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Zhu L, Ou L, Yang Y, Zhao D, Liu B, Liu R, Liu O, Feng H. A Bibliometric and Visualised Analysis of Proliferative Verrucous Leucoplakia From 2003 to 2023. Int Dent J 2025; 75:333-344. [PMID: 39043528 PMCID: PMC11806304 DOI: 10.1016/j.identj.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/14/2024] [Accepted: 07/01/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Proliferative verrucous leucoplakia (PVL) is a rare but slow-growing, aggressive leucoplakia lesion associated with the highest malignant transformation rate in oral potentially malignant disorders (OPMDs). With increasing attention paid to PVL, it is urgent for us to analyse and summarise the publications globally using comprehensive bibliometric studies to help researchers propose possible future research directions and guide them to further conduct relevant studies in the domain. OBJECTIVES The purpose of the study was to evaluate global academic productivity, impact, and collaboration of potentially malignant oral disorder PVL utilising bibliometrics based on annual number of publications, countries and regions, institution, authors, journals, citations and co-occurrences of author keywords over the last 20 years. METHODS This study searched publications pertaining to proliferative verrucous leucoplakia in the Web of Science Core Collection, spanning from 2003 to 2023. Utilizing VOSviewer, R software, Bibliometric online analysis platform, CiteSpace software, and Microsoft Excel, we conducted a bibliometric and visualised analysis of PVL. RESULTS The quantity of pertinent publications in this research domain displays a fluctuating but overall upward trend. In aggregate, there are 148 articles and 61 reviews, encompassing research contributions from 44 countries, 45 institutions, and involving 831 authors. Among these publications, the USA, Spain, and UK emerged as the predominant contributing nations. Predominantly, articles found their publication venue in "Pathology Research and Practice." Notably, the author with the highest number of publications and most influence is Warnakulasuriya S. The top 3 keywords include "Proliferative Verrucous Leucoplakia," "Squamous-Cell Carcinoma," "Oral Leucoplakia," and "Potentially Malignant Disorders." CONCLUSION In this investigation, statistical analysis and network visualisation were conducted to reveal the research progress, trends, and trending topics on PVL via a thorough bibliometric analysis. We found that current publications comprise mainly case reports, there is a significant research need to explore the molecular mechanisms, specific diagnostic criteria, and effective management options for PVL. Our work should serve as a key reference and a directional guide for future research in this domain.
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Affiliation(s)
- Long Zhu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Centre of Oral Care & Hunan Clinical Research Centre of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxillofacial and Regenerative Medicine & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Lijia Ou
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Centre of Oral Care & Hunan Clinical Research Centre of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxillofacial and Regenerative Medicine & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yang Yang
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Centre of Oral Care & Hunan Clinical Research Centre of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxillofacial and Regenerative Medicine & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Danwei Zhao
- Changsha Stomatological Hospital, Changsha, Hunan, China
| | - Binjie Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Centre of Oral Care & Hunan Clinical Research Centre of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxillofacial and Regenerative Medicine & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Rui Liu
- Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ousheng Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Centre of Oral Care & Hunan Clinical Research Centre of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxillofacial and Regenerative Medicine & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Hui Feng
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Centre of Oral Care & Hunan Clinical Research Centre of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxillofacial and Regenerative Medicine & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, Hunan, China.
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Villa A, Lodolo M, Ha P. Oncological Outcomes of Patients With Oral Potentially Malignant Disorders. JAMA Otolaryngol Head Neck Surg 2025; 151:65-71. [PMID: 39570632 PMCID: PMC11583019 DOI: 10.1001/jamaoto.2024.3719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/03/2024] [Indexed: 11/22/2024]
Abstract
Importance Understanding the clinical course and malignant transformation rate of oral potentially malignant disorders (OPMDs)-including oral leukoplakia, oral erythroplakia, oral submucous fibrosis, and oral lichen planus-is crucial for early detection and improved survival rates in patients with oral cancer. Objective To evaluate the progression of oral cancer from OPMDs using a large US electronic medical database. Design, Setting, and Participants This retrospective cohort study used data from the University of California, San Francisco's PatientExploreR database between January 1973 and March 2024. Patients with oral leukoplakia, oral erythroplakia, oral submucous fibrosis, and oral lichen planus were identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes and keywords. Demographics, tobacco and alcohol use, HIV status, and other known risk factors for oral cancer were recorded to identify factors associated with malignant transformation. Logistic regression and descriptive analyses were used. Exposure Diagnosis of oral leukoplakia, oral erythroplakia, oral submucous fibrosis, or oral lichen planus. Main Outcomes and Measures Incidence of oral cancer, malignant transformation rate, median time to progression, and associations between demographics and risk factors and the development of oral cancer. Results Among 4 225 251 individuals in the database, 4371 were diagnosed with oral cancer (median [IQR] age, 63 [53-71] years; 2610 [59.9%] male; 0.1% of the cohort), and 110 (2.5%) had a preceding OPMD. Oral leukoplakia was found in 1124 patients, with 94 (8.4%) undergoing malignant transformation (median [IQR] time to progression, 25 [7-129] months). HIV-positive patients with oral leukoplakia were more likely to develop oral cancer (odds ratio, 3.80; 95% CI, 1.35-10.70). Of 22 patients with oral erythroplakia, 11 (50.0%) developed oral cancer (median [IQR] time to progression, 3.7 [0.2-334] months). Those who smoked tobacco with oral erythroplakia showed a higher malignant transformation rate (odds ratio, 3.75; 95% CI, 0.54-26.05). Of the 78 patients with oral submucous fibrosis, 4 (5.1%) underwent malignant transformation (median [IQR] time to progression, 36 [36-48] months). Only 1 patient with oral lichen planus developed oral cancer after 5 years. Conclusions and Relevance This cohort study showed that OPMDs have notable but varying propensities to progress to oral cancer. Early detection and monitoring of OPMDs are crucial for improving patient outcomes. However, the risk, etiopathogenesis, and clinical presentation vary for each OPMD and should, therefore, be considered distinct diseases.
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Affiliation(s)
- Alessandro Villa
- Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco
- Oral Medicine, Oral Oncology and Dentistry, Miami Cancer Institute, Baptist Health South Florida, Miami
| | - Michele Lodolo
- Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco
| | - Patrick Ha
- Department of Otolaryngology–Head and Neck Surgery, University of California, San Francisco
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Zhang Y, Zhang X, Qin Z, Yan J, Li B. Prognostic nomogram for proliferative verrucous leukoplakia. J Dent Sci 2025; 20:238-247. [PMID: 39873058 PMCID: PMC11762630 DOI: 10.1016/j.jds.2024.07.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/30/2024] [Indexed: 01/30/2025] Open
Abstract
Background Proliferative verrucous leukoplakia (PVL) is a special type of leukoplakia characterized by high rate of malignant transformation into oral squamous cell carcinoma (OSCC). This study aimed to analyze the canceration risk and prognostic factors of PVL and establish effective diagnostic and prognostic predictive models. Materials and methods A total of 467 patients were enrolled, including 170 cases of PVL. The independent risk and prognostic factors of PVL were analyzed by univariable and multivariable logistic regression. Nomogram models were constructed to predict the canceration risk and prognosis of PVL. The predictive power was evaluated by Hosmer-Lemeshow test, receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis. Results Multivariable logistic regression analyses identified that canceration risk factors of PVL included sex, lesion sites, clinical presentation, non-smoker and oral epithelial dysplasia (OED). The independent prognostic factors of PVL were sex, clinical presentation, local irritants and OED. Diagnosis and prognostic nomogram models were constructed. The areas under the ROC curve were 0.945 and 0.893, respectively. The calibration plots showed strong agreement between the prediction and observation. Decision curve analysis indicated that the models provided significant clinical benefits for patients. Conclusion Our study established and validated the diagnosis and prognostic predictive nomogram models, which were accurate to predict the canceration risk and prognostic factors of PVL, providing individualized clinical decisions for clinical work.
