aggressive use of mouthwashes and antibiotics. Close dental follow up is needed.

White Lesions

Lichen Planus

Lichen planus is a chronic disease of the skin and mucous membranes which is felt to be due to basal cell layer destruction by activated lymphocytes. Characteristic skin lesions include violaceous, pruritic papules of ever the flexor surfaces of the extremities and several types of oral lesions have been described, including reticular, plaque and atrophic (erosive) variations.

Reticular lichen planus shows fine, slightly raised, white or violaceous threadlike lesions in a ringlike pattern (Wickham's striae). These lesions are often located on the buccal mucosa. The hypertrophic form resembles leukoplakia as homogenous white plaques. Atrophic or erosive lichen planus present as erythematous shallow ulcers that, in contrast to most forms of lichen planus, may be painful.

Histologically, lichen planus shows hyperkeratosis, "saw- tooth" rete ridges, liquefactive degeneration of the basal cell layer, and a "band-like" subepithelial inflammatory infiltrate. Discrete eosinophilic ovoid bodies (Civatte bodies) are occasionally seen in the basal cell layer.

Treatment is symptomatic and mild cases usually do not require therapy. Topical steroids may be useful in controlling local symptoms and topical retinoids, with antikeratinizing effects, can be used for the plaque form. Dapsone has also been used for severe forms with some success.

Candidiasis

Candida albicans is an oral commensal that can be found in the mouth of 40% - 60% of healthy individuals. Oral candidal infections almost always involve a compromised host. Local factors include decreased salivation (medications, radiation, or Sjogren syndrome) or dentures. Systemic factors include diabetes, antibiotic or systemic steroid use, AIDS, or pernicious anemia. Many clinical forms of candidiasis have been described, including: pseudomembranous, hyperplastic, and denture stomatitis.

Pseudomembranous candidiasis presents as tiny, soft, yellow- white plaques that consist of fungi, bacteria, desquamated cells and food debris. The lesions are readily scraped off and an underlying erythema is key to the diagnosis.

The hyperplastic variant (Candida leukoplakia) are white, firm, plaques that often involves the buccal mucosa, tongue or lips. The lesions are truly leukoplakic, as the overlying keratotic mucosa does not easily scrape away. These lesions are often resistant to standard therapy.

Denture stomatitis lesions occur in older patients and are most common with a complete maxillary denture. The lesions are red, flat plaques that extend right up to but not beyond the denture border. The patients often wear their dentures for extended periods of time and during sleep.

Diagnosis of candida infections is usually clinical and is confirmed by resolution of the lesions after 2 weeks of antifungal therapy. Cultures or smears are usually reserved to cases that fail treatment. Cultures are often unreliable and may take up to 2 weeks for growth. Fungal smears with PAS staining is faster and less expensive. The slides show hyphae and polymorphonuclear leukocytes in the superficial layers of the epithelium.

The three most commonly used antifungals include nystatin, clotrimazole, and ketoconazole. Nystatin has the advantage of being effective and safe for long term use, but is less potent that the latter two and may cause burning when swished orally. Patient compliance is also a problem with a regiment of swishing for two minutes and then expectorating four times a day. Clotrimazole is more potent and comes in a lozenge, which increases patient compliance. It has the disadvantage of causing occasional liver enzyme elevation and should not be used in patients with known liver disease. Ketoconazole is prescribed in 200 mg tablets taken once daily but also can cause liver enzyme elevation.

Leukoedema

Leukoedema is a benign condition in which the oral mucosa takes on an opaque, grey, film that may appear to hang like a "veil" on the mucosa, creating a "mother of pearl" appearance. It is more common in dark-skinned patients and is likely aa variant of normal in which there is incomplete shedding of parakeratotic cells, although some studies have shown as association with tobacco use. Histologically, leukoedema is characterized by marked intracellular edema and vacuoles. Its significance is important only in differentiating leukoedema from leukoplakia or white sponge nevus.

White Sponge Nevus

White sponge nevus is an autosomal dominantly inherited condition of the oral mucosa. The buccal mucosa is commonly affected and appears as white or grey, thickened, deeply folded lesions often described as "scrotal" in appearance. The lesions are asymptomatic and the rectal or vaginal mucosa is often involved. A defect causing faulty epithelial migration with impaired desquamation is suspected. Histology shows parakeratosis, acanthosis and prickle cell vacuolated cells giving a "washed out" appearance. The differential diagnosis includes lichen planus and candidiasis. No treatment is necessary.

