Acute Necrotizing Ulcerative Gingivitis in Children With Cancer Michael.E.

Ryan, DO; Kenneth Hopkins, DDS, MS; Richard B. Wilbur, MD We reviewed the findings for 15 immunosuppressed children with cancer who had 18 episodes of acute necrotizing ulcerative gingivitis. Predisposing factors were then assessed for their influence on the course of infection. The nutritional status and oral hygiene of most patients were poor. Eleven of the 18 episodes involved the spontaneous exfoliation of primary or permanent teeth, and 16 of the 18 episodes were complicated by other infections. The infection completely cleared in only two of ten patients who were not in remission and persisted for more than 15 weeks or until death in all of the remaining patients with active disease. By contrast, all six episodes of infection during remission cleared within an average of 4 weeks. Among the many contributing factors, decreased host resistance, relapse, and neutropenia seemed to have the most negative influence on recovery from this severe form of gingivitis. (Am J Dis Child 1983;137:592-594).

Acute necrotizing ulcerative gingivitis (ANUG) is rare in healthy children. When caused by malnutrition, ANUG can respond dramatically therapy and nutritional support.1,2 When associated with cancer or its treatment, however, ANUG to antibiotic is often difficult to eradicate. The main reason for this difficulty is not entirely clear because so many predisposing factors may be involved: drug- or disease-related immunosuppression with neutropenia and previous concurrent and frequent infections; oral disease following irradiation or treatment with anthracyclines and other drugs8"9; and Candida superinfection, as well as poor oral hygiene, nutritional deficits, cigarette smoking, and psychologic factors.10"15 To determine which of these features most influence the development of and recovery from ANUG, we retrospectively assessed all patients with cancer and ANUG who were treated at St Jude's Children's Research Hospital, Memphis, between 1970 and 1980. PATIENTS AND METHODS A complete dental examination for alpatients with childhood cancers is part of the initial examination at this hospital. Follow-up examinations and therapy for dental abnormalities were provided for all patients with the diagnosis of ANUG. Acute necrotizing ulcerative gingivitis was

defined as an inflammatory disorder of the gingiva that produced a necrotic ulcerative destruction of the free margin, crest, or interdental papillae.2 The presence of a pseudomembrane was not considered essential for diagnosis, as it is not seen in all patients with ANUG and can be similar to oral lesions produced by myeloproliferative diseases.14 Charts of all patients with this diagnosis were reviewed for the mode of ANUG initial appearance, the number of infections before and after ANUG, culture and other laboratory results, nutritional status, state of the primary disease, history of radiation and drug therapy, therapy for ANUG, and clinical follow-up. Photographs of the mouth were available for almost all patients. No specific oral hygiene index was used. The degree of oral hygiene was merely noted as being excellent, good,fair,or poor. RESULTS A total of 15 patients had 18 episodes of ANUG (Table). Ten of the 15 patients were receiving induction therapy or were in relapse when ANUG occurred. The infection completely cleared in only two often patients who were not in remission and persisted for more than 15 weeks or until death in all of the remaining patients with active disease. Five of these ten patients died within one month of the diagnosis of ANUG. By contrast, all six episodes of ANUG during remission cleared within an average of 4V weeks. Three of the five patients who had ANUG during remission are still alive after eight to 14 years. During 11 of the 18 episodes of ANUG, primary or permanent teeth spontaneously exfoliated. The loss of primary teeth was premature, and in three instances, exfoliation prompted dental consultation at which time the diagnosis of ANUG was made. All exfoliated permanent teeth showed complete root development. Other initial signs and symptoms of ANUG varied, with fever being the most common finding (14 of 18 episodes), and the frequency of episodes was as follows:

In most instances, fever was attributed to other causes, as 16 of the 18 episodes were preceded or accompanied by upper respiratory tract infections (six patients), pneumonia (four patients), herpes simplex of the lips (four patients), herpes zoster (two patients), candidiasis of the oropharynx and esophagus (one patient), urinary tract infection (one patient), rectal abscess (one patient), and suppurative parotitis (one patient).