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Affiliation(s)
- Yanning Zhang
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China
- Laboratory of Stomatology Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, PR China
| | - Xinning Zhang
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), PR China
| | - Zhiming Qin
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), PR China
| | - Jing Yan
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China
| | - Binbin Li
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), PR China
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Gabusi A, Gissi DB, Querzoli G, Sangiovanni A, Rossi R, Lucchi E, Tarsitano A, Montebugnoli L, Foschini MP, Morandi L. DNA methylation analysis from oral brushing reveals a field cancerization effect in proliferative verrucous leukoplakia. Pathologica 2024; 116:368-378. [PMID: 39748722 DOI: 10.32074/1591-951x-n838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 12/06/2024] [Indexed: 01/04/2025] Open
Abstract
Objectives The aim of the present study was to analyze the methylation status in patients who presented with an Oral Squamous Cell Carcinoma (OSCC) concomitantly with multifocal Proliferative Verrucous Leukoplakia (PVL)(PVL-OSCC). Methods Nine patients with OSCC and concomitant PVL lesions were selected. Two brushing samples were collected simultaneously from OSCC and PVL lesions in contralateral mucosa from each patient. 15 genes (272 CpGs) were used to compare methylation profiles of PVL-OSCC and paired OSCC. CpGs with a methylation level superimposable between PVL-OSCC and contralateral OSCC were selected for a comparative analysis between PVL-OSCC, 8 PVL patients with no history of OSCC (PVL) and 23 healthy donors. Samples were also tested using an algorithm that was recently validated for epigenetic alterations in OSCC. Results 220/272 CpGs islands (80%) showed a superimposable methylation level in OSCC and in PVL-OSCC. 10 genes (88 CpGs) and in particular PARP15 and ITGA4 (100% of the studied CpGs) were able to stratify PVL-OSCC from PVL and healthy donors. 3/4 (75%) PVL-OSCC patients with a "positive" algorithm score developed second neoplastic events compared to only 1/5 (20%) patients with a "negative" score. Conclusions The present study provides evidence that PVL shares an aberrant methylation profile with contralateral OSCC. In agreement with the theory of field cancerization, our data point towards the potential role of epigenetics in patients at risk of developing multiple neoplastic events.
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Affiliation(s)
- Andrea Gabusi
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Davide Bartolomeo Gissi
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Giulia Querzoli
- Section of Anatomic Pathology S. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Asia Sangiovanni
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Roberto Rossi
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Elisabetta Lucchi
- Oral and Maxillofacial Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Achille Tarsitano
- Oral and Maxillofacial Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
- Department of Biomedical and Neuromotor Sciences, Section of Maxillo-facial Surgery at Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy
| | - Lucio Montebugnoli
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Maria Pia Foschini
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology at Bellaria Hospital, University of Bologna, Bologna, Italy
| | - Luca Morandi
- Functional and Molecular Neuroimaging Unit, Bellaria Hospital, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
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Farah CS, Shearston K, Melton PE, Fox SA. Genome-wide characterization of the mutational landscape of proliferative verrucous leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radiol 2024; 138:99-111. [PMID: 38760284 DOI: 10.1016/j.oooo.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 04/02/2024] [Accepted: 04/09/2024] [Indexed: 05/19/2024]
Abstract
OBJECTIVES Proliferative verrucous leukoplakia (PVL) is a rare but highly aggressive variant of oral leukoplakia that almost inevitably progresses to oral squamous cell carcinoma (OSCC). The aims of this study were to perform whole exome sequencing of a cohort of patients diagnosed with PVL and identify potential mutational profiles and pathways in this disorder. STUDY DESIGN A total of 12 oral cavity mucosal biopsies from 6 patients with oral lesions clinically compatible with PVL were used. Of these, 9 were diagnosed as dysplasia, 1 OSCC, and 2 hyperkeratosis/hyperplasia. Exome sequencing used the Ion AmpliSeq Exome platform. Ion Reporter software was used for variant calling, annotation, and filtering. Analysis and visualization of somatic mutations was carried out using the MAFtools R package. RESULTS Following exome sequencing and mutational profiling, we analyzed the profiles for cancer associated genes and signatures. Genes previously associated with OSCC, including HYDIN, MUC16, MAML3, CDKN2A, FAT1, and CASP8, were mutated in multiple samples. Several DNA damage repair genes including PARP1 were mutated in PVL samples. NOTCH and Hippo pathways were the most frequently impacted by mutation. CONCLUSIONS This genome wide characterization of premalignant PVL identifies both known and potentially novel oncogenic mechanisms in this disorder.
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Affiliation(s)
- Camile S Farah
- Australian Centre for Oral Oncology Research & Education, Nedlands WA, Australia; Central Queensland University, Rockhampton, Queensland, Australia; Genomics for Life, Milton QLD, Australia.
| | - Kate Shearston
- Australian Centre for Oral Oncology Research & Education, Nedlands WA, Australia; UWA Dental School, University of Western Australia, Nedlands WA, Australia
| | - Phillip E Melton
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia; School of Population and Global Health, University of Western Australia, Crawley, WA, Australia
| | - Simon A Fox
- Australian Centre for Oral Oncology Research & Education, Nedlands WA, Australia; UWA Dental School, University of Western Australia, Nedlands WA, Australia
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Prabhu Venkatesh D, Ramalingam K, Ramani P, Krishnan M, Kumar Vadivel J. Epidemiological Trends and Clinicopathological Characteristics of Oral Leukoplakia: A Retrospective Analysis From a Single Institution in Chennai, Tamil Nadu, India. Cureus 2024; 16:e61590. [PMID: 38962636 PMCID: PMC11221497 DOI: 10.7759/cureus.61590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
Background India has a high prevalence of oral potentially malignant disorders and malignant transformation. Cases of oral leukoplakia are not commonly encountered, and only a small cohort of patients undergo biopsies for the same. This study aims to assess the various etiological factors causing leukoplakia, the clinical features, histopathological findings, and treatment received by the patients who were histopathologically diagnosed with oral leukoplakia. Methodology Oral leukoplakia cases were included in this study from total biopsy samples received in the oral pathology department. Details were collected from the Dental Information Archival Software of our institution. The period analyzed was from January 1, 2021, to December 31, 2023. Relevant clinical and histopathological details were retrieved and tabulated. Statistical analysis (chi-square test) was used to assess the association between the clinicopathological parameters using SPSS software version 21.0 (IBM Corp., Armonk, NY, USA) with a significance level set at a p-value <0.05. Results A total of 76 oral leukoplakia cases were retrieved from 2,600 biopsy samples. The prevalence of oral leukoplakia was 3.1% to 3.4% for the three years. Leukoplakia was commonly observed in those aged 51 to 60 years (33%). Overall, 21% of the patients with leukoplakia showed severe epithelial dysplasia, 22% showed mild epithelial dysplasia, and 39% showed moderate epithelial dysplasia. Moreover, 30% of the patients presented with leukoplakia and oral submucous fibrosis and showed varying degrees of epithelial dysplasia. Finally, 45% of the patients were managed conservatively using pharmacotherapy. Conclusions Severe epithelial dysplasia was commonly associated with oral leukoplakia. Oral submucous fibrosis was also found to be associated with leukoplakia and showed epithelial dysplasia. None of our proliferative verrucous leukoplakia cases showed any association with oral submucous fibrosis. Surgical management was the preferred treatment.
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Affiliation(s)
- Deeksheetha Prabhu Venkatesh
- Oral Pathology and Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Karthikeyan Ramalingam
- Oral Pathology and Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Pratibha Ramani
- Oral Pathology and Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Murugesan Krishnan
- Oral and Maxillofacial Surgery, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Jayanth Kumar Vadivel
- Oral Medicine and Radiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
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Farah CS, Shearston K, Turner EC, Vacher M, Fox SA. Global gene expression profile of proliferative verrucous leukoplakia and its underlying biological disease mechanisms. Oral Oncol 2024; 151:106737. [PMID: 38408418 DOI: 10.1016/j.oraloncology.2024.106737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 02/21/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND Proliferative verrucous leukoplakia (PVL) is a rare and enigmatic oral potentially malignant disorder which almost invariably results in oral squamous cell carcinoma (OSCC). The aims of this project were to use transcriptome profiling to characterise PVL gene expression patterns for biomarker identification and gain insight into the molecular aetiopathogenesis of PVL. METHODS Forty-three oral cavity mucosal biopsies from 32 patients with oral lesions clinically compatible with either PVL or non-PVL conventional oral leukoplakia (OLK) underwent transcriptome profiling by RNA sequencing. Data was analysed by hierarchical clustering, differential gene expression, functional enrichment and network analysis, sparse partial least squares discriminant analysis sPLS-DA, and immune cell phenotypic estimation. RESULTS We found 464 genes significantly differentially expressed at least 2-fold between PVL and non-PVL OLK (193 up and 271 down). HOX genes, including HOXA1 and HOXB7, keratin-associated proteins (KRTAPs) and olfactory receptor G proteins (OR) were significantly upregulated in PVL. Other upregulated genes in PVL included FOS, WNT16 and IFNA1. Pathway analysis showed that there was a significant downregulation of connective tissue signalling in PVL. Classifying multivariate models based upon 22 genes discriminated PVL from non-PVL OLK. Bioinformatic profiling showed that immune cell profiles in PVL and OLK were similar except that fibroblast markers were reduced in PVL. CONCLUSION These results demonstrate that PVL and conventional OLK are molecularly distinct with upregulation of many cancer-associated genes. They provide insight into the pathogenesis of PVL and show that biomarker based molecular diagnostics is feasible to discriminate and inform diagnosis and management.