Leukoplakia

Leukoplakia is defined as a white patch or plaque of the mucosa that cannot be rubbed off the mucosa and cannot be classified as any other disease entity. The term "leukoplakia" is strictly a clinical condition and lacks any histologic connotation. Although most leukoplakia are histologically benign, some may progress to dysplasia or eventually squamous cell carcinoma. Leukoplakia presents as an irregular, slightly raised white lesion that is sharply demarcated from surrounding tissue. The majority of cases occur between the ages of 40 and 60 and men are affected more than women. The most common sites include the buccal mucosa, alveolar mucosa and hard palate and these locations rarely malignantly transform. In contrast, leukoplakia of the floor of the mouth and tongue are less common, but much more frequently progress to malignancy. Multiple classifications of leukoplakia have been described based on the macroscopic appearance of the lesions, including planar, verruciform, and speckled forms, the latter two forms reported as associated with a higher rate of malignant transformation. Ten per cent transformation of dysplastic leukoplakias is a commonly quoted figure but the literature does not closely correlate with histology and biopsy with close follow up is mandatory.

Histologically, the majority of leukoplakias show combinations of hyperorthokeratosis, hyperkaratosis and acanthosis. Dysplasia is characterized by increased mitotic figures, abnormal mitosis in the upper strata, nuclear pleomorphism, individual cell keratinization, and loss of polarity and is generally considered to represent a shift toward malignant transformation.

Although the etiology of leukoplakia is unknown, it is widely believed that tobacco plays a major role. Other possible factors include chronic irradiation, dietary deficiencies, chronic candidiasis, and alcoholism. Many nondysplastic lesions disappear with removal of the irritating stimulus and those that do not respond usually can be cured by surgical excision. Dysplastic leukoplakias, on the other hand, are less likely to respond to nonsurgical treatment. They are also more likely to recur after excision. In general, the more severe the dysplasia, the higher potential for malignant transformation and dysplastic lesions of the ventral surface of the tongue or floor of the mouth should be approached with particular caution. <3>Red Lesions

Erythroplakia

Erythroplakia is the red counterpart to leukoplakia and represents a red plaque of the mucosa not attributable to a specific pathologic condition. Once again, "erythroplakia" implies no histologic connotation although virtually all erythroplakias show microscopic dysplasia. Several studies have shown an impressive 80% - 90% of lesions containing severe dysplasia, carcinoma-in-situ, or squamous cell carcinoma.

The lesions are often asymptomatic, homogenous, velvety-red flat plaques that are well circumscribed from normal mucosa. Erythroplakia and leukoplakia may be mixed, giving the so called "speckled" pattern. Like leukoplakia, the clinical appearance is unreliable with regard to histology and biopsy is mandatory.

Histologically, the lesions differ from erythroplakia by showing a lack of orthokeratin or parakeratin and an intense inflammatory infiltrate is often seen. A thinned epithelium with absent rete ridges and congested superficial capillaries give the lesions their red color.

The differential diagnosis of erythroplakia includes candidiasis, denture stomatitis, tuberculosis. Treatment usually requires complete surgical excision with frozen section margins and close follow up.

Radiation Mucositis

Radiation mucositis is a painful inflammatory reaction of the oral mucosa to radiation therapy. The degree of injury varies, depending on the dose, portal of the beam, age, and general health of the patient. The first reaction is usually noted during the second week of a 5 or 6 week treatment and consists of diffuse erythema, followed by desquamation and ulceration. Xerostomia adds to the discomfort and usually persists indefinitely to some degree. An alteration in taste often precedes the mucosal reaction and may persist, depending on the dose. Hydrogen peroxide and water (4:1 solution) and sodium bicarbonate solutions may improve symptoms. Numerous anesthetic mucosal coating agents are available, including combinations of benadryl, viscous lidocaine, and Dyclone.

Tongue Lesions

Geographic Tongue (Benign migratory glossitis)

Geographic tongue is a common condition of the tongue characterized by alternating areas of red desquamated zones bordered by sharp raised margins. Over a period of days to weeks, the "bald" areas migrate across the surface of the tongue by haling on one border and extending onto another border. The desquamated areas represent areas devoid of filiform papillae but intact red fungiform papillae. Psychological factors have been shown to correlate with the severity of involvement but the etiology is unknown. The course of the disease is variable but often persists for months to years. It is reported to exist in 1 - 2% of the general population and is usually asymptomatic, although patients may complain of mild burning with spicy foods or citrus fruits. Topical steroids may help with burning, but reassurance is usually the only required treatment.

