Punctate Oral Erosions: Self-Limited “Sore”—or Something More Serious?
ABSTRACT: Viral and fungal infections, autoimmune conditions, immunodeficiency, drug reactions, contact allergy, and trauma all can precipitate punctate oral lesions. Herpetic lesions must be distinguished from aphthous ulcers, which lack a preliminary vesicular phase and have a more intense erythematous halo; herpetic lesions tend to occur in clusters and involve the fixed mucosa. Extremely large aphthous ulcers that persist for several weeks or months can mimic a carcinoma; biopsy is indicated. Because of their rarity in immunocompetent persons, fungal and cytomegalovirus infections in the oral cavity are clinical markers for AIDS. Drug-induced oral lesions can be diagnosed on the basis of the drug and medical history and a complete blood cell count; lesions usually appear when the white blood cell count falls below 2000/µL. Eosinophilic ulcers are reactive lesions in the oral cavity that are deep and generally larger than 1.5 cm, with indurated borders; biopsy is essential to rule out carcinoma.
Key words: punctate lesion, gingivostomatitis, herpes simplex virus type 1, herpes simplex virus type 2, herpes zoster, cytomegalovirus infection, herpangina, hand-foot-and-mouth disease, aphthous stomatitis, Behçet’s syndrome, Reiter’s syndrome, acute necrotizing ulcerative gingivitis, pyostomatitis vegetans
Your patient complains of a painful erosive lesion of the oral mucosa. Is it merely a canker sore—or is there a more serious cause? The differential diagnosis will be simplified by the classification presented here.
Erosive oral lesions may be subdivided into punctate and bullous ulcers, depending on the extent of tissue destruction. Here (in the fourth article in a series on oral lesions) I focus on the manifestations of—and therapy for—punctate lesions. In an upcoming issue, I will consider bullous oral erosions.
Punctate lesions are generally 1 to 5 mm in diameter. They range from relatively superficial lesions, with loss primarily of the surface epithelium, to destructive erosions that produce deep ulcers and significant submucosal soft-tissue damage (Table). All may occur singly or in multiples, sporadically or recurrently.
A vesicle or fluid-filled bleb may develop before the ulceration appears. Most of these vesicular lesions are caused by a virus; beginning as blisters, they rapidly become abraded and create ulcers. Consequently, it is of great diagnostic importance to detect a mucosal vesicle during its early formation.
Herpesviruses and enteroviruses can produce ulcerative lesions in the oral cavity. Although these lesions look similar, the clinical history suggests the diagnosis. A precise diagnosis can be made by viral culture or serologic testing (acute and convalescent sera titers of complement-fixing or neutralizing antibodies). These studies are not routinely performed except in immunocompromised patients.
Herpes simplex virus type 1 (HSV-1) infection. HSV-1 infection appears in several forms. Most persons who acquire HSV-1 infection do so during early life; manifestations occur when the virus is activated in adulthood.
Figure 1 – Ulcera- tive lesions involve the entire oral cavity and extend onto the lips of this patient with primary herpetic gingivo- stomatitis. A severe erythematous gingi- vitis accompanies the condition.
Primary herpetic gingivostomatitis. The great majority of primary HSV-1 infections are asymptomatic; however, in some children and young adults, primary infection occurs as an explosive febrile disorder. Ulcerative lesions appear diffusely throughout the oral cavity, although they show a predilection for the lips and gingiva (Figure 1). Erythematous halos surround the lesions, and—as the name implies—there is an intense gingivitis.
Treatment consists of supportive care. Make sure that small children remain well hydrated and eat enough. Give antipyretics and control local pain by having patients rinse with a topical anesthetic, such as viscous xylocaine and diphenhydramine elixir. The disease is self-limited, and the lesions disappear in 10 to 14 days. Disseminated herpes (Pospischil-Feyrter syndrome) is a rare complication that has been reported in debilitated infants.