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Affiliation(s)
- Camile S Farah
- Australian Centre for Oral Oncology Research & Education, Nedlands, WA, Australia; Central Queensland University, Rockhampton, Queensland, Australia; Genomics for Life, Milton, QLD, Australia.
| | - Kate Shearston
- Australian Centre for Oral Oncology Research & Education, Nedlands, WA, Australia; UWA Dental School, University of Western Australia, Nedlands, WA, Australia.
| | - Emma C Turner
- UWA Dental School, University of Western Australia, Nedlands, WA, Australia; Special Needs Dental Unit, Royal Darwin Hospital, Tiwi, NT, Australia
| | - Michael Vacher
- The Australian eHealth Research Centre, CSIRO Health and Biosecurity, Kensington, WA, Australia.
| | - Simon A Fox
- Australian Centre for Oral Oncology Research & Education, Nedlands, WA, Australia; UWA Dental School, University of Western Australia, Nedlands, WA, Australia.
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Nissanka-Jayasuriya EH, Fenton TR, Rose-Zerilli MJJ. Molecular landscape of proliferative verrucous leukoplakia: a systematic review. Br J Oral Maxillofac Surg 2024; 62:118-127. [PMID: 38296711 DOI: 10.1016/j.bjoms.2023.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/28/2023] [Indexed: 02/02/2024]
Abstract
Proliferative verrucous leukoplakia (PVL) is a rare oral potentially malignant disorder characterised by multifocal origin and unpredictable long-term evolution to oral squamous cell carcinoma (OSCC) or oral verrucous carcinoma (OVC). Currently no predictive biomarkers are in clinical use. We aimed to explore the genomic profile of PVL. A total of 685 cases in 26 studies were included in this review. Genomic data were presented in 15% of studies and biomarker analysis was reported in 85% of studies. At first clinical presentation, PVL is characterised by a high loss of heterozygosity (LOH), similar to OSCC, and low copy number alterations (CNA). As these progress, more CNAs and mutations in CDKN2A and alterations to ELAVL1 expression are noted, but no TP53 mutations are identified. There is significantly lower LOH at 17p in early PVL compared with OSCC (p = 0.037). Deletions in chromosomal loci 17q12, 5q31.1 and amplifications in 7q11.2, 7q22 are shared between early lesions and OVC. PVL shows CNAs at 11q31. WNT signalling pathway genes (SUZ12, CTTN and FOLR3) are enriched in CN-altered regions. PVL stroma shows significantly lower α-SMA and higher CD34 expression than OVC and OSCC. The exact genomic landscape is currently unclear, and further studies are necessary to unravel this mystery.
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Affiliation(s)
- Eranga H Nissanka-Jayasuriya
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Histopathology, William Harvey Hospital, East Kent Hospitals University NHS Trust, Ashford, Kent, UK.
| | - Tim R Fenton
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; School of Biosciences, University of Kent, Canterbury, UK
| | - Matthew J J Rose-Zerilli
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK
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Hanna GJ, Villa A, Nandi SP, Shi R, ONeill A, Liu M, Quinn CT, Treister NS, Sroussi HY, Vacharotayangul P, Goguen LA, Annino DJ, Rettig EM, Jo VY, Wong KS, Lizotte P, Paweletz CP, Uppaluri R, Haddad RI, Cohen EEW, Alexandrov LB, William WN, Lippman SM, Woo SB. Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial. JAMA Oncol 2024; 10:32-41. [PMID: 37971722 PMCID: PMC10654930 DOI: 10.1001/jamaoncol.2023.4853] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/07/2023] [Indexed: 11/19/2023]
Abstract
Importance Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy. Objective To determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL. Design, Setting, and Participants This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia). Intervention Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit. Main Outcomes and Measures The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response. Results A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss. Conclusions and Relevance This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study. Trial Registration ClinicalTrials.gov Identifier: NCT03692325.
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Affiliation(s)
- Glenn J. Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Alessandro Villa
- Miami Cancer Institute and Herbert Wertheim College of Medicine, Florida International University, Miami
| | - Shuvro P. Nandi
- Moores Cancer Center, UC San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California
| | - Ruichao Shi
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Anne ONeill
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Mofei Liu
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Charles T. Quinn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Nathaniel S. Treister
- Division of Oral Medicine and Dentistry, Dana-Farber Cancer Institute and Brigham & Women’s Hospital, Boston, Massachusetts
| | - Herve Y. Sroussi
- Division of Oral Medicine and Dentistry, Dana-Farber Cancer Institute and Brigham & Women’s Hospital, Boston, Massachusetts
| | - Piamkamon Vacharotayangul
- Division of Oral Medicine and Dentistry, Dana-Farber Cancer Institute and Brigham & Women’s Hospital, Boston, Massachusetts
| | - Laura A. Goguen
- Division of Otolaryngology–Head and Neck Surgery, Brigham & Women’s Hospital and Head and Neck Surgical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Donald J. Annino
- Division of Otolaryngology–Head and Neck Surgery, Brigham & Women’s Hospital and Head and Neck Surgical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Eleni M. Rettig
- Division of Otolaryngology–Head and Neck Surgery, Brigham & Women’s Hospital and Head and Neck Surgical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Vickie Y. Jo
- Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts
| | - Kristine S. Wong
- Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts
| | - Patrick Lizotte
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Cloud P. Paweletz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ravindra Uppaluri
- Division of Otolaryngology–Head and Neck Surgery, Brigham & Women’s Hospital and Head and Neck Surgical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Robert I. Haddad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Ludmil B. Alexandrov
- Moores Cancer Center, UC San Diego, La Jolla, California
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California
- Department of Bioengineering, UC San Diego, La Jolla, California
| | - William N. William
- Oncology Center, Hospital BP, a Beneficência Portuguesa de São Paulo, São Paulo, Brazil
| | | | - Sook-bin Woo
- Division of Oral Medicine and Dentistry, Dana-Farber Cancer Institute and Brigham & Women’s Hospital, Boston, Massachusetts
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10
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Alabdulaaly L, Villa A, Chen T, Kerr A, Ross N, Abreu Alves F, Guollo A, Woo SB. Characterization of initial/early histologic features of proliferative leukoplakia and correlation with malignant transformation: a multicenter study. Mod Pathol 2022; 35:1034-1044. [PMID: 35184151 DOI: 10.1038/s41379-022-01021-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/07/2023]
Abstract
The aim of this multicenter retrospective study is to characterize the histopathologic features of initial/early biopsies of proliferative leukoplakia (PL; also known as proliferative verrucous leukoplakia), and to analyze the correlation between histopathologic features and malignant transformation (MT). Patients with a clinical diagnosis of PL who have at least one biopsy and one follow-up visit were included in this study. Initial/early biopsy specimens were reviewed. The biopsies were evaluated for the presence of squamous cell carcinoma (SCCa), oral epithelial dysplasia (OED), and atypical verrucous hyperplasia (AVH). Cases that lacked unequivocal features of dysplasia were termed "hyperkeratosis/parakeratosis not reactive (HkNR)". Pearson chi-square test and Wilcoxon test were used for statistical analysis. There were 86 early/initial biopsies from 59 patients; 74.6% were females. Most of the cases had a smooth/homogenous (34.8%) or fissured appearance (32.6%), and only 13.0% had a verrucous appearance. The most common biopsy site was the gingiva/alveolar mucosa (40.8%) and buccal mucosa (25.0%). The most common histologic diagnosis was OED (53.5%) followed by HkNR (31.4%). Of note, two-thirds of HkNR cases showed only hyperkeratosis and epithelial atrophy. A lymphocytic band was seen in 34.8% of OED cases and 29.6% of HkNR cases, mostly associated with epithelial atrophy. Twenty-eight patients (47.5%) developed carcinoma and 28.9% of early/initial biopsy sites underwent MT. The mortality rate was 11.9%. Our findings show that one-third of cases of PL do not show OED with most exhibiting hyperkeratosis and epithelial atrophy, but MT nevertheless occurred at such sites in 3.7% of cases.