Median Rhomboid Glossitis

Median rhomboid glossitis is a well-circumscribed red area devoid of papillae in the midline dorsum of the tongue. Once felt to be a developmental abnormality due to failure of withdrawal of the tuberculum impar, recent evidence has implicated candida albicans as a causative agent. The lesion is asymptomatic and usually picked up on routine examination. No treatment is necessary unless candida is cultured.

Hairy Tongue

Hairy tongue is a striking condition caused by hypertrophy of the filiform papillae. The individual "hairlike" papillae (sometimes reaching 15-20 mm in length) always occur anterior to the terminal sulcus and tend to migrate laterally and anteriorly. The pathogenesis is unknown but antibiotic therapy, steroids, radiation therapy, and smoking have been implicated. Most cases are considered idiopathic. In the cases of hairy tongue after antibiotics, it has been postulated that antibiotics alter the normal flora of the mouth, leading to the overgrowth of fungi. Attempts to culture these fungi have been inconsistent. The color of the filiform fibers may be black ("black hairy tongue") or yellow and is felt to be due to overgrowth of chromogenic organisms or smoking. Treatment consists of withdrawing antibiotics if applicable and meticulous oral hygiene, including brushing the tongue with a soft bristle brush.

Hairy Leukoplakia

This new clinical entity has recently been described in association with HIV infection. Thee lesion presents as a white, corrugated patch on the lateral surface of the tongue and is often bilateral. The lesions may be present in as many as 20% of HIV patients and is often confused with candidiasis. Histologically, the lesions show epithelial projections in a "hairlike" configuration and marked hyperkaratosis. Recent immunohistochemical studies have shown Epstein-Barr virus DNA in the epithelium. The patients often complain of a "cotton-wool" feeling in the mouth and the lesions may become superinfected with candida. Treatment is symptomatic.

BIBLIOGRAPHY

Bailey, Byron J, ed. Head and Neck Surgery-Otolaryngology. Philadelphia, PA: J.B. Lippencott 1993.

Lee, K.W. Color Atlas of Oral Pathology. Lea and Febiger - Philadelphia, 1985.

Pindborg, J.J. Atlas of Diseases of the Oral Mucosa. W. B. Saunders. Munksgaard-Copenhagen 1993.

Smith, R.M. et al. Atlas of Oral Pathology. C.V. Mosby Co. Toronto. 1981.

Rondu, B., Mattingly, B.S. Oral Mucosal Ulcers: Diagnosis and Management. JADA, Vol 123, Oct 1992:883-86.

Rogers, R. Common Lesions of the Oral Mucosa. Postgraduate Medicine. May 1992:141-53.

Zegarreli, D.J. Fungal Infections of the Oral Cavity. Otolaryngologic Clinics of North America. Dec 1993, Vol 26, No3 1069-88.

Discussion by Dr. Quinn:

( Outline of discussant's remarks)

GLOSSODYNIA: (glossopyrosis, glossalgia, orofacial dysesthesia, "burning tongue syndrome")

Incidence: middle aged females (73% in one study)

Physical findings: occasionally xerostomia, usually completely normal mouth, pharynx, gums & tongue.

Lab: occasionally anemia (one case of large intestine tumor - glossodynia subsided after removal of tumor; two cases of pernicious anemia) possible manifestation of diabetic neuropathy?

Psychiatric concommitants: Many patients score high on somatization, depression, anxiety scales More common in patients who are living alone Correlated positively with psychological stress but not related to recent life changes (Recent Life Changes questionnaire) In one study, 60% showed a psychiatrically relevant disorder, usually depression.

Treatment: Reassurance by carful history ("homework"*) with thorough physical examination of upper aerodigestive passages; screening labs (RPR, ?HIV)
Then referral for:

Caution: Don't forget to look for a cylindroma (adenoid cystic carcinoma, psuedoadenomatous basal cell carcinoma) (Sometimes the presenting symptom of this rare tumor is sometimes burning pain about the mouth & jaws.)

* "Homework:" assign to patient the task of writing out in exhaustive detail the entire history of her/his complaint, including its waxing and waning, any associated symptoms/disorders/treatments, or stressful events or conditions. Assignment to be delivered to the physician BEFORE the next visit, to enable thoughtful perusal of the patient's account and interpretation of the problem. This assures that all pertinent historical information is in the hands of the physician.

Quinn's rule for stomatitis: "Call it aphthous stomatitis. Treat it for two weeks. If it's still there, biopsy it."