Immunohistochemical features of 3,3',4,4'-tetrachloroazobenzene-induced rat gingival lesions.

Gingival lesions of squamous hyperplasia, cystic keratinizing hyperplasia (CKH), and squamous cell carcinoma (SCC) can be induced in rats treated by chronic gavage with 10-100 mg/kg 3,3',4,4'-tetrachloroazobenzene. We evaluated gingival squamous hyperplasia (GSH), CKH, and SCC for the immunohistochemical pattern of expression of carcinogenesis-associated markers. The 3 types of lesions and controls were stained with proliferation markers (proliferating cell nuclear antigen [PCNA] and cyclin-D1), tumor-suppressor markers (ß-catenin and mammary serine protease inhibitor [maspin]) and stroma-related markers (α-smooth muscle actin [SMA] and osteonectin/SPARC). The lesions had common immunohistochemical characteristics that differed in their expression patterns among the various diagnoses. PCNA and cyclin-D1 expression was higher in GSH, CKH, and SCC than in controls. The normal membranous expression of ß-catenin was lower in GSH, and almost absent in CKH and SCC. Maspin expression was similar in GSH and controls, whereas both CKH and SCC showed decreased expression. SMA and/or osteonectin/SPARC were seen in stromal cells in CKH and SCC. Collectively, there appears to be a progression from hyperplastic and cystic lesions toward malignancy based on the morphological changes, supported by the expression of carcinogenesis-associated proteins. The exact sequence of events leading to SCC remains to be defined in a time-dependent manner.

Gingival carcinogenicity in female Harlan Sprague-Dawley rats following two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.

We evaluated gingival toxicities induced by chronic exposure of female Harlan Sprague-Dawley rats to dioxin and dioxin-like compounds (DLCs) and compared them to similarly induced oral lesions reported in the literature. This investigation represents part of an ongoing initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and 2,3',4,4',5-pentachlorobiphenyl (PCB118); control animals received corn oil-acetone vehicle (99:1) alone. A full complement of tissues, including the palate with teeth, was examined microscopically. In the groups treated with TCDD and the mixtures of TCDD, PCB126, and PeCDF; PCB126 and 153; and PCB126 and 118, the incidences of gingival squamous hyperplasia increased significantly. Moreover, in the groups treated with TCDD, PCB126, and the mixture of PCB126 and 153, squamous cell carcinoma (SCC) in the oral cavity increased significantly. This investigation constitutes the first report documenting that chronic administration of dioxin-like PCBs can induce gingival SCC in rats. These results indicate that dioxin and DLCs target the gingiva of the oral cavity, in particular the junctional epithelium of molars.

Diffuse Large B-Cell Lymphoma of the Gingiva in a Patient on Long-Term Use of Methotrexate Being Treated for Psoriasis.

An 81-year-old male patient presented with a large gingival ulcer of 2 months' duration. He had been taking methotrexate, a potent anti-inflammatory/immunosuppressant, for the past 50 years to treat psoriasis. A biopsy revealed diffuse large B-cell lymphoma Epstein-Barr virus positive. Remission occurred after discontinuing the medication. Clinicians noting a non-healing ulcer in the mucosal or keratinized tissue of the oral cavity of a patient on immunosuppressants should perform a biopsy examination to rule out lymphoma or other malignancy.

The enhancing effect of excess retinol palmitate on induction of odontogenic tumors and inhibitory effect on squamous cell carcinoma of the gingiva in hamsters treated with N-methylnitrosourea.

The influence of excess retinol palmitate on induction of tumors in the oral region was examined histopathologically. Sixty-three weanling Syrian golden hamsters were divided into five groups and received either 0.2% N-methylnitrosourea (MNU) (1 mg/100 g body weight) or retinol palmitate (RP) (25,000 IU/100 g body weight) twice a week for 16 weeks, singly or in combination. Animals received RP intraperitoneally or intragastrically and then, 6 hours later, the animals received intragastric administration of MNU. To accelerate the cell activity of the incisal tooth buds, intentional disocclusion of the left upper and lower incisor of all hamsters was carried out by repeated cutting with cooled diamond disks to a level just above the inter-dental papilla twice a week for 12 weeks. The right incisors were left in occlusion. In all animals exposed to RP + MNU, while the induction of squamous cell carcinomas of the gingiva and forestomach were prevented, the notable findings were a significantly increased incidence of odontogenic tumors in cut incisal regions of the animals with intragastric administration of RP + MNU and an induction of maxillary neurogenic tumors. The incidence of MNU-induced disturbances in odontogenesis in the incisors was reduced but marked disturbances were increased. RP seemed to have opposite effects of prevention and enhancement for development of neoplastic changes in the oral region.