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Affiliation(s)
- Lama Alabdulaaly
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, 02115, USA. .,Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, 02115, USA. .,Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. .,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
| | - Alessandro Villa
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, 94193, USA
| | - Tiffany Chen
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Alexander Kerr
- Department of Oral & Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, NY, 10010, USA
| | - Nicholas Ross
- Department of Oral & Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, NY, 10010, USA
| | - Fabio Abreu Alves
- Stomatology Department, AC Camargo Cancer Center, São Paulo, SP, 01525, Brazil
| | - Andre Guollo
- Stomatology Department, AC Camargo Cancer Center, São Paulo, SP, 01525, Brazil
| | - Sook-Bin Woo
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, 02115, USA.,Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, 02115, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
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11
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Alkan U, Bachar G, Nachalon Y, Zlotogorsky A, Gal Levin E, Kaplan I. Proliferative verrucous leukoplakia: a clinicopathological comparative study. Int J Oral Maxillofac Surg 2022; 51:1027-1033. [DOI: 10.1016/j.ijom.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 12/26/2021] [Accepted: 01/04/2022] [Indexed: 10/19/2022]
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12
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Hanna GJ, Villa A, Mistry N, Jia Y, Quinn CT, Turner MM, Felt KD, Pfaff K, Haddad RI, Uppaluri R, Rodig SJ, Woo SB, Egloff AM, Hodi FS. Comprehensive Immunoprofiling of High-Risk Oral Proliferative and Localized Leukoplakia. CANCER RESEARCH COMMUNICATIONS 2021; 1:30-40. [PMID: 36860910 PMCID: PMC9973379 DOI: 10.1158/2767-9764.crc-21-0060] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 11/16/2022]
Abstract
Oral leukoplakia is common and may, in some cases, progress to carcinoma. Proliferative leukoplakia is a progressive, often multifocal subtype with a high rate of malignant transformation compared with the more common localized leukoplakia. We hypothesized that the immune microenvironment and gene expression patterns would be distinct for proliferative leukoplakia compared with localized leukoplakia. We summarize key clinicopathologic features among proliferative leukoplakia and localized leukoplakia and compare cancer-free survival (CFS) between subgroups. We analyze immunologic gene expression profiling in proliferative leukoplakia and localized leukoplakia tissue samples (NanoString PanCancer Immune Oncology Profiling). We integrate immune cell activation and spatial distribution patterns in tissue samples using multiplexed immunofluorescence and digital image capture to further define proliferative leukoplakia and localized leukoplakia. Among N = 58 patients (proliferative leukoplakia, n = 29; localized leukoplakia, n = 29), only the clinical diagnosis of proliferative leukoplakia was associated with significantly decreased CFS (HR, 11.25; P < 0.01; 5-year CFS 46.8% and 83.6% among patients with proliferative leukoplakia and localized leukoplakia, respectively). CD8+ T cells and T regulatory (Treg) were more abundant among proliferative leukoplakia samples (P < 0.01) regardless of degree of epithelial dysplasia, and often colocalized to the dysplasia-stromal interface. Gene set analysis identified granzyme M as the most differentially expressed gene favoring the proliferative leukoplakia subgroup (log2 fold change, 1.93; P adj < 0.001). Programmed death ligand 1 (PD-L1) was comparatively overexpressed among proliferative leukoplakia samples, with higher (>5) PD-L1 scores predicting worse CFS (P adj < 0.01). Proliferative leukoplakia predicts a high rate of malignant transformation within 5 years of diagnosis. A prominent CD8+ T-cell and Treg signature along with relative PD-L1 overexpression compared with localized leukoplakia provides strong rationale for PD-1/PD-L1 axis blockade using preventative immunotherapy. Significance This is the first in-depth profiling effort to immunologically characterize high-risk proliferative leukoplakia as compared with the more common localized leukoplakia. We observed a notable cytotoxic T-cell and Treg signature with relative overexpression of PD-L1 in high-risk proliferative leukoplakia providing a strong preclinical rationale for investigating PD-1/PD-L1 axis blockade in this disease as preventative immunotherapy.
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Affiliation(s)
- Glenn J. Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Corresponding Author: Glenn J. Hanna, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Dana Building, Room 2-140, Boston, MA 02215. Phone: 617-632-3090; Fax: 617-632-4448; E-mail:
| | - Alessandro Villa
- Oral Medicine Clinic, University of California San Francisco School of Dentistry, San Francisco, California
| | - Nikhil Mistry
- Division of Oral Medicine and Dentistry, Harvard School of Dental Medicine, Boston, Massachusetts
| | - Yonghui Jia
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - Charles T. Quinn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Madison M. Turner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kristen D. Felt
- ImmunoProfile, Brigham & Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kathleen Pfaff
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Robert I. Haddad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ravindra Uppaluri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Brigham & Women's Hospital, Boston, Massachusetts
| | - Scott J. Rodig
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sook-Bin Woo
- Division of Oral Medicine and Dentistry, Harvard School of Dental Medicine, Boston, Massachusetts
| | - Ann Marie Egloff
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - F. Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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13
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Immune expression profile identification in a group of proliferative verrucous leukoplakia patients: a pre-cancer niche for oral squamous cell carcinoma development. Clin Oral Investig 2020; 25:2645-2657. [PMID: 32918120 DOI: 10.1007/s00784-020-03575-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/03/2020] [Indexed: 12/26/2022]
Abstract
OBJECTIVES To explore the pathophysiology of proliferative verrucous leukoplakia, a rare oral disorder that exhibits high rates of recurrence and malignant transformation, through a RNAseq case-control study. MATERIAL AND METHODS We obtained oral biopsies from 10 patients with verrucous leukoplakia lesions and from the mucosa of 5 healthy individuals for sequencing using RNAseq technology. Using bioinformatic methods, we investigated gene expression and enrichment differences between patients both with and without the disorder. We applied network biology methods to investigate functional relations among those genes that were differentially deregulated. RESULTS We detected 140 differentially expressed genes with distinct roles in immune surveillance, tissue and organ morphogenesis, development, and organization. Of these 140 genes, 111 have been previously described as cancer expression biomarkers, being oral squamous cell carcinoma the most represented type of cancer among them. Of these 140 genes, 26 were prioritized for further investigation as biomarkers using larger sample sizes. CONCLUSIONS The gene expression patterns of healthy and unhealthy patients differed in 140 genes whose deregulation has a functional impact on normal functioning of the immune system. This immune expression profile provides a plausible hypothesis to explain the transformation to oral squamous cell carcinoma observed in 6 of the 10 assayed cases. CLINICAL RELEVANCE By determining the molecular bases of the proliferative verrucous leukoplakia disorder and identifying early biomarkers of malignancy, this can allow us to develop new treatment strategies.
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14
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Farah CS. Molecular, genomic and mutational landscape of oral leukoplakia. Oral Dis 2020; 27:803-812. [PMID: 33448555 DOI: 10.1111/odi.13608] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/24/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022]
Abstract
Oral leukoplakia (OLK) and its more aggressive clinical variant proliferative verrucous leukoplakia (PVL) remain enigmatic disorders clinically and histopathologically. Despite decades of research into both, there has been only incremental advancement in our understanding of their aetiology and pathogenesis and only minimal improvement in effective management strategies. Currently, no specific prognostic genetic or molecular marker has been reported for leukoplakia. There is, however, an emerging body of evidence characterising the genomic and transcriptomic profile of OLK. Regardless of the significance of cellular and architectural features of OLK and PVL, it is clear from studies reported in this review that new emerging evidence points to the presence of premalignant molecular subtypes of leukoplakia which require further investigation. This up-to-date review explores the contemporary genomic, transcriptomic and mutational landscape of leukoplakia broadly, discusses concepts that may not be widely recognised or accepted and purposefully highlights studies with juxtaposed findings in an effort to challenge dogma. It also highlights the urgent need for a concerted international effort of original collaborative research which will only occur by pooling collective efforts, resources and intellect to define the molecular fingerprint of this enigmatic disorder, in the hope it will better inform diagnosis, stratification and treatment.
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Affiliation(s)
- Camile S Farah
- Australian Centre for Oral Oncology Research & Education, Nedlands, WA, Australia.,Perth Oral Medicine & Dental Sleep Centre, West Leederville, WA, Australia.,Oral, Maxillofacial and Dental Surgery, Fiona Stanley Hospital, Murdoch, WA, Australia.,Australian Clinical Labs, Subiaco, WA, Australia.,Genomics for Life, Brisbane, QLD, Australia
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15
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Clinicopathologic analysis of verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma as part of the clinicopathologic spectrum of oral proliferative verrucous leukoplakia: A literature review and analysis. Pathol Res Pract 2019; 215:152670. [PMID: 31630872 DOI: 10.1016/j.prp.2019.152670] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Proliferative verrucous leukoplakia is classified as a potentially malignant disorder because of its high rate of malignant transformation. PVL progresses in a series of clinical stages where the early stage represents multiple, multifocal leukoplakias with a high recurrence rate. The intermediate and late stages are clinically exophytic lesion, diagnosed microscopically as verrucous hyperplasia that often progresses into verrucous carcinoma and/or squamous cell carcinoma. There is no single histologic definition and the diagnosis is retrospective following observed progression of the disorder. The goal of the current study was to conduct a literature review and analysis of PVL in the later stages to gain further knowledge on their clinicopathologic features. DATA SOURCES Medline's PubMed and Google Scholar were searched for adequately documented cases from 1985 to 2018. References of published articles were searched for additional cases. REVIEW METHODS Overall, 57 manuscripts were analyzed. 35/57 manuscripts provided adequate data on the clinicopathologic features in the premalignant and malignant stages. RESULTS Malignant transformation rate was 50% (average of 57 months). Gingiva, palate and buccal mucosa were the most common locations. Clinicopathologic features included; well differentiated carcinoma (78%), perineural invasion (3%), lymph node metastasis (4%); distant metastasis (0%), average duration of illness (65 months), DOD-dead of disease (44%). Moderate dysplasia, severe dysplasia and carcinoma in situ were exceptionally uncommon in the premalignant stages (0.8%). CONCLUSION Prognostic factors such as perineural invasion, lymph node metastasis and distant metastasis were uncommon occurrences which may have practical implications on treatment. Further studies are needed to substantiate our findings.
