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PubMed2026

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↗

PubMed2026

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↗

PubMed2007

Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: a follow-up study based in a Taiwanese hospital.

BACKGROUND: It is generally accepted that the development of cancer in the oral mucosa is preceded by an identifiable non-invasive precursor lesion. The aim of this follow-up study was to estimate the rate and the time to transformation in a group of patients from southern Taiwan with potentially malignant oral epithelial lesions. METHODS: The follow-up time is defined as the duration between the onset of the initial diagnosis and the occurrence of confirmed oral cancer. A total of 1458 patients with histological diagnoses of various pre-malignant oral lesions were followed up between 1991 and 2001. The average age at initial diagnosis was 47.5 years. The histological diagnoses were divided into six categories: epithelial dysplasia with hyperkeratosis/epithelial hyperplasia (8.85%); epithelial dysplasia with submucous fibrosis (2.54%); submucous fibrosis (27.57%); hyperkeratosis/epithelial hyperplasia (29.01%); lichen planus (9.80%) and verrucous hyperplasia (22.22%). RESULTS: Within the cohort of 1458 patients, 44 patients progressed to oral cancer in the same site as the initial lesions with an overall transformation rate of 3.02% and a mean follow-up time of 42.64 months. Eight of the 166 patients with dysplastic lesions and 15 of 423 patients with hyperkeratosis/epithelial hyperplasia progressed to malignancy. The other patients with malignant transformation originated from various pre-cancerous oral lesions and conditions (submucous fibrosis, eight of 402; lichen planus, three of 143; verrucous hyperplasia, 10 of 324). CONCLUSION: These results indicate that patients with pre-malignant oral lesions need long-term follow up.

Adolescent↗

PubMed2022

Krüppel-like factor 5 promotes the progression of oral squamous cell carcinoma via the baculoviral IAP repeat containing 5 gene.

BACKGROUND: Krüppel-like factor 5 (KLF5) is highly expressed in a variety of tumors, and our study aimed to investigate the role of KLF5 in oral squamous cell carcinoma (OSCC). METHODS: To explore the differential expression of KLF5, next-generation sequencing (NGS) and further analyses were conducted in paired premalignant and tumor tissues and adjacent normal mucosa. We then analyzed the mRNA expression data from The Cancer Genome Atlas (TCGA) and performed gene set enrichment analysis (GSEA) to predict the function of KLF5. Small interfering RNA (siRNA) targeting KLF5 was used to knock down its expression in cells and further evaluate the changes in cell apoptosis, proliferation, and migration. We predicted whether baculoviral inhibitor of apoptosis protein (IAP) repeat containing 5 (BIRC5) was the potential target gene of KLF5 via the NCBI and JASPAR databases. Furthermore, we analyzed BIRC5 expression after KLF5 knockdown and explored its function in athymic BALB/c nude mice. RESULTS: KLF5 expression in clinical samples gradually increased from normal mucosa tissues to premalignant and then to OSCC tissues. Analysis of TCGA data and GSEA also suggested that KLF5 was expressed at higher levels in OSCC and involved apoptosis and the protein 53 (P53), transforming growth factor-β (TGF-β), and wingless/integrated (Wnt) signaling pathways. Cell apoptosis was promoted, whereas proliferation and migration were inhibited after KLF5 knockdown. Furthermore, we found KLF5 transcription binding sites on the BIRC5 promoter and BIRC5 expression was inhibited after suppressing KLF5 in vitro and in vivo. CONCLUSIONS: Our findings indicate that KLF5 promotes the development of OSCC via BIRC5, and could be a potential diagnostic and therapeutic target for OSCC.