Recurrent HSV-1 oral infection. Once believed to be rare, this condition generally presents as a crop of vesicles that are limited to the palate. In immunocompromised persons, however, ulcerative lesions of varying sizes that culture positive for HSV-1 may appear anywhere within the oral cavity. While systemic acyclovir has been of limited benefit in many viral infections, this agent prevents or delays recurrences of herpetic lesions in immunocompromised persons.
Herpes labialis (cold sore). The most common recurrent HSV-1 infection, herpes labialis represents a reactivation of the latent herpesvirus on the lips. It can be precipitated by trauma, sunlight, stress, or another viral or febrile illness. Cold sores usually appear on the vermilion border of either lip as a cluster of vesicles that are soon covered by a fibrin crust (Figure 2). The lesions may extend onto the adjacent skin.
Patients may experience a prodrome of burning and itching several hours to 24 hours before the eruption appears. The highest degree of viral shedding is from ulcerative lesions, and the lowest is from crusted ones. Cold sores are distinguished by their focal nature, lack of involvement with the oral mucosa, and spontaneous healing.
Acyclovir ointment (5% or 10%) decreases the duration of viral shedding, but it neither shortens the duration of herpes labialis nor promotes healing. An alternative is penciclovir cream (1%), which may be applied every 2 hours during waking hours for 4 days.
Although oral acyclovir is not consistently beneficial, it helps reduce relapses in immunocompetent as well as immunocompromised patients who have severe recurrent disease.1 The usual dosage is 400 mg tid.
Oral herpetic lesions must be differentiated from aphthous ulcers, which have no preliminary vesicular phase and have a more intense erythematous halo. Recurrent herpetic ulcers also tend to be smaller (less than 0.5 cm) than aphthous ulcers, occur in clusters rather than singly, and arise on fixed mucosa (such as the palate, gingiva, and alveolus) rather than on buccal mucosa or the lips.
Herpes simplex virus type 2 (HSV-2) infection. Genital herpes may occur in the oral cavity in areas other than the palate; however, such infections are uncommon. The lesions are clinically indistinguishable from those of HSV-1 infection, and treatment is identical.
Herpes zoster (human herpesvirus 3 infection). Primary infection with the varicella-zoster virus (chickenpox) presents as an explosive, diffuse, vesicular eruption that is usually intensely pruritic. It starts on the face and scalp and spreads centripetally. Fever and lymphadenopathy are usually present. In addition to the exanthem, oral vesicles often appear, especially on the palate.
Following initial infection, the varicella-zoster virus remains latent in the dorsal root ganglia of sensory nerves. If it becomes activated, secondary varicella-zoster infection (herpes zoster, or shingles) appears; this typically presents as a unilateral, vesicular skin eruption in a dermatomal distribution, principally on the trunk.
If, however, the gasserian ganglion is infected, clusters of dermal and mucosal lesions may appear in the distribution of the maxillary and mandibular nerves (Figure 3). Fever and regional lymphadenopathy may develop. The distinctive appearance and distribution of the dermal and mucosal lesions are diagnostic.
Meningitis may complicate varicella-zoster virus infection. Patients suffering from lymphoma and other lymphoproliferative malignancies are at increased risk for herpes zoster.2 Varicella-zoster virus infection has been associated with occult lymphoma, leukemia, and carcinoma. Consequently, always rule out an underlying malignancy in patients who have herpes zoster.
Herpes zoster of the 9th and 10th cranial nerves, while rare, is manifested as a collection of vesicles along the posterior pharyngeal wall, the tonsils, and the base of the tongue. Patients have severe throat pain and difficulty in swallowing. Because this condition is unilateral, it can be differentiated from the more extensive involvement of herpangina (described later).
Herpes zoster is a self-limited infection, and the lesions crust over within 7 to 10 days. Treatment is supportive. Acyclovir, 800 mg four or five times daily, reduces pain during the acute phase and promotes healing of lesions. Alternatively, 3 g/d of valacyclovir may be administered for 5 days.