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16
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Villa A, Hanna GJ, Kacew A, Frustino J, Hammerman PS, Woo SB. Oral keratosis of unknown significance shares genomic overlap with oral dysplasia. Oral Dis 2019; 25:1707-1714. [PMID: 31295753 DOI: 10.1111/odi.13155] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/04/2019] [Accepted: 06/22/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To identify molecular characteristics of keratosis of unknown significance and to nominate pathways of molecular progression to oral cancer. Our work could provide a rationale for monitoring and treating these lesions definitively. METHODS Patients with oral leukoplakia were eligible for our prospective observational study. We correlated alterations in cancer-associated genes with clinical and histopathologic variables (keratosis of unknown significance vs. moderate-to-severe dysplasia) and compared these alterations to a previously molecularly characterized oral cancer population. RESULTS Of 20 enrolled patients, 13 (65%) had evidence of keratosis of unknown significance, while seven (35%) had dysplasia. Nine patients (45%) developed oral cancer (4/13 with keratosis of unknown significance, 5/7 with dysplasia). At a median follow-up of 67 (range 22-144) months, median overall survival was significantly shorter for patients with dysplasia (hazard ratio 0.11, p = .02). KMT2C and TP53 alterations were most frequent (75% and 35%, respectively). There were molecular similarities between keratosis of unknown significance and dysplasia patients, with no significant differences in mutational frequency among genes with ≥15% rate of alteration. CONCLUSIONS Among patients with leukoplakia, both patients with keratosis of unknown significance and patients with dysplasia developed oral cancer. Molecular alterations between these two groups were similar at this sample size.
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Affiliation(s)
- Alessandro Villa
- Division of Oral Medicine and Dentistry, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts
| | - Glenn J Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Alec Kacew
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jennifer Frustino
- Division of Oral Oncology and Maxillofacial Prosthetics, Department of Dentistry, Erie County Medical Center Corporation (ECMC), Buffalo, New York
| | - Peter S Hammerman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sook-Bin Woo
- Division of Oral Medicine and Dentistry, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts
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17
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Rintala M, Vahlberg T, Salo T, Rautava J. Proliferative verrucous leukoplakia and its tumor markers: Systematic review and meta‐analysis. Head Neck 2018; 41:1499-1507. [DOI: 10.1002/hed.25569] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 05/29/2018] [Accepted: 11/21/2018] [Indexed: 01/09/2023] Open
Affiliation(s)
- Mirjami Rintala
- Faculty of Medicine, Department of Oral Pathology, Institute of DentistryUniversity of Turku Turku Finland
| | - Tero Vahlberg
- Biostatistics, Department of Clinical MedicineUniversity of Turku and Turku University Hospital Turku Finland
| | - Tuula Salo
- Helsinki University Central Hospital Helsinki Finland
- Department of Oral Pathology, Institute of DentistryUniversity of Helsinki Helsinki Finland
- Finland Cancer and Translational Medicine Research UnitUniversity of Oulu Oulu Finland
- Medical Research Center Oulu Oulu Finland
| | - Jaana Rautava
- Faculty of Medicine, Department of Oral Pathology, Institute of DentistryUniversity of Turku Turku Finland
- Department of PathologyTurku University Hospital Turku Finland
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18
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Okoturo E, Risk J, Schache A, Shaw R, Boyd M. Molecular pathogenesis of proliferative verrucous leukoplakia: a systematic review. Br J Oral Maxillofac Surg 2018; 56:780-785. [DOI: 10.1016/j.bjoms.2018.08.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 08/17/2018] [Indexed: 01/10/2023]
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19
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Villa A, Menon RS, Kerr AR, De Abreu Alves F, Guollo A, Ojeda D, Woo SB. Proliferative leukoplakia: Proposed new clinical diagnostic criteria. Oral Dis 2018; 24:749-760. [PMID: 29337414 DOI: 10.1111/odi.12830] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/13/2017] [Accepted: 01/07/2018] [Indexed: 11/29/2022]
Abstract
OBJECTIVE We aimed to characterize proliferative verrucous leukoplakia (PVL) from a clinical and histopathological standpoint and suggest an updated classification. SUBJECTS AND METHODS Records of patients seen at three oral medicine centers with a clinical diagnosis of PVL were reviewed for clinical and histopathological features and malignant transformation (MT). RESULTS There were 42 patients (median age: 69 years [range: 36-88]; 35 females). 12.2% were current smokers. Family history of cancer was present in 43.7% of patients. Partial demarcation of lesion margins was present in 31.3% of lesions, followed by verrucous (27.5%), smooth (22.7%) erythematous (22.3%), and fissured (18.3%) appearance. Large and contiguous and multisite and non-contiguous lesions comprised 57.1% (24/42) and 35.7% (15/42) of PVL cases, respectively. 19.1% had prominent erythema (erythroleukoplakia). The most common histopathological diagnosis at first visit was hyperkeratosis without dysplasia (22/42; 56.4%). MT occurred in 71.4% patients after a median of 37 months [range: 1-210] from initial visit; erythroleukoplakia exhibited MT in 100% of cases. CONCLUSION The generic term "proliferative leukoplakia (PL)" may be more appropriate than PVL because 18.3% were fissured and 22.7% erythematous. We also propose the term proliferative erythroleukoplakia to more accurately describe the subset of PL with prominent erythema, which had the highest MT rate.
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Affiliation(s)
- A Villa
- Division of Oral Medicine and Dentistry, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA, USA.,Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
| | - R S Menon
- Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
| | - A R Kerr
- Department of Oral & Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, NY, USA
| | - F De Abreu Alves
- Stomatology Department at AC Camargo Cancer Center, Sao Paulo, Brazil
| | - A Guollo
- Stomatology Department at AC Camargo Cancer Center, Sao Paulo, Brazil
| | - D Ojeda
- Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, TX, USA
| | - S B Woo
- Division of Oral Medicine and Dentistry, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA, USA.,Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
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20
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Capella DL, Gonçalves JM, Abrantes AAA, Grando LJ, Daniel FI. Proliferative verrucous leukoplakia: diagnosis, management and current advances. Braz J Otorhinolaryngol 2017; 83:585-593. [PMID: 28209441 PMCID: PMC9444738 DOI: 10.1016/j.bjorl.2016.12.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 06/17/2016] [Accepted: 12/08/2016] [Indexed: 01/04/2023] Open
Abstract
Introduction Proliferative verrucous leukoplakia is a multifocal and progressive lesion of the oral mucosa, with unknown etiology, and commonly resistant to all therapy attempts with frequent recurrences. It is characterized by a high rate of oral squamous cell carcinoma and verrucou carcinoma transformations. Objective To analyze the studies about Proliferative verrucous leukoplakia and develop a concise update. Methods A Pubmed search identifying studies (laboratory research, case series and reviews of literature) that examined patients with Proliferative verrucous leukoplakia was realized. Results There are not enough studies about Proliferative verrucous leukoplakia in the literature. The few found studies not present a consensus about its etiology and diagnosis criteria. Although several treatment strategies have been proposed, most of them still show a high recurrence rate. Conclusion More research about Proliferative verrucous leukoplakia is necessary to understand and treat this disease.
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Affiliation(s)
- Diogo Lenzi Capella
- Universidade Federal de Santa Catarina (UFSC), Programa de Pós-graduação em Odontologia, Florianopolis, SC, Brazil
| | - Jussara Maria Gonçalves
- Universidade Federal de Santa Catarina (UFSC), Programa de Pós-graduação em Odontologia, Florianopolis, SC, Brazil
| | | | - Liliane Janete Grando
- Universidade Federal de Santa Catarina (UFSC), Departamento de Patologia, Florianopolis, SC, Brazil
| | - Filipe Ivan Daniel
- Universidade Federal de Santa Catarina (UFSC), Departamento de Patologia, Florianopolis, SC, Brazil.
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21
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Flores IL, Santos-Silva AR, Coletta RD, Leme AFP, Lopes MA. Low expression of angiotensinogen and dipeptidyl peptidase 1 in saliva of patients with proliferative verrucous leukoplakia. World J Clin Cases 2016; 4:356-363. [PMID: 27900324 PMCID: PMC5112355 DOI: 10.12998/wjcc.v4.i11.356] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 06/14/2016] [Accepted: 09/18/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To elucidate the profile of the salivary proteome.
METHODS Unstimulated whole mouth saliva was collected from 30 volunteers [15 proliferative verrucous leukoplakia (PVL) patients and 15 controls] and proteins were submitted for mass spectrometry-based proteomics using the discovery approach, followed by analyses of variance and logistic regression tests.
RESULTS A total of two hundred and eighty-three proteins were confidently identified in saliva. By combining two low abundance proteins from the PVL group, angiotensinogen (AGT) and dipeptidyl peptidase 1 (DPP1), a model for group differentiation was built with a concordance index of 94.2%, identifying both proteins as potential etiologic biomarkers for PVL.
CONCLUSION This study suggests that both AGT and DPP1 may be involved in developmental mechanisms of PVL.