Krüppel-like factor 5 (KLF5)↗

PubMed2026

ceRNA network of lncRNAs and mRNAs in OSF-to-OSCC progression: Diagnostic biomarkers and functional pathways.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic potentially malignant disorder that can progress to oral squamous cell carcinoma (OSCC). Although dysregulated non-coding RNAs have been implicated in oral carcinogenesis, the competing endogenous RNA (ceRNA)-mediated regulatory mechanisms underlying OSF-to-OSCC progression remain poorly understood. This study aimed to identify candidate regulatory molecules and construct a putative lncRNA-miRNA-mRNA network associated with malignant transformation. METHODS: Publicly available microarray datasets (GSE117973 and GSE125866) were analyzed to identify differentially expressed genes between OSF and OSCC. Differentially expressed transcripts were classified into mRNAs and lncRNAs based on public transcript annotations. Highly correlated lncRNA-mRNA pairs were identified using Pearson correlation analysis and integrated with multiMiR-supported miRNA-mRNA interactions obtained from public databases to construct a putative ceRNA regulatory network. Functional characterization focused on apoptosis, epithelial-mesenchymal transition (EMT), and immune checkpoint-related pathways. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance, and selected biomarkers were externally validated using The Cancer Genome Atlas (TCGA) OSCC cohort. RESULTS: Integrated transcriptomic analysis identified several dysregulated mRNAs and lncRNAs associated with OSF-to-OSCC progression. Network analysis highlighted TBC1D3B, RREB1, TEAD3, SREBF1, TMEM41B, FOXK2, and KIAA1958 as prominent hub genes within the putative regulatory network. Functional analyses demonstrated significant associations with apoptosis-, EMT-, and immune checkpoint-related genes, suggesting potential involvement in multiple biological processes contributing to malignant transformation. Several hub genes exhibited strong diagnostic performance, with ROC analysis yielding AUC values ranging from 0.891 to 1.000, indicating excellent discrimination between OSF and OSCC samples. External validation using TCGA further supported the relevance of the identified biomarkers in OSCC. CONCLUSIONS: This study provides a comprehensive transcriptomic framework describing putative lncRNA-miRNA-mRNA regulatory interactions associated with OSF progression to OSCC. The identified hub genes and regulatory networks represent candidate biomarkers for early detection and provide a foundation for future mechanistic and experimental validation. As the proposed ceRNA interactions are computationally inferred, further biological validation is required before clinical application.

RNA, Long Noncoding↗

PubMed2002

The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients.

BACKGROUND: Although oral lichen planus (OLP) is a relatively common disorder, reports comprising large numbers of patients with the disease are lacking in the dermatology literature. OBJECTIVE AND METHODS: The purpose of this investigation was to describe the clinical characteristics of 723 patients with biopsy-proven OLP who were followed up from 6 months to 8 years (mean, 4.5 years). RESULTS: Of the 723 patients, 75% were women and 25% men. The erosive form of the disease was the predominant type in 40% of patients at initial presentation, and symptoms were present in the majority of patients with all forms of the disease. Isolated gingival lichen planus was observed in 8.6% of patients. Precipitating factors that resulted in an exacerbation of the disease were frequently noted and included stress, foods, dental procedures, systemic illness, and poor oral hygiene. In 195 patients prospectively screened, no liver abnormalities or antibodies to hepatitis B or C were detected. Oral squamous cell carcinoma developed in 6 patients (0.8%) at sites previously diagnosed by clinical examination as erosive or erythematous lichen planus. CONCLUSIONS: Patients with OLP usually display lesions with distinctive clinical morphology and characteristic distribution but may also present with a confusing array of forms and patterns mimicking other diseases. Because patients with OLP may be at an increased risk for the development of squamous cell carcinoma, periodic follow-up is mandatory to detect malignant transformation. Routine screening of American patients with OLP for hepatitis C and other liver abnormalities does not appear to be warranted as in Italian and Japanese patients with OLP.

Adolescent↗

PubMed2004

Recalcitrant osteomyelitis following tooth extraction in a case of malignant osteopetrosis.

Malignant osteopetrosis generally begins in utero and often results in stillbirth. Besides, failure to thrive, increased bone fragility resulting in frequent fractures and recurrent bone infections are the other characteristic features. Infections after tooth extraction and fracture of the sclerotic bone following mild trauma are serious complications, as these ordinarily common problems are very difficult to treat in such patients. Poor bone vascularisation and reduced local defences prolong the defensive response. A rare case of malignant osteopetrosis in a 19-year-old girl, who presented with the complication of osteomyelitis of the mandible following tooth extraction, is presented. The case is of interest for two reasons: it is very rare for a case of malignant osteopetrosis to survive until adulthood and to be aware of the potential dental and oral complications of the disorder.

Adult↗

PubMed1996

Studies of the inflammatory process and malignant potential of oral mucosal lichen planus.

Oral mucosal lichen planus (OMLP) is a well recognized mucosal disease with unknown aetiology. Considerable controversy exists as to whether OMLP is intrinsically premalignant, or if the disorder facilitates the development of oral mucosal squamous cell carcinoma (OMSCC) by external factors. The aim of the present studies was to investigate the expression of c-erbB-2 protein in the keratinocytes of the initial biopsies of oral mucosal disorders diagnosed as OMLP with no evidence of epithelial dysplasia and to compare the results with the expression of c-erbB-2 protein in subsequent biopsies obtained from the same patients. These results were compared with the findings from another 26 biopsies from patients with OMLP and control groups (patients with dysplasia with no evidence of OMLP, patients with OMSCC with no evidence of OMLP and normal oral mucosa). The expression of the c-erbB-2 protein was evaluated by immunohistochemical staining of the gene product with the avidin-biotin-complex method using both fresh frozen and paraffin-embedded tissue sections. Five of the initial biopsies from patients with OMLP expressed the c-erbB-2 protein and one did not. None of the OMLP cases that subsequently showed evidence of dysplasia expressed the c-erbB-2 protein and of the OMSCC specimens from the patients with OMLP, 2 were negative and 1 expressed c-erbB-2 protein. Within the other group of OMLP specimens 3 (3/26) were negative for c-erbB-2 staining. The specimens from the control groups all expressed the c-erbB-2 protein. The results indicated the probability of the absence of c-erbB-2 staining being an indication of a potential for neoplastic transformation in OMLP with dysplastic changes.

