Proliferative verrucous leukoplakia: a case report

Proliferative verrucous leukoplakia (PVL) is a particularly aggressive form of oral leukoplakia that is resistant to treatment and presents a high risk of recurrence and malignant transformation. This article describes the microscopic and clinical characteristics of one case of PVL, which initially presented as hyperkeratosis with mild dysplasia and posteriorly developed multifocal areas and verrucous carcinoma despite treatment.     

Clinicopathological features and immunohistochemical expression of p53, Ki‐67, Mcm‐2 and Mcm‐5 in proliferative verrucous leukoplakia

J Oral Pathol Med (2010) 39 : 447–452 Background: Proliferative verrucous leukoplakia (PVL) is a distinct and aggressive type of oral leukoplakia which affects elderly women without risk behavior and presents high rates of malignant transformation. The objective of the present study was to evaluate the clinicopathological characteristics and the distribution of cell proliferation markers, aiming to elucidate the distinct biological behavior of the PVL. Methods: Clinical and microscopical features of 12 patients with PVL were reviewed. Immunohistochemical analysis for p53, Ki‐67, Mcm‐2 and Mcm‐5 were performed and the data were correlated. Results: All patients were women, above 50 years of age, 91.7% were non‐smoker and 100% were non‐habitual drinker. Alveolar ridge (66.6%), tongue (50%) and buccal mucosa (41.6%) were the most affected sites. Four patients developed squamous cell carcinoma (SCC). The immunohistochemical findings showed higher positivity for p53, Ki‐67, Mcm‐2 and Mcm‐5 in SCCs. However, some patients with mild or moderate dysplasia, specially the patients who developed SCC, presented high expression of Mcm‐2 and Mcm‐5. Conclusions: High immunoexpression of Mcm‐2 and Mcm‐5 in mild and moderate dysplasia could be helpful to predict the malignant transformation of PVL.     

Malignant transformation of oral proliferative verrucous leukoplakia: a series of 48 patients with suggestions for management

Proliferative verrucous leukoplakia (PVL) is a rare and refractory form of oral mucosal leukoplakia of unknown origin, characterized by high rates of malignant transformation. Different diagnostic criteria, terminologies, and therapeutic approaches have been proposed since the first report in 1985. There remains no general agreement regarding the clinical and histological diagnosis, prevention, and correct management of this disease. This retrospective study investigated 48 patients affected by PVL showing at least one malignant transformation and followed up at 2-month intervals. Twenty-five were female (52.1%) and 23 (47.9%) were male; their median age was 67 years (range 40–93 years). Follow-up ranged from 18 to 240 months. Clinical examination included the use of Lugol’s solution to prevent clinical underestimation of the margins and toluidine blue for suspicious areas. Surgical excision by scalpel was the preferred treatment for suspicious lesions, with only five carcinomas surgically removed by diode laser and two by CO₂ laser. All specimens were accurately mapped after formalin fixation. Fifteen patients (31.3%; 10 female, five male) developed one oral carcinoma, while 33 (68.7%) developed two or more primary tumours (range 3–12). Only four patients (8.3%), who developed between 2 and 8 oral squamous cell carcinomas (OSCCs), died of tumour-related causes. The pre-surgical clinical workup, subsequent surgical treatment, and follow-up are key to success for patients affected by PVL with malignant transformation into stage 1 OSCC and/or verrucous carcinoma, leading to a high overall survival rate.     

Aggressive,multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?

BACKGROUND: Some oral verrucal lesions may constitute parts of the clinicopathological spectrum of proliferative verrucous leukoplakia (PVL). Because of its idiopathic yet sinister nature, it is possible that PVL may exist in other populations. The aim of this study was to review the clinicopathological features of persistent, multifocal, oral verrucal lesions in Malaysian population. METHODS: Patients with multifocal oral verrucal lesions were selected from surgical and histopathological records. RESULTS: Nine patients of diverse ethnicity with 43 biopsies were reviewed. The mean age at the presentation was 62 years. The most frequent sites affected were gum, sulci, cheek and tongue. Indulgence in risk habits was reported in about 70% of patients. Four cases developed multifocal carcinoma from multifocal leukoplakia. CONCLUSIONS: In retrospect, none of the cases fulfilled the original PVL criteria, although three cases were suggestive of PVL. Nevertheless, these findings do not necessarily preclude the existence of PVL as a clinicopathological entity in Malaysian population.     