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Abstract
Oral squamous cell carcinoma is the most common neoplasia of the mouth. Downregulation of p16(INK4a) (a cyclin-dependent kinase inhibitor) has been reported for mouth cancer and it is believed that its inactivation is an early event in oral carcinogenesis. The goal of this article is to quantitatively report expression of p16(INK4a) and the state of methylation in oral squamous cell carcinoma, and evaluate its relationship with the clinical and prognostic factors, in addition to setting out a multivariate model that predicts survival. The mean expression of p16(INK4a) was 7.70 (SD=14.07) (F=0.894; P=0.449). According to the semiquantitative analysis, there were statistically significant differences, where 19 cases were negative (<2 %), 11 at initial stages, and 8 at advanced stages (χ(2)=6.016; P<0.05). The methylation of p16(INK4a) was not associated with any of the clinical or pathologic variables. Kaplan-Meier curve showed a better survival for patients in initial stages (40.72 mo) compared to those in advanced stages (28.6 mo) (P<0.01). Survival was also reduced in a statistically significant manner in patients with any degree of dysplasia in the adjacent margin (P<0.05). During univariate Cox regression analysis, it was observed that individuals with relapse had a higher risk (almost 9 times higher) [P<0.001; hazard ratio=8.91; 95% confidence interval (CI), 4.18-19.02]. During the Cox multivariate analysis for each unit of decrease in p16(INK4a), the risk increased by 1.06) (P<0.05; hazard ratio=0.94; 95% CI, 0.89-1.00). p16(INK4a) expression is reduced with advancing tumor stage and its gene silencing is associated with an increased risk of death.
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Ottavioli A, Campana F, Catherine JH, Massereau E, Del Grande J, Ordioni U. [Proliferative verrucous leukoplakia: Three cases and literature review]. Ann Dermatol Venereol 2016; 143:187-96. [PMID: 26832120 DOI: 10.1016/j.annder.2015.12.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 09/30/2015] [Accepted: 12/15/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND The aim of this study was to collect epidemiological, aetiopathogenic, clinical, histological and therapeutic data concerning proliferative verrucous leucoplakia (PVL) and to report three new cases. PATIENTS AND METHODS A literature review performed using the Medline database enabled us to collate 39 studies involving 607 cases. Three new cases were added. RESULTS PVL is a rare disease characterized by extensive and multifocal oral leucoplakic lesions. Its histological pattern depends on the stage of the disease: hyperkeratosis, verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma. The aetiopathogenesis of PVL is poorly understood and there is no clear consensus concerning therapy. Malignant transformation occurs in over 50 % of cases. DISCUSSION Diagnosis of PVL is difficult because of the presenting signs, which can be mistaken for those of other diseases. Management may be complicated and long-term follow-up is essential.
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Affiliation(s)
- A Ottavioli
- Service d'odontologie, hôpital de la Timone, Assistance publique-Hôpitaux de Marseille, 264, rue Saint-Pierre, 13005 Marseille, France
| | - F Campana
- Centre massilien de la face, 24, avenue du Prado, 13006 Marseille, France
| | - J-H Catherine
- Service d'odontologie, hôpital de la Timone, Assistance publique-Hôpitaux de Marseille, 264, rue Saint-Pierre, 13005 Marseille, France; UMR 7268 ADES, Aix-Marseille/EFS/CNRS, faculté de médecine-secteur Nord, boulevard Pierre-Dramard, 13344 Marseille cedex 15, France
| | - E Massereau
- Service d'odontologie, hôpital de la Timone, Assistance publique-Hôpitaux de Marseille, 264, rue Saint-Pierre, 13005 Marseille, France
| | - J Del Grande
- Service d'anatomie pathologique et de cytologie, hôpital de la Timone, Assistance publique-Hôpitaux de Marseille, 264, rue Saint-Pierre, 13005 Marseille, France
| | - U Ordioni
- Service d'odontologie, hôpital de la Timone, Assistance publique-Hôpitaux de Marseille, 264, rue Saint-Pierre, 13005 Marseille, France; Centre massilien de la face, 24, avenue du Prado, 13006 Marseille, France.
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Bagan L, Sáez GT, Tormos MC, Labaig-Rueda C, Murillo-Cortes J, Bagan JV. Salivary and serum interleukin-6 levels in proliferative verrucous leukoplakia. Clin Oral Investig 2015; 20:737-43. [DOI: 10.1007/s00784-015-1551-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 07/27/2015] [Indexed: 10/23/2022]
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25
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Dillenburg CS, Martins MAT, Almeida LO, Meurer L, Squarize CH, Martins MD, Castilho RM. Epigenetic Modifications and Accumulation of DNA Double-Strand Breaks in Oral Lichen Planus Lesions Presenting Poor Response to Therapy. Medicine (Baltimore) 2015; 94:e997. [PMID: 26222871 PMCID: PMC4554108 DOI: 10.1097/md.0000000000000997] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Epigenetics refers to changes in cell characteristics that occur independently of modifications to the deoxyribonucleic acid (DNA) sequence. Alterations mediated by epigenetic mechanisms are important factors in cancer progression. Although an exciting prospect, the identification of early epigenetic markers associated with clinical outcome in premalignant and malignant disorders remains elusive. We examined alterations in chromatin acetylation in oral lichen planus (OLP) with distinct clinical behavior and compared the alterations to the levels of DNA double-strand breaks (DSBs). We analyzed 42 OLP patients, who had different responses to therapy, for acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, and the presence of DSBs, as determined by accumulation of phosphorylated γH2AX foci. Patients with high levels of H3K9ac acetylation failed to respond to therapy or experienced disease recurrence shortly after therapy. Similar to H3K9ac, patients who responded poorly to therapy had increased accumulation of DNA DSB, indicating genomic instability. These findings suggest that histone modifications occur in OLP, and H3K9ac and γH2AX histones may serve as epigenetic markers for OLP recurrence.
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Affiliation(s)
- Caroline S Dillenburg
- From the Department of Oral Pathology (CSD, MDM), School of Dentistry; Department of Oral Medicine (MATM), Hospital de Clínicas de Porto Alegre (HCPA/UFRGS); Department of Pathology (LM), School of Medicine, Hospital de Clínicas de Porto Alegre (HCPA/UFRGS), Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; and Laboratory of Epithelial Biology (CSD, MATM, LOA, CHS, MDM, RMC), Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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26
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Mochizuki Y, Harada H, Ikuta M, Shimamoto H, Tomioka H, Tanaka K, Hirai H, Omura K. Clinical characteristics of multiple primary carcinomas of the oral cavity. Oral Oncol 2015; 51:182-9. [DOI: 10.1016/j.oraloncology.2014.11.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 11/17/2014] [Accepted: 11/20/2014] [Indexed: 10/24/2022]
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27
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Pentenero M, Meleti M, Vescovi P, Gandolfo S. Oral proliferative verrucous leucoplakia: are there particular features for such an ambiguous entity? A systematic review. Br J Dermatol 2015; 170:1039-47. [PMID: 24471527 DOI: 10.1111/bjd.12853] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2014] [Indexed: 12/31/2022]
Abstract
Proliferative verrucous leucoplakia (PVL) is a distinct, particularly aggressive form of oral leucoplakia. Given the low prevalence of PVL, data are sparse and are mostly from case reports, case series and only a few case-control studies, meaning that the literature is able to provide only weak evidence. The present systematic literature review aims to collate the available evidence on the following issues: patient demographics, aetiology, lesion location(s), malignant potential, location and histopathological features of transformed lesions, disease-specific survival rates and treatment response. Electronic databases were searched for studies in the English language reporting original data from at least 10 patients with PVL on the target issues of the present review. The retrieved data were merged and a descriptive analysis performed. The 20 studies selected indicated that PVL does not seem to be correlated with the major risk factors for oral carcinoma (tobacco, alcohol and/or areca nut/betel leaf chewing). The disorder affects mainly adult/elderly women and has a very high malignant transformation rate, particular site distribution and particular location and histopathological features of transformed lesions. The present results may be limited by some articles being unintentionally excluded as they were not found during the electronic search, a lack of worldwide accepted diagnostic criteria for PVL, and overlapping data from multiple studies performed in a limited number of centres. Despite these potential drawbacks, the present results demonstrate that PVL does have particular features.