The effect of intraperitoneal N-methyl-N-nitrosourea on hamster palatal gingiva and intermolar mucosa.

Fifty 4- to 6-week-old male random-bred golden hamsters were injected intraperitoneally with a weight-related dose (12.5 mg/kg body weight) of N-methyl-N-nitrosourea (NMU) three times a week for 4 weeks. Groups of seven animals were killed 10, 16 and 22 weeks after the first injection. The palatal gingiva from six animals and the intermolar mucosa from 21 animals was examined. Seven male age-matched untreated control animals were killed at each period. Although all NMU-treated hamsters showed dysplastic and neoplastic changes similar to those in human oral squamous-cell carcinoma, other changes such as acantholytic dyskeratosis, invading cysts, duct-like structures and basaloid islands and cords were not. The extent and severity of the changes increased with time so that by 22 weeks there was extensive involvement of the palatal bone and marrow spaces, the molar periodontal ligament and the greater palatine neurovascular bundle by neoplastic epithelium. The invading epithelium was derived from the junctional, crevicular and palatal gingival and intermolar epithelium. The latent period for the crevicular and junctional epithelia was shorter than that for the palatal gingival and intermolar epithelium. The invasive changes from the latter epithelium were often preceded by exophytic changes such as epithelial projections, papillae and papillomas. Such changes were infrequent for the gingival, crevicular and junctional epithelia. The study shows that intraperitoneal NMU acts as a complete carcinogen on the palatal gingival and intermolar epithelium in hamsters.

Verrucous hyperplasia and verrucous carcinoma of the rat oral mucosa. Experimental oral carcinogenesis using 4-nitroquinoline 1-oxide.

Verrucous hyperplasia and carcinoma are recognized entities in the human pathology, but not documented experimentally. During application of the carcinogen 4-nitroquinoline 1-oxide to the oral cavity of rats three times a week for a maximum of 18 weeks an increasing frequency of verrucous hyperplasias and carcinomas were noted. The majority of the carcinomas were localized to the palate and 3/4 of these were verrucous carcinomas, with or without anaplastic transformation to infiltrating squamous cell carcinomas. The oral verrucous lesions have all the histological characteristics of their human counterparts. The present experimental study supports the idea that tobacco consumption may represent an important etiological factor in the development of human, oral verrucous carcinomas.

Histopathologic study of squamous cell carcinoma of the gingiva in edentulous and dentulous jaws of hamsters treated with N-methylnitrosourea.

Unilateral maxillary or mandibular molars were extracted from twenty-four, 25-day-old male syrian golden hamsters; 25 days after extraction, 20 received MNU intragastrically twice a week for 3 months. All animals were killed 1 month later. High degrees and incidence of invasion of gingival SCC were observed in dentulous jaws without functional occlusion, followed by dentulous jaws with functional occlusion and edentulous jaws. Invasion of carcinomas with extensive bone destruction was observed commonly in the gingiva of dentulous maxillary jaws without functional occlusion, but was scarcely observed in the gingiva of edentulous jaws. By analogy, disuse atrophy of the periodontium due to loss of functional occlusion may result in early deeper invasion, while loss of periodontal ligament due to tooth extraction and disappearance of so-called inner gingival epithelium may result in less invasive carcinomas.

Histological studies on early changes of the hamster gingival epithelium by N-nitrosomethylurea.

The effect of repeated intragastric administration of N-nitrosomethylurea on the molar gingival epithelium of the hamster was investigated both higtologically and histoautoradiographically. Thickening and downward proliferation of the gingival epithelium were evident from the second month of the treatment, in the attachment epithelium and interdental epithelium. Subsequently, the apical part of the crevicular epithelium, epithelium of the oral aspect of the gingiva, and the marginal crevicular epithelium thickened. About three months after the beginning of the administration, thickening, hyperkeratosis, and downward proliferation of the gingival epithelium were widespreas and proliferated epithelial cell nests were parakeratotic, often assuming a structure of keratotic cyst, which invaded the periodontium, accompanied with compressive resorption of the alveolar bone and involvement of bone marrows. Cellular atypia appeared three months after the first treatment, occasionally suggesting early malignancy. Epithelial proliferation was generally not accompanied with any distinct inflammatory change. In the autoradiographic analysis, it was clearly noticed that labeled cells had increased in each epithelial zone before the histological changes became evident- The results of the present experiment were discussed in reference to the pathogenesis of gingival carcinoma.