The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective study

OBJECTIVES: The possible malignant transformation of oral lichen planus (OLP) is the subject of an ongoing and controversial discussion in the literature. The main criticism of studies on this subject relates to the lack of sufficient data to support the initial diagnosis of OLP in cases that finally developed into squamous cell carcinoma. We describe the possible premalignant character of OLP and oral lichenoid lesions (OLL) of a prospectively followed cohort of patients with detailed documentary data. STUDY DESIGN: A study group of 173 patients, 62 patients diagnosed with OLP and 111 patients with OLL, according to revised, modified World Health Organization diagnostic criteria, was followed up from 6.6 to 72.0 months (mean, 31.9 months). The expected number of patients with oral cancer in the group of patients with OLP and in the group of patients with OLL was estimated by comparing the number of patients, their ages, sex, and the length of follow-up to annual incidence rates of oral cancer for the general Dutch population, to explore the possibility of coincidental carcinomas. The binomial test was used to determine whether the observed number of cases of cancer in the OLP group and the OLL group exceeded the expected numbers. RESULTS: Three of 173 patients (1.7%), 2 men and 1 woman, developed squamous cell carcinomas of the oral mucosa during follow-up. All malignant transformations occurred in the OLL group. The annual malignant transformation rate, based on a mean follow-up of 31.9 months, was calculated as 0.65% per year. A comparison of the expected against actual figures for the development of carcinomas revealed no increase in patients with OLP and a 219-fold increase in patients with OLL, with the latter not statistically significant, but with a P value of .083, suggesting at least a trend. CONCLUSION: Our results give support to the hypothesis that patients with OLL have an increased risk of oral cancer, but this increased risk was not detected in our sample of patients with OLP. Before a final statement with regard to the premalignant character of OLP and OLL can be formulated, the present follow-up study should be prolonged and expanded with a larger number of patients. Until then, we advise that patients with OLP and OLL should undergo biannual follow-up examinations. Follow-up will be particularly important in patients with OLL who have atrophic/erosive/ulcerative lesions.     

Proliferative verrucous leukoplakia and its progression to oral carcinoma: a review of the literature

BACKGROUND: Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathological features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically. METHODS: A PubMed search was conducted which identified studies that examined patients with PVL and reported data meeting inclusion criteria. RESULTS: PVL is seen much more frequently in females and most often diagnosed after the sixth decade of life. Tobacco use is not strongly linked to the presence of PVL (63% of patients did not use tobacco products). Most (74%) of the patients with PVL progressed to oral carcinoma. CONCLUSION: PVL is a persistent and progressive oral lesion that requires very close follow-up along with early and aggressive treatment to increase the chances of a favorable outcome.     

Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases

Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathologic features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically. We present three cases of PVL that progressed to carcinoma and discuss the histopathologic findings that may either hinder or assist in the diagnosis.     

Leucoplachia verrucosa proliferativa. Analisi retrospettiva di 12 casi

Objectives

Proliferative verrucous leukoplakia (PVL) is a potentially malignant disorder characterized by highly aggressive behavior and a marked tendency to neoplastic transformation. In this retrospective study, we analyzed the epidemiologic, clinical and histopathological features of 12 cases of PVL with particular emphasis on the type and outcome of treatment.

Materials and methods

Using the original diagnostic criteria proposed by Hansen, we selected 12 patients with PVL who were referred to the Unit of Oral Medicine and Oral Pathology (Odontostomatology Department) of the University Hospital of Parma between January 1993 and January 2010.

Results

Ten patients (83.3%) were females; the mean age of the total group was 70.1 years. The buccal mucosa, tongue, and adherent gingiva were the most frequently involved oral sites. Eight patients (60.0%) developed an oral carcinoma during the follow-up. The mean interval between the first visit and the diagnosis of malignancy was 33.8 months. The cancers involved the tongue (3 cases), buccal mucosa (2 cases), gingiva (2 cases), and hard palate (1 case). Different therapeutic approaches were utilized: medical therapy with topical retinois or topical clobetasol, surgical removal of the lesions with traditional cold-blade technique, quantic molecular resonance scalpel, Nd:YAG laser, and Er:YAG laser vaporization. Only one patient was disease-free at the last follow-up visit.

Conclusions

This experience confirms the high rate of malignant transformation and recurrence associated with PVL. None of the therapeutic approaches proved to be completely effective. Therefore, patients with PVL need close follow-up (every 3-4 months) to insure early detection of malignant lesions.     