When ANUG developed, most children (ten of 15 patients) had active disease that was recently diagnosed (four patients), or they were in relapse (six patients with eight episodes of infection). Eight of these patients had acute leukemia, one had non-Hodgkin's lymphoma, and one had malignant histiocytosis. Their median age was TV2 years (age range, 1 year 3 months to YIV2 years). The five patients with ANUG during remission were older (median age, 17 years 3 months; age range, 3 years 10 months to 23 years 5 months): two had leukemia, one had lymphoma, and three had Hodgkin's disease. This small sample of 15 patients did not overly represent any of the malignant diseases treated at this center. The state of oral hygiene was poor to fair in ten of the 15 patients at the time of diagnosis of ANUG. None of the patients smoked cigarettes. Specific pathogens were not identified by routine cultures of the gingiva or blood. However, since cultures for anaerobes and stains for spirochetes were not always done, these pathogens could not be excluded in every case. The nutritional status of these 15 patients was described as good, but the weights of seven patients were less than the third percentile for their age. Of these seven patients, five died with recurrent malignant disease less than 30 days after the diagnosis of ANUG. And one died four months later with monomyelocytic leukemia in relapse and persistent ANUG. At the onset of ANUG, the 15 patients were receiving vincristine sulfate (12 patients), methotrexate (11 patients), prednisone (nine patients), cyclophosphamide (seven patients), and

cytarabine (cytosine arabinoside) (seven patients), or asparaginase, daunorubicin hydrochloride (daunomycin), or mercaptopurine (six patients each). Seven of the 15 patients had received radiation (1,745 to 3,750 rad) to the head or neck region as part of their treatment for Hodgkin's disease or acute leukemia. Therapy for ANUG during remission maintenance therapy included dbridement of necrotic tissue and good local dental hygiene thereafter. Penicillin G potassium was given orally, and all of these patients recovered within an average of 4V2 weeks (range, one to 13 weeks). Patients with active primary disease and ANUG received intravenous antibiotics, usually an aminoglycoside and a penicillinase resistant penicillin or cephalosporin, in addition to intensive local mouth care. In severe cases of ANUG, chemotherapy was often discontinued. The assessment of the main contributing factors to the slow recovery from ANUG showed relapse and neutropenia as important factors. In nine of 12 episodes, neutropenia was present at the onset of ANUG, and two of the three patients with neutrophil counts greater than 1,000 did become neutropenic during the next seven days. It should be noted that neutropenia was not as common in the group with ANUG and in remission of the underlying disease. Previous radiotherapy to the head or neck, different chemotherapy agents, oral candidiasis, and preceding viral infections were not significantly related to clearing of ANUG. COMMENT Acute necrotizing ulcerative gingivitis is a specific type of gingivitis that has been recognized for centuries.2"613 Most investigators believe the cause of ANUG is complex with predisposing conditions, such as malnutrition and poor oral hygiene, causing physical debilitation and decreased host resistance which allow normal oral flora to become synergistic pathogens. Acute necrotizing ulcerative gingivitis frequently occurs in an epidemic pattern, although bacteria are no longer suspected as the primary cause. Cancer, concurrent infections, and immunosuppressive therapy sharply decrease host defenses and increase the risk of ANUG.3"7 Thus, it is not surprising

that we had 18 cases of ANUG among a large pediatrie cancer population. Differentiating ANUG from other types of oral pathologic conditions is not difficult. The necrotic ulcrations of the free margin, crest, or interdental papillae are pathognomonic for ANUG as long as the process has not extended to other areas of the mucous membrane, as seen in diffuse gangrenous stomatitis.1 When alveolar bone is exposed or the facial tissue is destroyed, the diagnosis is noma or cancrum oris.11,1416 On rare occasions, the lesions spread to the soft palate and tonsillar areas causing Vincent's angina.16"19 None of our patients' conditions progressed to these more severe forms. Radiotherapy and specific chemotherapeutic agents were nonspecific contributors to the problem of ANUG. Chemotherapeutic agents are known to be toxic to the oral mucosa, producing painful, shallow, white patches with red borders located on the gingivae, buccal mucosa, palate, and pharynx Methotrexate was the most used agent (11 of 15 patients) that has substantial oral toxicity, although about half of the patients received anthracyclines which are also known to induce severe stomatitis, mucositis, and gingivitis. We emphasize that most patients who had ANUG were in relapse and not expected to survive much longer. None of these patients died as a result of ANUG. Relapse and neutropenia were related to poor clearing of ANUG. This is also true for most other bacterial infections in the immunocompromised host. The neutropenia may be both a natural consequence of the malignant disease and a result of the chemotherapy. Typically, ANUG is preceded by A severe infection elsewhere and is another indication of diminishing immune defenses in the child with activemalignant disease. Poor oral hygiene was noted in two thirds of this group of patients with

ANUG. Since the oropharynx is a major source and pathway of infection, careful oral hygiene should be stressed. Most authorities recommend brushing with a soft brush, flossing and using antiseptic mouth wash after each meal, and periodontal care for patients with gum disease.20 For patients in remission, good oral hygiene and oral penicillin should be adequate therapy. For patients with cancer who are in relapse, broad-spectrum antibiotics given for systemic effects are indicated. Antineoplastic therapy may have to be suspended until the infection has subsided.