Cytomegalovirus (human herpesvirus 5) infection. While cytomegalovirus (CMV) infection is common (present in 80% to 90% of adults) and asymptomatic, it may become manifest during periods of immunosuppression, especially in AIDS patients, in whom it is a clinical marker for the disease.3 CMV infection in the oral cavity is uncommon; however, ulcerative lesions on the palate, gingiva, lips, and tongue have been reported, as has bone involvement.
Biopsy reveals distinctive intranuclear inclusion bodies with clear halos (“owl’s eye” bodies). Immunohistochemistry and DNA in situ hybridization may also be employed for diagnosis. The majority of patients are HIV-positive. Treatment consists of intravenous (5 mg/kg bid) or oral (3 to 6 g/d) ganciclovir for 2 weeks.
Figure 4 – Vesicles that cluster on the soft palate—as shown here—char- acterize herpan- gina. The infection is generally accompanied by an extremely sore throat, fever, malaise, and lymphadenopathy.
Coxsackievirus infection. Both the A and B groups of coxsackievirus (as well as some echoviruses) produce oral lesions—principally in children and young adults. Multiple vesicles that are distributed over the soft palate, tonsillar fauces, and tonsils are characteristic of herpangina (Figure 4). The extremely sore throat that results causes marked difficulty in swallowing and is accompanied by fever, malaise, and lymphadenopathy.
As with the previously described viral stomatitis, the condition is self-limited; the ulcerations spontaneously heal in 7 to 10 days. Treat patients with anodyne mouthwashes, such as viscous lidocaine and diphenhydramine elixir.
Hand-foot-and-mouth disease, which is caused by coxsackievirus A16, also afflicts children and young adults. Rapidly ulcerating vesicles appear simultaneously in the oral cavity, particularly on the lips and buccal mucosa (Figure 5), and on both surfaces of the hands and feet. As with other coxsackievirus infections, constitutional signs are present. The clinical picture is virtually diagnostic.
Hand-foot-and-mouth disease is extremely contagious and may reach epidemic proportions among school children. It occurs most frequently in late summer and autumn; treatment is symptomatic.
ORAL ULCERS IN AIDS PATIENTS
Mouth ulcers in AIDS patients are caused by a wide range of organisms. Their clinical appearance is nondiagnostic; the lesion’s response to treatment most often suggests its cause. In addition, aphthous stomatitis occurs in these patients, possibly from a breakdown in the local immune system. Biopsy generally results in nonspecific findings; however, in some cases, viral inclusion bodies, fungal elements, or clusters of eosinophils that suggest a traumatic eosinophilic ulcer are detected.
Liang and associates4 studied 16 AIDS patients with oral ulcers. Culture and biopsy of the ulcer with polymerase chain reaction analysis to detect viral DNA revealed a causative agent in only about 50% of patients. The agents identified were HSV-1 (4 patients), HSV-2 (1 patient), Candida (1 patient), and Histoplasma capsulatum (1 patient). Other organisms implicated in oral ulcers in HIV-infected patients include Klebsiella pneumoniae, Enterobacter cloacae, Mycobacterium avium-intracellulare, Cryptococcus, and CMV.
Treatment of mouth ulcers in these patients is often empiric. It includes antiviral and antifungal agents as well as local and systemic corticosteroids and thalidomide. If a virus (such as HSV or CMV) is detected after the lesions are swabbed and cultured on Hank’s medium, oral acyclovir, 400 mg tid, or valacyclovir, 500 mg bid, is given for 10 days.
Opportunistic fungal infection of the oral cavity generally occurs in patients with disseminated disease and is often associated with an immunocompromised state. Lesions may be ulcerative or nodular. Ulcers are often deep with indurated borders, mimicking carcinoma. The tongue and buccal mucosa are common sites of involvement. Causative organisms include His capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and Cryptococcus neoformans.
The infrequent occurrence of such fungal infections in the oral cavity makes them markers for AIDS.5 Diagnosis is by identification of an organism by biopsy and periodic acid–Schiff or methenamine silver staining and by culture on Sabouraud medium. Skin and serologic tests are not always reliable.