Evaluation on Malignant Transformation of Oral Lichen Planus

目的：口腔扁平苔藓（oral lichen planus,OLP)是否属于癌前病变，至今仍存在较大的争论。本文的目的在于评估OLP的癌变性质。方法：报告1995－2002年之间9例OLP的癌变病例。结果：5例OLP患者同时或继发为口腔鳞状细胞癌，1例为疣状癌，3例为上皮异常增生。其中7例发生在原OLP存在的部位，1例发生在其它部位，1例在同一部位同时存在OLP和鳞状细胞癌。OLP的癌变常发生在糜烂型和萎缩型，发生于颊粘膜，舌或牙龈。根据所制定的OLP的诊断及癌变标准，4例OLP患者发生了癌变。结论：OLP具有一定的癌变潜力，对OLP患者应每年随访2－4次，尤其是对发生在颊粘膜，舌或牙龈的糜烂型和萎缩型的患者。     

口腔扁平苔藓、白斑及鳞癌棘细胞形态计量学分析

目的:从形态计量学角度探讨口腔扁平苔藓(OLP)癌变的可能性,并为口腔黏膜良恶性病变的鉴别诊断提供客观参考资料。方法:采用多功能图象分析系统对取自口腔黏膜的正常、口腔扁平苔藓(OLP)、伴轻、中度上皮异常增生白斑(LK)、鳞癌(SCC)的上皮棘层细胞及胞核进行形态计量学研究分析,选择表示细胞及细胞核大小和形状的二维参数9个,体视学参数10个,并比较这些参数在各组间的变化趋势及差异。结果:无论从二维或三维的各项形态学指标,OLP的测量值都处于正常与LK和鳞癌之间,与正常组相比,各参数值多无显著性差异,而与鳞癌组差异显著。结论:OLP是一种介于正常与轻、中度上皮异常增生之间的病变,具有一定的癌变倾向,但癌变潜能低于癌前白斑。二维定量和三维定量结合可更全面地反映口腔黏膜癌变过程中细胞及细胞核的量变质变过程;核质比值、细胞核体积密度可作为鉴别良恶性病变的参考指标。     

Urban legends series: oral leukoplakia

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.     

The malignant transformation of oral lichen planus and oral lichenoid lesions: A systematic review

BackgroundDetermining the potential for malignant transformation of oral lichen planus (OLP) is complicated by difficulties in diagnosis, differentiation from oral lichenoid lesions (OLLs) and the phenomenon of premalignant lesions' exhibiting lichenoid characteristics. The authors of this systematic review evaluated evidence regarding malignant transformation of OLP and characterized transformation prevalence, clinical characteristics of OLP lesions developing into squamous cell carcinoma (SCC) and time to transformation.Types of Studies ReviewedThe authors searched PubMed, Embase and Thomson Reuters Web of Science in a systematic approach. They evaluated observational English-language studies involving human participants published in peer-reviewed journals. Inclusion required patients to have the diagnosis of OLP or OLL as confirmed with biopsy results on initial enrollment. They excluded all patients who had dysplasia on initial biopsy of OLP or OLL lesions.ResultsSixteen studies were eligible. Among 7,806 patients with OLP, 85 developed SCC. Among 125 patients with OLL, four developed SCC. The rate of transformation in individual studies ranged from 0 to 3.5 percent. The overall rate of transformation was 1.09 percent for OLP; in the solitary study in which investigators evaluated OLL, the rate of transformation was 3.2 percent. Patients' average age at onset of SCC was 60.8 years. The authors noted a slight predominance of female patients among those who experienced malignant transformation. The most common subsite of malignant transformation was the tongue. The average time from diagnosis of OLP or OLL to transformation was 51.4 months.Practical ImplicationsA small subset of patients with a diagnosis of OLP eventually developed SCC. The most common demographic characteristics of patients in this subset were similar to the most common demographic characteristics associated with OLP in general (that is, being female, being older and being affected in areas common to this condition). It is prudent for clinicians to pursue continued regular observation and follow-up in patients with these conditions, even in patients who do not fit a traditional high-risk category for oral SCC.     