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Affiliation(s)
- M Pentenero
- Unit of Oral Medicine and Oral Oncology, Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, Italy
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Oral squamous cell carcinoma associated with proliferative verrucous leukoplakia compared with conventional squamous cell carcinoma--a clinical, histologic and immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 119:318-25. [PMID: 25547823 DOI: 10.1016/j.oooo.2014.10.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 10/13/2014] [Accepted: 10/29/2014] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Proliferative verrucous leukoplakia (PVL), a potentially malignant disorder, often undergoes malignant transformation to oral squamous cell carcinoma. The aim of our study was to document and compare the histologic, immunohistochemical, and clinical features and the survival rates of carcinoma arising in patients with PVL (p-scca) with conventional squamous cell carcinoma (c-scca) in order to determine if p-scca should be categorized as a separate clinical entity. MATERIALS AND METHODS A retrospective review of 11 patients with PVL, 38 with p-scca tumors and 49 with c-scca tumors: buccal mucosa (n = 28) and gingiva or palate (n = 21). Immunohistochemistry was performed by using antibodies directed against p16, p53, and ki67. RESULTS P-scca had lower clinical stage (P = .0001), smaller tumor size (P = .0033), no lymph node metastasis (P = .0002) or distant metastasis (P = .05), and better short term (P = .03), but not long term (P = .12) survival. Microscopically, p-scca tumor thickness was significantly less (P = .0001). P-53 overexpression was more common in p-scca (P = .0043) but not ki67 or p16 overexpression. CONCLUSIONS P-scca, compared with c-scca, presented with significantly better prognostic factors and short-term survival rates and longer duration of disease. Our results suggest that p-scca may represent a distinct entity, which may have practical implications when deciding on treatment. Further studies on a larger cohort of patients are recommended.
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Gillenwater AM, Vigneswaran N, Fatani H, Saintigny P, El-Naggar AK. Proliferative verrucous leukoplakia: recognition and differentiation from conventional leukoplakia and mimics. Head Neck 2014; 36:1662-8. [PMID: 24115154 DOI: 10.1002/hed.23505] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 09/14/2012] [Accepted: 09/10/2013] [Indexed: 12/24/2022] Open
Abstract
The majority of conventional leukoplakia remains constant and only a subset progress to high-grade dysplasia or invasive carcinoma. A less recognized form known as proliferative verrucous leukoplakia (PVL) represents a unique progressive and elusive variant. Identifying patients with this form can only be achieved through the keen clinical observation of the temporal gross and histologic progression in individual patients with squamous cell carcinoma. The difficulty in the early diagnosis of PVL stems from the overlapping clinical and pathologic features with conventional multifocal leukoplakia with dysplasia. We present the current view on the clinicopathologic and biological characteristics of PVL and discuss their diagnosis, differential diagnosis, and management.
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Affiliation(s)
- Ann M Gillenwater
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
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30
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Abstract
UNLABELLED Proliferative Verrucous Leukoplakia (PVL) is a multifocal form of progressive leukoplakia with a high rate of malignant transformation that requires early recognition by oral health care providers for proper management. BACKGROUND AND PURPOSE PVL will frequently appear as an innocuous white lesion or lesions that can easily be overlooked or considered clinically insignificant, yet it has a high rate of malignant transformation. There is limited in-depth knowledge about the pathobiology of PVL. Oral health care providers lack familiarity with this lesion; consequently the intent of this article is to increase awareness of the clinical aspects of PVL. METHODS Case reports, case series and review articles provide a profile of PVL. CONCLUSION It is essential that health care providers performing intraoral examinations are aware that PVL is a distinct and rare form of multifocal oral leukoplakia. PVL commonly affects females above the age of 62. Currently, little is known about its etiopathogenesis. Additionally, no specific treatment modality has proven to be effective in aborting its progression. Because of its high recurrence potential and relentless progression to squamous cell carcinoma, all recurrent and multifocal white lesions of the oral cavity should be viewed with suspicion.
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Affiliation(s)
- Pallavi Parashar
- Department of Diagnostic and Biological Sciences, University of Colorado School of Dental Medicine, Aurora, CO 80045, USA.
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31
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Abstract
Premalignant lesions of the oral cavity present as visibly abnormal areas of mucosa and may be a source of significant anxiety for the patient and the clinician. Suspicious lesions should be biopsied to evaluate for dysplasia. The risk of malignant transformation may relate to patient characteristics, environmental risk factors and genetic alterations. Management of such lesions hinges on risk modification, surveillance, symptom management and directed biopsies. Excision or ablation of dysplastic lesions is indicated. We review the current evidence relating to management of premalignant lesions of the oral mucosa and make recommendations for practice patterns.
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Affiliation(s)
- Aru Panwar
- Division of Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE, USA
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32
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Mallery SR, Tong M, Shumway BS, Curran AE, Larsen PE, Ness GM, Kennedy KS, Blakey GH, Kushner GM, Vickers AM, Han B, Pei P, Stoner GD. Topical application of a mucoadhesive freeze-dried black raspberry gel induces clinical and histologic regression and reduces loss of heterozygosity events in premalignant oral intraepithelial lesions: results from a multicentered, placebo-controlled clinical trial. Clin Cancer Res 2014; 20:1910-24. [PMID: 24486592 DOI: 10.1158/1078-0432.ccr-13-3159] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Approximately 30% higher grade premalignant oral intraepithelial neoplasia (OIN) lesions will progress to oral cancer. Although surgery is the OIN treatment mainstay, many OIN lesions recur, which is highly problematic for both surgeons and patients. This clinical trial assessed the chemopreventive efficacy of a natural product-based bioadhesive gel on OIN lesions. EXPERIMENTAL DESIGN This placebo-controlled multicenter study investigated the effects of topical application of bioadhesive gels that contained either 10% w/w freeze-dried black raspberries (BRB) or an identical formulation devoid of BRB placebo to biopsy-confirmed OIN lesions (0.5 g × q.i.d., 12 weeks). Baseline evaluative parameters (size, histologic grade, LOH events) were comparable in the randomly assigned BRB (n = 22) and placebo (n = 18) gel cohorts. Evaluative parameters were: histologic grade, clinical size, and LOH. RESULTS Topical application of the BRB gel to OIN lesions resulted in statistically significant reductions in lesional sizes, histologic grades, and LOH events. In contrast, placebo gel lesions demonstrated a significant increase in lesional size and no significant effects on histologic grade or LOH events. Collectively, these data strongly support BRB's chemopreventive impact. A cohort of very BRB-responsive patients, as demonstrated by high therapeutic efficacy, was identified. Corresponding protein profiling studies, which demonstrated higher pretreatment levels of BRB metabolic and keratinocyte differentiation enzymes in BRB-responsive lesions, reinforce the importance of local metabolism and differentiation competency. CONCLUSIONS Results from this trial substantiate the LOH reductions identified in the pilot BRB gel study and extend therapeutic effects to significant improvements in histologic grade and lesional size.
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Affiliation(s)
- Susan R Mallery
- Authors' Affiliations: Divisions of Oral Maxillofacial Pathology & Radiology and Oral Maxillofacial Surgery & Anesthesiology, College of Dentistry, The Ohio State University; The Ohio State University Comprehensive Cancer, Columbus, Ohio; Departments of Oral & Maxillofacial Pathology and Oral & Maxillofacial Surgery, School of Dentistry, University of Louisville, Kentucky; Departments of Diagnostic Sciences and Oral and Maxillofacial Surgery, University of North Carolina at Chapel Hill School of Dentistry, Chapel Hill, North Carolina; and Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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Panwar A, Lindau R, Wieland A. Management for premalignant lesions of the oral cavity. Expert Rev Anticancer Ther 2014:1-9. [PMID: 24397698 DOI: 10.1586/14737140.2014.842898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Premalignant lesions of the oral cavity present as visibly abnormal areas of mucosa and may be a source of significant anxiety for the patient and the clinician. Suspicious lesions should be biopsied to evaluate for dysplasia. The risk of malignant transformation may relate to patient characteristics, environmental risk factors and genetic alterations. Management of such lesions hinges on risk modification, surveillance, symptom management and directed biopsies. Excision or ablation of dysplastic lesions is indicated. We review the current evidence relating to management of premalignant lesions of the oral mucosa and make recommendations for practice patterns.
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Affiliation(s)
- Aru Panwar
- Division of Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE, USA
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34
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Squamous-cell carcinoma. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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35
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Poi MJ, Knobloch TJ, Sears MT, Warner BM, Uhrig LK, Weghorst CM, Li J. Alterations in RD(INK4/ARF) -mediated en bloc regulation of the INK4-ARF locus in human squamous cell carcinoma of the head and neck. Mol Carcinog 2013; 54:532-42. [PMID: 24302590 DOI: 10.1002/mc.22119] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Revised: 10/31/2013] [Accepted: 11/13/2013] [Indexed: 01/24/2023]
Abstract
The presence of RD(INK4/ARF) (RD) enhancer in the INK4-ARF locus provides a novel mechanism to simultaneously increase the transcription of p15(INK4b) (p15), p14ARF (p14), and p16(INK4a) (p16). While such upregulation can be repressed through interactions between RD and oncoproteins CDC6 and BMI1, little is known about the involvement of RD in cancer. In this study we investigated RD deletions in 30 squamous cell carcinoma of the head and neck (SCCHN) and the patient-matched High At-Risk Mucosa specimens (HARM, "phenotypically normal" tissues neighboring SCCHN foci but beyond the surgical resection margin). RD was deleted (homozygously/heterozygously) in SCCHN and HARM at the incidence of 36.7% (11/30) and 13.3% (4/30), respectively. In comparison, no RD deletion was detected in 26 oral buccal brush biopsy specimens from healthy donors. Both p16 and p14 were lowly expressed in SCCHN and HARM, and their mRNA expression levels were positively associated with each other (P < 0.01). Moreover, BMI1 was highly expressed in both SCCHN and HARM, and BMI1 overexpression was associated with p16 downregulation in SCCHN (P < 0.05). These results indicate that RD deletion and BMI1 overexpression frequently occur in the early stage of oral carcinogenesis and BMI1 overexpression may downregulate the transcription of p16 and p14 through interfering with RD.