Treat disseminated disease with intravenous amphotericin B. The oral lesions of histoplasmosis, blastomycosis, and coccidioidomycosis may be treated with oral itraconazole, 200 mg/d. For patients with cryptococcosis, the suggested regimen is oral fluconazole, 400 mg/d.
The role of bacteria in the formation of oral ulcers is unclear; their presence is generally considered to represent contamination or secondary colonization. Streptococcus sanguis was once thought to be a factor in the development of aphthous stomatitis; however, this theory has been discarded.
In a study of oral ulcers in 29 immunocompetent patients, Leimola-Virtanen and colleagues6 found spiral bacteria in 14 of the ulcers—6 of which revealed Helicobacter pylori DNA on in situ hybridization. All the ulcers that were positive for H pylori arose on the buccal mucosa.
Bacterial pathogens rarely cause oral lesions. However, infection with Francisella tularensis can produce a painful, indurated mouth ulcer that is associated with lymphadenopathy, fever, and chills.
APHTHOUS STOMATITIS (CANKER SORE)
The most common ulcerative condition of the oral cavity, aphthous stomatitis occurs in persons of all ages and affects both sexes equally. It was initially confused with HSV infection, but there is no evidence for a viral origin of these lesions. Considerable immunologic evidence points to autoimmunity as the cause. The lesions are believed to be precipitated by emotional stress.
Aphthous ulcers are shallow, solitary or multifocal, round or oval, and 2 to 5 mm in diameter. They have an erythematous border and a necrotic center and are extremely painful. A preliminary vesicle has never been demonstrated.7 Although canker sores can occur anywhere in the oral cavity, they have a predilection for the lateral border of the tongue, buccal mucosa, lips, and floor of the mouth. Gingival lesions are uncommon. A few large ulcers may occasionally develop, and crops of lesions sometimes reappear at varying intervals.
Diagnosis of aphthous ulcers is based on the history and physical appearance of the lesions. Pain is the predominant symptom. Lesions generally last 7 to 10 days, and the more commonly encountered minor form usually heals spontaneously without scarring.
Some investigators have subdivided recurrent aphthous ulcers into three categories:
•Minor (several lesions smaller than 10 mm that heal without scarring).
•Major (one or several lesions 10 mm or larger that heal with scarring; these are termed “Sutton’s disease,” or “periadenitis mucosa necrotica recurrens”).
•Herpetiform (numerous 1- to 2-mm ulcers that become confluent and may heal with scarring). Despite its name, there is no evidence that this type of ulcer has a viral source.8
A well-recognized association exists between recurrent aphthous stomatitis and ulcerative colitis, Crohn’s disease, and gluten-sensitive enteropathy. The significance is unknown, however.
Many types of therapeutic agents have been used for canker sores (eg, antibiotics, basic dyes, ether, and vaccination) but with limited success. Silver nitrate cautery of single lesions eliminates the pain; however, it results in scarring. A topical antihistamine (eg, diphenhydramine elixir) promotes healing and serves as a topical anesthetic. The most effective treatment is a topical corticosteroid, particularly 0.1% triamcinolone in an adhesive base; this is a paste form. Intralesional injection and systemic administration of prednisone (30 mg/d for 3 days) have also been used.
The large aphthous ulcers (10 to 15 mm) of Sutton’s disease last longer than their smaller counterparts and recur more rapidly. Extremely large lesions (2 to 3 cm) may develop; these persist for several weeks or months and mimic a carcinoma (Figure 6). Biopsy is indicated. Oral corticosteroid therapy may reduce the severity of the attack.
This condition is characterized by oral, genital, ocular, and cutaneous lesions, as well as visceral involvement. Complex aphthosis describes recurrent oral and genital lesions without systemic involvement.9
The mean age at onset of Behçet’s syndrome is in the 20s, with a male preponderance. Regional differences exist in its prevalence; the highest is in Japan and the Middle East, and it is uncommon in Europe and the United States.