口腔白斑、扁平苔藓细胞凋亡相关蛋白Bax表达的研究

目的 :探讨口腔白斑、扁平苔藓的癌变机理及发病机制。方法 :采用免疫组化法检测 10例正常口腔黏膜上皮 ,18例扁平苔藓 ,2 3例白斑 ,2 2例口腔鳞癌上皮组织中凋亡相关蛋白Bax的表达水平。结果 :白斑中上皮单纯增生、轻度、中度不典型增生和低分化鳞癌及糜烂型扁平苔藓的Bax蛋白显过度表达 ,与正常口腔黏膜上皮相比有显著性差异。结论 :Bax参与了口腔白斑癌变的早期过程 ,Bax的表达水平可作为临床监测白斑癌变倾向的参考指标。扁平苔藓的发病机制可能与细胞免疫亢进刺激Bax过度表达诱导角朊细胞凋亡有关 ,扁平苔藓的癌变机理有待进一步研究     

Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma

BACKGROUND: Proliferative verrucous leukoplakia (PVL) is a multifocal and progressive lesion of the oral mucosa, often associated with papillomavirus, seen mainly in older females, and characterized by a high recurrence rate and high rate of transformation into verrucous or oral squamous cell carcinoma (OSCC). The aim of this study was to analyse the clinical characteristics of a substantial group of patients with PVL, evaluating the characteristics of those who developed cancer, and comparing them with a group of patients with OSCC but no preceding PVL. METHODS: A group of 30 patients with PVL was studied for the clinical aspects and characteristics, age, sex, location, recurrence, the appearance of new lesions, and the frequency of development of oral cancer. A disease control group was formed with 110 patients with OSCC chosen randomly from among those treated in the same Service in this period of time. The patients were grouped as PVL and no cancer (Group 1); PVL developing cancer (Group 2) and patients with OSCC without clinical lesions associated with PVL (Group 3). RESULTS: The average age of the PVL patients (Groups 1 and 2 combined) was 70.97 +/- 12.73 years, of which 80% were women. Only 23.3% were cigarette smokers. The area most frequently affected with PVL was the lower gingiva. Recurrence after treatment was seen in 86.7%, and new lesions appeared in 83.3%. Many (63.3%) developed cancer (Group 2). Comparison of Groups 2 and 3 patients showed that those with PVL developing cancer were more likely to develop gingival carcinoma and also to be older, more often females, and less likely to smoke tobacco. CONCLUSION: Cancer developing in patients with PVL manifested particularly on the gingiva.     

Proliferative verrucous leukoplakia. A long-term study of thirty patients

Up to 6% of oral leukoplakia, a relatively common mucosal disease, can be expected to become malignant. This report describes a long-term study of 30 patients in whom a particular form of leukoplakia was identified and labeled proliferative verrucous leukoplakia (PVL), a disease of unknown origin, which exhibits a strong tendency to develop areas of carcinoma. PVL begins as a simple hyperkeratosis but tends to spread and become multifocal. PVL is slow-growing, persistent, and irreversible, and in time areas become exophytic, wartlike, and apparently resistant to all forms of therapy as recurrence is the rule. The disease was most commonly seen in elderly women and had been present for many years. Patients were followed for 1 to 20 years. Thirteen died of or with their disease, 14 were alive with PVL, and 3 were alive without PVL at last contact. PVL rarely regressed despite therapy. All patients who died had persistent or recurrent disease. PVL appears to constitute a continuum of hyperkeratotic disease, ranging from a simple hyperkeratosis at one end to invasive squamous cell carcinoma at the other. Microscopic findings are dependent upon the stage of the disease's development and the location and adequacy of the biopsy.     

Epstein-Barr virus in oral proliferative verrucous leukoplakia and squamous cell carcinoma: A preliminary study

The aim of this study was to analyze proliferative verrucous leukoplakia (PVL) and oral squamous cell carcinoma (OSCC) for the possible presence of Epstein-Barr virus (EBV). We studied three groups: Sub-Group 1 was composed of 10 patients with PVL, (6 of whom had developed OSCC); Sub-Group 2 comprised 5 patients with OSCC but no preceding PVL; and Sub-Group 3 were 5 controls with clinically normal oral mucosa. Oral biopsies from all cases were examined for Epstein-Barr virus (EBV) by nested PCR. EBV was detected in 60% of Sub-Group 1 patients (PVL ) and in 40% of Sub-Group 2 (OSCC), but in 0% of Sub-Group 3 (controls).     