Carcinoma, Squamous Cell↗

PubMed2002

Mast cell/T cell interactions in oral lichen planus.

Lichen planus is a disorder characterized by lesions of the skin and oral mucous membranes. Although many patients have involvement of both skin and oral mucosa at some stage during the progress of the disease, a larger group has oral involvement alone. It has been reported that oral lichen planus (OLP) affects one to two percent of the general population and has the potential for malignant transformation in some cases (1, 2). Like many chronic inflammatory skin diseases, it often persists for many years. Numerous disorders may be associated with OLP such as graft-vs.-host disease and Hepatitis C virus infection (3), however, it is unclear how such diverse influences elicit the disease and indeed whether they are identical to idiopathic OLP. Available evidence supports the view that OLP is a cell-mediated immunological response to an induced antigenic change in the mucosa (4-6). Studies of the immunopathogenesis of OLP aim to provide specific novel treatments as well as contributing to our understanding of other cell-mediated inflammatory diseases. In this paper, the interactions between mast cells and T cells are explored from the standpoint of immune regulation. From these data, a unifying hypothesis for the immunopathogenesis of OLP is then developed and presented.

Antigens↗

PubMed1996

Phase II trial of all-trans retinoic acid in metastatic non-small cell lung cancer.

The toxicity and marginal effectiveness of cytotoxic chemotherapy in metastatic non-small cell lung cancer (NSCLC) necessitates the search for new agents. Preliminary data in lung cancer and other malignant and premalignant disorders have identified retinoid compounds as potentially useful antitumor agents. Twenty-eight patients with metastatic NSCLC were treated with oral all-trans retinoic acid in a phase II trial. The study population consisted of patients with excellent performance status and minimal weight loss. Toxicities were generally mild and included cutaneous effects, headache, and myalgia. A significant number of patients developed elevations of hepatic transaminases or hyperlipidemia and 3 patients had treatment-related leukocytosis. Two patients (8%) achieved a partial response, and 1 had a mixed response. The duration of remission in the 2 responders was 7 and 13 months and the median survival of all patients 7 months. Therefore, all-trans retinoic acid has minimal activity as a single agent in NSCLC but warrants further study in combination with biological agents and chemotherapy.

Adult↗

PubMed2005

Premalignant nature of oral lichen planus.

The issue as to whether oral lichen planus is a premalignant disorder is still controversial. This study aimed to examine oral malignancies associated with oral lichen planus and to investigate whether oral lichen planus has an intrinsic malignant potential or whether there are also contributing external risk factors. A retrospective cohort study in 200 Caucasian patients with oral lichen planus was conducted between 1991 and 2003. Aspects such as sex, age, clinical variant, affected anatomical sites, duration of the disease, histopathology, prior immunosuppressive treatment, exposure to potential carcinogens and other concomitant diseases were examined. Histopathological examination was repeated during the follow-up if a malignancy was suspected. Three (1.5%) of the 200 patients developed an oral squamous cell carcinoma at the same site following the initial diagnosis of oral lichen planus after a period of 3-6 years (mean 4.3 years). Contributing external risk factors were also noted in two of the three patients (smoking for 20 years and systemic immunosuppressive treatment for 2 years). The exact incidence of malignant transformation is difficult to establish, because of the low number of patients and because of the possible contribution of external risk factors, which may be relevant in oral malignancy.

Adult↗

PubMed2005

The role of the dental team in preventing and diagnosing cancer: 5. Alcohol and the role of the dentist in alcohol cessation.

Alcohol use contributes to many health disorders and social problems which may affect both the individual and the community, and is a major risk factor for oral cancer and potentially malignant lesions - leukoplakia and erythroplakia. Counselling by doctors and dentists can increase users' motivation to stop alcohol use but is not often applied in a systematic or frequent manner to people presenting with potentially malignant oral lesions. This paper makes recommendations for interventions by health professionals to encourage and aid cessation of alcohol use as a part of prevention of oral cancer.

Alcohol Drinking↗

PubMed1992

Oral contraceptives and risk of benign proliferative epithelial disorders of the breast.