Ulcerative lesions that are indistinguishable from those of aphthous stomatitis appear in the oral cavity, eyes, and genitourinary tract. The oral ulcers may be single or multiple, shallow or deep, with a yellow, necrotic base (Figure 7). Ocular lesions consist of conjunctivitis, uveitis, and hypopyon; genital lesions may be cutaneous or mucosal.
Behçet’s syndrome is believed to be an autoimmune condition, but the findings are not completely conclusive. The tissue antigen, HLA-B5, has been found principally in Turkish patients, and its significance is unclear.10 Microscopic examination shows a nonspecific epithelial ulcer filled with necrotic debris, as well as chronic inflammatory cell infiltrates in the connective tissue.
Treat patients who have limited lesions with topical corticosteroid creams; broad-spectrum antibiotics are often given in conjunction. Systemic corticosteroids may be required for widespread disease. Colchicine (0.5 mg tid) has also been effective in managing mucocutaneous lesions.
Oral, ocular, genital, and cutaneous lesions and arthritis typify this disease, which primarily affects young men. The classic triad described by Reiter is arthritis, conjunctivitis, and urethritis. The arthritis is seronegative and involves the peripheral joints. Cutaneous manifestations are typically yellowish macules on the soles of the feet (keratoderma blennorrhagica) and pustular and psoriatic lesions.
The numerous small oral ulcers—generally on the buccal mucosa, palate, and tongue—are indistinguishable from those of aphthous stomatitis and Behçet’s syndrome. Large erosions and a migratory stomatitis occasionally develop. Microscopic findings (epithelial ulceration with acute and chronic dermal inflammation) are also nonspecific. Consequently, consider the total clinical picture in making the diagnosis.
The cause of Reiter’s syndrome is unclear, but it may be related to the presence of the tissue antigen HLA-B27. Bacillary dysentery or a mycoplasmal infection may precipitate an attack, and there is an association with psoriasis and ankylosing spondylitis.
Treat patients initially with NSAIDs. Later, systemic corticosteroids may be required.
This condition may give rise to multifocal oral ulcers of variable size that contain necrotic debris in their craters. The neutropenia may result from a primary hematologic disorder, sepsis, or cytotoxic suppression of the bone marrow. The last is caused principally by chemotherapy for neoplastic disorders.
Oral lesions are especially prominent in patients who take methotrexate. Other drugs associated with agranulocytosis are aminopyrine and chloramphenicol; however, these are rarely used today because of their established toxicity. Neutropenia may also represent an allergic reaction to many medications, including penicillin, barbiturates, sulfonamides, and ß-histamine antagonists.
These lesions are not clinically distinguishable from any other form of punctate erosive stomatitis. Diagnosis is based on the medical and drug histories and on the results of a complete blood cell count. Lesions usually appear when the white blood cell (WBC) count falls below 2000/µL.
Cyclic neutropenia is rare and of unknown origin; it generally appears during childhood. Periodic eruptions of oral ulcers, usually of the gingiva, accompany a drop in the number of granulocytes; arthralgias and lymphadenitis may also develop. Healing occurs when the WBC count returns to normal, but the pattern is one of repeated exacerbations. Premature development of advanced periodontal disease is another oral manifestation of the impaired host defense.
ACUTE NECROTIZING ULCERATIVE GINGIVITIS
This severe form of gingivitis is marked by loss of the interdental papillae and free gingiva, leaving a gray pseudomembrane over a bleeding base (Figure 8). The clinical picture is virtually diagnostic. Acute necrotizing ulcerative gingivitis (ANUG) results from a combination of decreased host resistance and poor oral hygiene. This leads to invasion by normal oral anaerobic fusiform bacteria and spirochetes, especially Borrelia vincentii. Because of the distinctive clinical picture, microbiologic studies are rarely performed.
The symptoms of ANUG consist of pain, foul breath, metallic taste, and fever. Prescribe oral penicillin (500 mg qid for 7 to 10 days), oral rinses with 3% hydrogen peroxide, gingival curettage, and periodontal treatment.
Drug-induced lesions may appear as multiple small ulcers or as large, irregular areas of mucosal destruction of variable depth. Although they may be seen anywhere in the oral cavity, they have a predilection for the buccal mucosa and gingiva.