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Affiliation(s)
- Ming J Poi
- Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Thomas J Knobloch
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.,Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Marta T Sears
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio
| | - Blake M Warner
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio
| | - Lana K Uhrig
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio
| | - Christopher M Weghorst
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.,Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Junan Li
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.,Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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Issrani R, Prabhu N, Keluskar V. Oral proliferative verrucous leukoplakia: A case report with an update. Contemp Clin Dent 2013; 4:258-62. [PMID: 24015023 PMCID: PMC3757896 DOI: 10.4103/0976-237x.114887] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
White lesions both physiologic as well as pathologic are relatively frequent in the oral cavity, the most common pathology being oral leukoplakia (OL). There are many variants of OL, one of which is oral proliferative verrucous leukoplakia (OPVL). OPVL is a rare clinico-pathological entity, which is slow growing, long-term progressive lesion, but remains an enigmatic and difficult to define. The etiology of OPVL remains still unclear. Tobacco use does not seem to have a significant influence on the appearance of OPVL. These lesions may occur both in smokers and non-smokers. It is observed more frequently in women and elderly patients over 60 years at the time of diagnosis. The buccal mucosa and tongue are the most frequently involved sites. It develops initially as a white plaque of hyperkeratosis that eventually becomes a multifocal disease with confluent, exophytic and proliferative features. Various published case series have presented OPVL as a disease with aggressive biological behavior due to its high probability of recurrence and a high rate of malignant transformation. Prognosis is poor for this seemingly harmless-appearing white lesion of the oral mucosa. This article describes the clinical aspects and histologic features of an OPVL case that demonstrated the typical behavior pattern in a long-standing, persistent lesion and discusses this relatively rare entity in light of current information.
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Affiliation(s)
- Rakhi Issrani
- Department of Oral Medicine and Radiology, Saraswati Dental College, Lucknow, Uttar Pradesh, India
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37
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Arduino PG, Bagan J, El-Naggar AK, Carrozzo M. Urban legends series: oral leukoplakia. Oral Dis 2013; 19:642-59. [PMID: 23379968 DOI: 10.1111/odi.12065] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 11/29/2012] [Accepted: 12/18/2012] [Indexed: 02/06/2023]
Abstract
To date, the term oral leukoplakia (OL) should be used to recognize 'predominantly white plaques of questionable risk, having excluded (other) known diseases or disorders that carry no increased risk of cancer'. In this review, we addressed four controversial topics regarding oral leukoplakias (OLs): (i) Do tobacco and alcohol cause OLs?, (ii) What percentage of OLs transform into oral squamous cell carcinoma (OSCC)?, (iii) Can we distinguish between premalignant and innocent OLs?, and (iv) Is proliferative verrucous leukoplakia (PVL) a specific entity or just a form of multifocal leukoplakia? Results of extensive literature search suggest that (i) no definitive evidence for direct causal relationship between smoked tobacco and alcohol as causative factors of OLs, (ii and iii) the vast majority of OLs follow a benign course and do not progress into a cancer, and no widely accepted and/or validated clinical and/or biological factors can predict malignant transformation, and (iv) the distinction between multifocal/multiple leukoplakias and PVL in their early presentation is impossible; the temporal clinical progression and the high rate of recurrences and development of cancer of PVL are the most reliable features for diagnosis.
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Affiliation(s)
- P G Arduino
- Department of Surgical Sciences, Oral Medicine Section, Lingotto Dental School, University of Turin, Italy.
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38
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Current Management Strategies for Verrucous Hyperkeratosis and Verrucous Carcinoma. Oral Maxillofac Surg Clin North Am 2013; 25:77-82, vi. [DOI: 10.1016/j.coms.2012.11.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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39
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Li J, Knobloch TJ, Poi MJ, Zhang Z, Davis AT, Muscarella P, Weghorst CM. Genetic alterations of RD(INK4/ARF) enhancer in human cancer cells. Mol Carcinog 2012; 53:211-8. [PMID: 23065809 DOI: 10.1002/mc.21965] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 08/25/2012] [Accepted: 08/29/2012] [Indexed: 11/12/2022]
Abstract
Recent identification of an enhancer element, RD(INK4/ARF) (RD), in the prominent INK4/ARF locus provides a novel mechanism to simultaneously regulate the transcription of p15(INK4B) (p15), p14(ARF) , and p16(INK4A) (p16) tumor suppressor genes. While genetic inactivation of p15, p14(ARF) , and p16 in human tumors has been extensively studied, little is known about genetic alterations of RD and its impact on p15, p14(ARF) , and p16 in human cancer. The purpose of this study was to investigate the potential existence of genetic alterations of RD in human cancer cells. DNAs extracted from 17 different cancer cell lines and 31 primary pheochromocytoma tumors were analyzed for deletion and mutation of RD using real-time PCR and direct DNA sequencing. We found that RD was deleted in human cancer cell lines and pheochromocytoma tumors at frequencies of 41.2% (7/17) and 13.0% (4/31), respectively. While some of these RD deletion events occurred along with deletions of the entire INK4/ARF locus, other RD deletion events were independent of genetic alterations in p15, p14(ARF) , and p16. Furthermore, the status of RD was poorly associated with the expression of p15, p14(ARF) , and p16 in tested cancer cell lines and tumors. This study demonstrates for the first time that deletion of the RD enhancer is a prevalent event in human cancer cells. Its implication in carcinogenesis remains to be further explored.
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Affiliation(s)
- Junan Li
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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Kobayashi T, Maruyama S, Abé T, Cheng J, Takagi R, Saito C, Saku T. Keratin 10-positive orthokeratotic dysplasia: a new leucoplakia-type precancerous entity of the oral mucosa. Histopathology 2012; 61:910-20. [DOI: 10.1111/j.1365-2559.2012.04283.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, Bagan L. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: A series of 55 cases. Oral Oncol 2011; 47:732-5. [DOI: 10.1016/j.oraloncology.2011.05.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 05/15/2011] [Accepted: 05/18/2011] [Indexed: 10/18/2022]
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42
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Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry 2011; 50:5566-82. [PMID: 21619050 PMCID: PMC3127263 DOI: 10.1021/bi200642e] [Citation(s) in RCA: 240] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
P16(INK4A) (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly because of the prevalence of genetic inactivation of the p16(INK4A) (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that an elevated level of expression (upregulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications for the structure-function relationship of P16 and for human cancers.
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Affiliation(s)
- Junan Li
- Division of Environmental Health Sciences, College of Public Health, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.
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43
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p16(INK4a)/CDKN2 expression and its relationship with oral squamous cell carcinoma is our current knowledge enough? Cancer Lett 2011; 306:134-41. [PMID: 21411222 DOI: 10.1016/j.canlet.2011.02.039] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Revised: 02/21/2011] [Accepted: 02/23/2011] [Indexed: 11/23/2022]
Abstract
Oral squamous cell carcinomas (OSCC) are the most common malignancy of the oral cavity and their multistep development requires the accumulation of multiple genetic and epigenetic alterations. Inactivation of p16(INK4a), encoded by the CDKN2 gene has been widely associated with this type of tumors. The purpose of this review is to elucidate the relationship between p16(INK4a) expression and the different clinical and pathological aspects of OSCC, analyze the variation in results between studies, detailing the described genetic/epigenetic alterations that result in gene silencing and the relationship between p16(INK4a) and HPV infection.
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Liu W, Shen XM, Liu Y, Li J, Zhou ZT, Wang LZ. Malignant transformation of oral verrucous leukoplakia: a clinicopathologic study of 53 cases. J Oral Pathol Med 2011; 40:312-6. [DOI: 10.1111/j.1600-0714.2011.01016.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Abstract
Proliferative verrucous leukoplakia (PVL) is of uncertain etiology but may be associated with human papillomavirus (HPV) infection. Proliferative verrucous leukoplakia is seen mainly in older women, beginning as a simple slow-growing, persistent leukoplakia that tends to spread and become multifocal and affect the gingival frequently. In time, PVL develops exophytic, wart-like or erythroplakic areas that become squamous carcinomas. Proliferative verrucous leukoplakia appears to resist to all attempts at therapy and often recurs.
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Affiliation(s)
- J Bagan
- Valencia University and Hospital General Universitario de Valencia, Valencia, Spain.
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46
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No mutations found in exon 2 of gene p16CDKN2A during rat tongue carcinogenesis induced by 4-nitroquinoline-1-oxide. J Mol Histol 2009; 40:71-6. [DOI: 10.1007/s10735-009-9215-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2009] [Accepted: 02/18/2009] [Indexed: 10/21/2022]
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