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Tissue-based genomic instability markers for predicting malignant transformation in oral leukoplakia and proliferative verrucous leukoplakia: a systematic review.

OBJECTIVES: Although several biomarkers have been described for predicting malignant transformation in oral leukoplakias (OLs) and proliferative verrucous leukoplakias (PVLs), no systematic review has comprehensively evaluated tissue-based genomic instability markers. This review aimed to evaluate the evidence for these markers and their potential role in biomarker panel development. METHODS: A systematic review across PubMed, Embase and Cochrane Library was performed to identify studies evaluating the differences in tissue-based genomic markers between OL and PVL patients with and without malignant transformation. RESULTS: 34 observational studies comprising 3,237 patients were included, and genomic aberrations were categorised into DNA-level, chromosomal, and gene-specific alterations. For studies on OLs, DNA-level and chromosomal markers for which individual studies reported associations with malignant transformation included aneuploidy, impaired DNA repair capacity, loss of heterozygosity, chromosomal instability, and copy number alterations. Multiple gene-specific alterations also showed associations (e.g., TP53, MKI67, FGFR1), but findings varied across studies. The genomic markers of PVLs differed substantially, with fewer consistent predictors found. No meta-analysis was performed as all included studies were observational. CONCLUSIONS: Genomic instability across multiple levels contributes to malignant transformation, and represents a promising biological framework for predicting malignant transformation for OLs. While no single marker reliably demonstrates sufficient predictive performance, the integration of complementary genomic alterations with clinical and histopathological risk factors may provide a basis for the development of robust multi-marker panels. Future prospective studies using standardised detection methods and multivariable prediction models are required before clinical implementation. SYSTEMATIC REVIEW REGISTRATION: identifier CRD42024585830.

carcinoma

Decoding protein signatures and protein interactions in oral potentially malignant disorders: a systematic review and network analysis.

BACKGROUND: Proteomic profiling offers thorough insights into protein structure and function, as well as it acts as an essential approach for analyzing molecular changes at the tissue level. However, because of the proteome's diversity and dynamic nature, biomarker discovery remains challenging. By combining proteomics with bioinformatics, the level of understanding in relation to molecular interactions and disease processes can be improved. Through an integrative approach, few limitations can be addressed, thereby promoting proteomic profiling for the discovery of new therapeutic targets and novel biomarkers for a variety of disorders. AIM: To identify differentially expressed protein markers and their key molecular pathways associated with Oral Potentially Malignant Disorders. METHODS: Systematic Review was conducted following the PRISMA guidelines and the protocol registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration ID number CRD42024557545. A comprehensive literature review was performed using electronic databases, yielding 12,797, studies from which 15 eligible articles were selected. The Newcastle-Ottawa Scale was used to assess the risk of bias. Vote counting was performed to identify proteins reported in more than one study. A bipartite network was constructed using Cytoscape to identify shared and disease-specific protein markers. Lesion-wise protein-protein interaction networks were generated using STRING and analysed in Cytoscape to identify highly interconnected hub proteins, and pathway enrichment analysis for these hubs was performed using Reactome. RESULTS: A total of fifteen studies (Leukoplakia (LK) - n = 1, Proliferative Verrucous Leukoplakia (PVL) - n = 2, Oral Submucous Fibrosis (OSMF) - n = 7, and Oral Lichen Planus (OLP) - n = 5) were included. The Newcastle-Ottawa Scale was used to evaluate methodological quality and the quality of studies included in this systematic review was high for 4 articles and moderate in the remaining 11. The most commonly employed technique was mass spectrometry. A total of 318 candidate proteins (LK - 14, PVL - 82, OSMF - 172, and OLP - 50) were identified across the oral potentially malignant disorders. Key markers identified through vote counting included ERO1A, NUCB1, RHOA, and IL36A for PVL; LUM, KRT1, KRT9, ALB, and VIM for OSMF; and ALB, LYZ, HP, HBB, and AMY1A for OLP. The bipartite network showed that OSMF and OLP shared the highest number of proteins, indicating the strongest overlap among lesions. Network analysis further highlighted distinct hub proteins for each lesion: for LK- AMY1A, AMY1B and APOA1; for PVL- CFL1, RHOA and CDC42; for OSMF- HSP90AA1, ENO1 and SERPINA1; and for OLP- HP, B2M, and ORM1. Lesion-specific pathway enrichment revealed that LK was associated with epithelial differentiation, PVL with oncogenic signaling, OSMF with stress-driven fibrosis, and OLP with immune-mediated inflammation. CONCLUSIONS: Proteomic expression offers insights into disease pathogenesis by identifying important molecular changes across OPMDs. However, the majority of biomarkers are still in the exploratory stage due to the considerable variation in lesion types, sample sources, proteomic techniques, and reporting systems. In order to create reliable and clinically applicable biomarkers, future studies should concentrate on combining multi-omics techniques with large-scale, standardized cohorts.

Humans

Comparative cytologic and histologic studies in oral leukoplakia.

Comparative analysis of cytologic and histologic results and clinical types of 201 oral leukoplakias has shown: 1) an agreement between cytologic and histologic results in 76.6% of all cases; 2) an occurrence of carcinoma in 32.9% of the erosive leukoplakias in 3.2% of the verrucous leukoplakias, and none in the leukoplakia simplex group; 3) a higher efficacy of cytology in detecting malignancy in the erosive leukoplakia group.