In a case-control study conducted in Adelaide, South Australia, we investigated the hypothesis that use of oral contraceptives is associated with increased risk of benign proliferative epithelial disorders (BPED) of the breast, conditions strongly associated with increased risk of breast cancer and thought to have pre-malignant potential. The study was restricted to women with no prior history of breast biopsy, and involved 383 cases of biopsy-confirmed BPED, 192 controls whose biopsy did not show epithelial proliferation, and 383 unbiopsied community controls individually matched to cases by age and socio-economic grading of area of residence. When cases were compared with community controls, the adjusted odds ratio (OR) for the association between ever-use of oral contraceptives and risk of BPED was 1.1 (95% CI 0.7 to 1.7), while when cases were compared with biopsy controls, the adjusted OR was 0.9 (95% CI 0.5 to 1.5). There was little variation in risk of BPED with total duration of use of oral contraceptives, and with duration of use before first pregnancy, while current users had a statistically significant 60% reduction in risk, irrespective of the control group used for comparative purposes. Also, there was little variation in risk with years since first and last use of oral contraceptives, and there was no trend in the association between ever-use of oral contraceptives and risk of BPED by degree of cytological atypia.

Adult↗

PubMed1978

[Precancerous skin lesions in the aged (author's transl)].

The term "precancerous" needs a new definition since it includes still malignant diseases like Morbus Paget of the nipple, Morbus Bowen and Erythroplasie Queyrat. The degree of malignancy of these disorders is analyzed. Precancerous conditions in the sense of benignant disorders which necessarily develop into malignant tumors are Melanosis circumscripta praeblastomatosa Dubreuilh and actinic keratoses. Potential precanceroses may be X-ray-atrophy, Leukoplakia and oral papillomatosis. Some actinic, chemic and cytostatic cancerogens are mentioned. Reference is made to the diagnosis, differential diagnosis, prognosis and treatment of precancerous skin lesions. The problem of potential malignancy of nevi is considered in detail. Prevention of cancer needs regular careful clinical control of skin and mucous membranes at least after the 50th year of life.

Age Factors↗

PubMed1994

Herpes simplex virus and human papillomavirus infections of the oral cavity.

Herpes simplex virus and human papillomavirus are epitheliotrophic viruses common to the oral cavity. They produce acute and chronic disorders of oral mucosa of interest to the dermatologist. Most of these lesions are benign in nature. However, both viruses are harbored latently, and their malignant potential remains to be defined.

Adult↗

PubMed2006

[White sponge naevus. Report of a family with respect to histopathologic, cytopathologic and DNA-cytometric aspects].

The white sponge naevus is a rare benign, hereditary autosomal dominant disorder of the mucosa. The oral mucosa is most often affected, but vaginal and anal mucosal surfaces may also be involved. Clinically, a whitish-grey, ragged, and folded surface that has no clear demarcation and appears sponge-like is characteristic, often creating problems in differential diagnosis. A potential risk for malignant transformation of white sponge naevus lesions has not been reported. The therapy for this benign hereditary disorder is unknown, however does not appear to be necessary. In the present report of a family with known white sponge naevus in three different generations, clinical, histopathologic, cytopathologic, DNA-cytomertric, and genetic aspects are described and discussed.

Adolescent↗

PubMed2000

Toxic epidermal necrolysis associated with acetaminophen ingestion.

OBJECTIVE: To report a case of toxic epidermal necrolysis (TEN) associated with acetaminophen ingestion. SUMMARY: A seven-year-old girl developed TEN after acetaminophen ingestion. The diagnosis was based on clinical evaluation and skin biopsy. A later acetaminophen challenge, undertaken by an allergist who questioned the diagnosis, resulted in a similar skin reaction. DISCUSSION: TEN is a severe disease with a high mortality rate. TEN may be either idiopathic or associated with several clinical conditions, such as viral infections, autoimmune disorders, malignancy, and drug hypersensitivity. Because of the rarity of its association with acetaminophen, the diagnosis in our patient was questioned by an allergist who performed an oral acetaminophen rechallenge test despite the potential risk. This caused a severe skin reaction that required rehospitalization. CONCLUSIONS: TEN can be caused by over-the-counter medications such as acetaminophen. Rechallenge with the causative drug carries a risk of severe complications and should be avoided.

Acetaminophen↗

PubMed1996

Oral submucous fibrosis. A review.

Oral submucous fibrosis (OSF) affects an estimated 2.5 million people, mostly in the Indian subcontinent. Limitation of oral opening resulting in difficulty in eating is the main presenting feature. Although nutritional deficiencies and immunological processes may play a part in the pathogenesis, the available epidemiological evidence indicates that chewing betel quid (containing areca nut, tobacco, slaked lime or other species) is an important risk factor for OSF. Genetically determined susceptibility could explain why only a small fraction of those using betel quid develop the disease. In OSF there is an incidence of oral cancer of 7.6 per cent for a median 10-year follow-up period. Risk markers for malignant transformation in OSF include epithelial dysplasia, silver binding nucleolar organizer region counts, and sister-chromatid exchange frequencies; p53 tumour suppressor gene mutations may be involved in these potentially malignant changes.

Areca↗