Pre-malignant lesions of the oral mucosa in a South African sample--a clinicopathological study

The clinicopathological features of 130 cases of leukoplakia and 8 patients with erythroplakia of the oral mucosa are reviewed. Cases were selected on the basis of definitions agreed to at an international seminar. The patients with leukoplakia were predominantly men, (1.5:1), most were White (86.2%) and the peak age frequency was the 7th decade. The sites most frequently affected were the buccal mucosa (28.8%), floor of mouth (18.3%), alveolar ridge and gingivae (17.3%) and tongue (12.0%). Clinically, they were classified as homogeneous leukoplakia (70.6%), erythroleukoplakia (11.2%), verrucous leukoplakia (10.6%) and nodular leukoplakia (7.6%). There were no differences in age or site distribution between the sexes but the women tended to have more nodular and verrucous lesions. Most of the patients were smokers (71.5%). There was a highly significant sex difference (p less than 0.01) in the use of tobacco with 42.3 per cent of the women and 19.2 per cent of the men never having used tobacco. The tobacco users were significantly younger (p less than 0.05). Of the 143 lesions biopsied, 60.8 per cent showed no dysplasia, 28.0 per cent mild or moderate dysplasia, 4.2 per cent severe dysplasia/carcinoma-in-situ and 7.0 per cent verrucous or squamous carcinoma. Homogeneous leukoplakias have a very low frequency of dysplasia while in the case of the other clinical types the frequencies of dysplasia and malignancy are substantially higher reaching 33.3 per cent invasive malignancy in the case of the nodular lesions. The sites at greatest risk are the floor of the mouth, soft palate, alveolar ridge/gingivae, tongue and buccal mucosa in order of decreasing frequency.(ABSTRACT TRUNCATED AT 250 WORDS)     

口腔黏膜癌前病变及口腔鳞癌中bFGF的表达及意义

目的　探讨口腔黏膜癌前病变及口腔鳞癌的发生、发展过程中bFGF的表达及意义。方法　应用免疫组织化学方法对 10例正常口腔黏膜、2 7例口腔扁平苔藓、2 4例口腔白斑及 3 0例口腔鳞癌分别进行检测。结果　口腔鳞癌组织中bFGF高表达 ,明显高于正常口腔黏膜、口腔扁平苔藓和口腔白斑组织 (P <0 .0 5 ) ;口腔扁平苔藓和口腔白斑组织中bFGF表达高于正常口腔黏膜 (P <0 .0 5 )。结论　bFGF的过表达在口腔鳞癌的发生、发展过程中起着十分重要的作用 ,可以将其作为预测口腔黏膜恶变潜能的重要标志物     

凋亡蛋白Bcl-2、Bax在白斑、口腔扁平苔藓中的表达

目的:观察凋亡蛋白Bcl-2、Bax在白斑、口腔扁平苔藓上皮细胞中的表达,探讨其在口腔白斑、口腔扁平苔藓癌变过程中的作用机制。方法:采用免疫组化法检测10例正常口腔黏膜上皮、18例口腔扁平苔藓、23例白斑、22例口腔鳞癌上皮组织中凋亡相关蛋白Bcl-2、Bax的表达水平。结果:Bcl-2在白斑、口腔扁平苔藓上皮细胞层无异常表达,但在口腔扁平苔藓淋巴细胞浸润带过度表达。Bcl-2在鳞癌组织中呈高表达,与正常黏膜相比有显著性差异(P<0.05)。Bax在上皮单纯增生、轻度、中度不典型增生和低分化鳞癌及糜烂型口腔扁平苔藓组织中呈过度表达,与正常黏膜相比有显著性差异(P<0.05)。结论:Bax参与了口腔白斑癌变的早期事件,而Bcl-2在不典型增生转化为鳞癌的阶段并未发生作用。口腔扁平苔藓的发病机制可能与Bcl-2抑制淋巴细胞凋亡,使细胞免疫亢进,从而刺激上皮细胞Bax过度表达,诱导角朊细胞凋亡有关。     

口腔黏膜癌前病变及鳞状细胞癌中VEGF的表达及意义

目的 :探讨VEGF在口腔扁平苔藓、口腔白斑、口腔鳞状细胞癌中的表达及其在口腔鳞癌发生、发展过程中的意义。方法 :应用VEGF多克隆抗体对 10例正常黏膜、2 7例口腔扁平苔藓、2 4例口腔白斑及 30例口腔鳞状细胞癌分别进行免疫组化检测。结果 :VEGF在口腔鳞状细胞癌组织中高表达 ,与口腔扁平苔藓、口腔白斑、正常口腔黏膜组织存在着显著性差异 (P <0 .0 5 ) ;在口腔扁平苔藓和口腔白斑中VEGF有一定的表达 ,且表达强度强于正常口腔黏膜组 (P <0 .0 5 )。结论 :VEGF的过表达与口腔鳞癌的发生、发展有关 ,可以将其作为预测口腔黏膜恶变潜能的重要标志物。