Carcinoma in Situ

Multimodal risk assessment for oral potentially malignant disorders: Integrating patient-centered and specimen-derived data.

BACKGROUND: Oral potentially malignant disorders exhibit heterogeneous malignant transformation risk that clinical approaches fail to adequately predict. Histopathologic dysplasia grading, the reference standard of risk assessment, is associated with poor interobserver reliability and limited prognostic discrimination. It is necessary to define other potential patient- and tissue-associated risk modifiers to improve patient-specific disease prediction. TYPES OF STUDIES REVIEWED: PubMed was queried for patient- and specimen-derived factors as they relate to oral cancer and oral potentially malignant disorders, with preference for systematic review and meta-analysis articles published within the past 5 years. When not available, guidelines from the American Cancer Society, National Cancer Institute, or other national organizations or the most recent best articles were referenced to support the data presented. RESULTS: Within patient-associated factors, validated measures of tobacco and alcohol exposure, clinical lesion characteristics, systemic health factors including metabolic syndrome components, comorbidity risk, and dental health indexes were found. Within specimen-derived data, tissue-based analyses encompassing histopathology and advanced molecular profiling (genomic, epigenomic, transcriptomic, spatial approaches), blood-based germline and somatic mutation analysis, and saliva-based microbiome characterization and inflammatory biomarker assessment were addressed. PRACTICAL IMPLICATIONS: Malignant transformation reflects intersecting patient and specimen risk pathways that affect each patient differently; no single modality captures this complexity. Realizing precision prognostication in oral precancer will require coordinated expansion and standardization of data collection across research groups. This review is intended to guide covariate selection for prospective study design, improve reproducibility, and ultimately enable the development of validated multimodal risk prediction tools for clinical deployment.

Humans

Transoral management of localized carcinoma of the oral cavity using the CO2 laser.

Since 1972 we have been cautiously exploring the use of CO2 laser in the management of carefully selected cases of localized carcinoma of the oral cavity. At the present time our experience is based on the treatment of 57 patients with cancer of the oral cavity. The CO2 laser has been found to be an indispensable tool in the transoral management of T1 carcinomas, multiple superficial carcinoma, extensive leukoplakia and verrucous carcinoma. The laser allows precise excision of the lesion and involved mucosa and provides and excellent specimen for histologic verification of the margins. The morbidity of laser excision is minimal, so that a tracheotomy is not needed and patients can almost always be discharged on the following day. (Follow-up data on those patients at risk for 30 months indicate excellent control rates).

Adult

Leukokeratosis nicotina glossi-smokers' tongue.

"Leukokeratosis nicotina glossi" or "smokers' tongue" is a homogeneous leukoplakia with evenly distributed pin-point hemispherical depressions. Histologically, there is a loss of glossal papillae, hyperkeratosis, acanthosis and the formation of large drop-shaped rete pegs with central clefting and occasional parakeratotic plugging. Mitotic activity and atypia are not marked and there is no evidence of Candida species infection. In some respects the lesion histologically resembles verrucous carcinoma but, unlike that condition, papillomatosis is not clinically noticeable and an invasive "leading edge" is not apparent. All but one of the subjects in which the lesion was seen were men, all had concurrent leukokeratosis nicotina palati and two gave histories of laryngeal carcinoma.

Adult

Oral florid papillomatosis (verrucous carcinoma).

1. Florid Papillomatosis (FP) seems to be another form of verrucous carcinoma. 2. Besides the mouth, FP can be found in the larynx, nose, genitalia, skin, etc. 3. FP would appear to be a carcinoma with a low degree of malignancy, and is locally aggressive. They do not cause generalized metastases and rarely metastasize locally. 4. In the mouth, the lesions, either single or multiple, usually occur in adult men. The most frequent sites are the buccal mucosa and the alveolar-gingival area. They develop on a healthy mucosa, or on preexisting lesions, namely, leukoplakia, atypical lichen, abrasive cheilitis and traumatic ulcers. FP may cause fistulas and jaw destruction. 5. Histologically, three stages can be recognized: type I, with acanthosis and papillomatosis, etc., type II, with the aspect of an in situ carcinoma, and type III, carcinoma-like in aspect but with some characteristics of FP. 6. Ten percent of the cases may develop an anaplastic carcinoma or may become associated with other types of carcinomas in other organs and near the area where the FP appeared. 7. Predisposing factors are the same as those for classical carcinomas (especially smoking and chewing tobacco or betel). FP may develop on preexisting lesions similar to those described for regular carcinomas. No virus has been isolated. Some authors believe FP is a precancerous condition; we think it is a cancer with a low degree of malignancy. 8. Treatment should be initiated with cytostatic drugs, especially methotrexate, followed by electrocoagulation, radium implantation and surgery. If the lesions are small in size, methotrexate is not required. If the lesions are large or there is bone destruction, surgery is the treatment of choice after methotrexate and sometimes high-voltage therapy with 60Co. 9. A cure rate of 75% can be obtained in properly treated cases.

Adolescent