Chemotherapy-induced ulcerative stomatitis is produced either directly, by a cytotoxic effect on the oral mucosa, or secondarily, by myelosuppression. Virtually all the chemotherapeutic drugs, including antimetabolites, alkaloids, alkylating agents, and antibiotics, can cause oral ulcerations. Both HSV and Candida species have been isolated from such ulcers.11
Other drugs that may cause ulcerative stomatitis include the salicylates, NSAIDs, gold salts, and immunosuppressive agents. Within the last group, both the antimetabolite (azathioprine) and the fungal metabolite (cyclosporine) produce an erosive stomatitis. This is also true of penicillamine, which is used in rheumatoid disorders and scleroderma.
Among cardiac medications, captopril, an antihypertensive, can cause tongue ulcers, and procainamide, an antiarrhythmic, can produce the denuded bullous lesions that are characteristic of systemic lupus erythematosus. Penicillamine and gold can cause a similar reaction.
INFLAMMATORY BOWEL DISEASE
Ulcerative colitis and Crohn’s disease (regional enteritis) may produce lesions anywhere throughout the length of the alimentary tract—from the mouth to the rectum. In Crohn’s disease, the inflammatory process is more severe, with granuloma formation in the submucosal tissues.
In a review of 79 patients with oral manifestations of Crohn’s disease, Plauth and associates12 found that small ulcers, ulcerated fissures, angular cheilitis, and hyperplastic lesions preceded the intestinal symptoms in 60% of patients. The hyperplastic lesions (pyostomatitis vegetans) are pathognomonic of inflammatory bowel disease (Figure 9). Common sites of involvement were the lips, gingiva, and vestibular sulci. Remission of the oral lesions was achieved with systemic and topical corticosteroids.
Thornhill and co-workers13 reviewed 32 cases of pyostomatitis vegetans and reported that the gingiva and the labial and buccal mucosa are the most common sites. Typically, multiple pustules covered an area of hyperplastic mucosa. Direct immunofluorescence, which was performed in 50% of patients, showed only weak evidence of immune complexes.
I find that the oral manifestations are more severe in Crohn’s disease than in ulcerative colitis. In the latter, aphthous-like ulcers are the principal finding. A glossitis occurs in both forms of inflammatory bowel disease; depapillated and erythematous areas develop on the tongue because of folic acid deficiency.
Gold dental restorations can induce mucosal changes ranging from erythema to ulceration. This is believed to result from the slow production of gold salts, which may precipitate a contact allergy. The lesion is adjacent to the restoration; this aids in the diagnosis, since skin patch testing is not completely reliable. Healing occurs with the removal of the restoration.
The majority of traumatic ulcers have an identifiable cause, such as a carious tooth, an ill-fitting denture, a recent dental procedure, the ingestion of hot foods, or regional radiotherapy. Initially, there is a painful mucosal defect; over time, the margins of the lesion thicken, granulation tissue fills the crater, and the lesion becomes nontender. The buccal mucosa, the lower lip, and the lateral border of the tongue are primarily involved. All chronic oral ulcers require biopsy to rule out a malignancy, even in the presence of a likely cause, such as an adjacent broken tooth.
The so-called Riga’s ulcer (Riga-Fede disease) refers to traumatic ulcers of the lingual frenum in nursing infants. These ulcers are caused by neonatal teeth.
Often associated with trauma, eosinophilic ulcers are reactive lesions in the oral cavity that are deep and generally larger than 1.5 cm, with indurated borders. They may or may not be painful. As with other traumatic ulcers, they occur most commonly on the tongue, the lip, and the buccal mucosa.
Biopsy is essential to rule out carcinoma. Eosinophilic ulcers have a characteristic histologic appearance; microscopic examination reveals eosinophils, histiocytes, lymphocytes, and plasma cells, often with extension of the inflammatory infiltrate into muscle. Spontaneous healing occurs after weeks or months; topical or intralesional corticosteroids can shorten the interval.