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.

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.

Risk Factors Associated With Malignant Transformation in Patients With Oral Leukoplakia in a Chinese Population: A Retrospective Study.

PURPOSE: The study aim was to investigate the risk factors for the progression of oral leukoplakia (OLK) to malignancy. PATIENTS AND METHODS: The data from 2,628 patients with OLK were retrospectively reviewed. Of these 2,628 patients, 192 had undergone sequential biopsies and were separated into 4 groups according to their final diagnosis. The risk factors were analyzed using Kaplan-Meier univariate survival analysis and Cox multivariate analysis. RESULTS: In 41 of the 2,628 patients (1.7%), the OLK had progressed to cancer, with a mean interval to malignancy of 26.7 months. Of the 192 patients with sequential biopsies, OLK was maintained or had progressed to mild, moderate, or severe dysplasia or carcinoma in 50, 66, 35, and 41 patients, respectively. The 3- and 5-year oral cancer-free survival (OCFS) was 78.9 and 72.5%, respectively. The factors associated with worse overall survival were lesions located in the ventral tongue (P = .04), alcohol use (P = .025), nonhomogeneous lesions (P < .01), and high-risk dysplasia (P < .01). Cox regression analyses indicated that nonhomogeneous lesions (P = .03) and high-risk dysplasia (P < .01) were independent prognostic factors for the progression of OLK to malignancy. CONCLUSIONS: High-risk dysplasia and nonhomogeneous lesions were shown to be important factors for progression to malignancy in patients with OLK. Thus, such patients should receive close follow-up and undergo sequential biopsies in the first 2 to 3 years for early screening of OLK evolving into a malignancy.

Expression of programmed cell death-ligand 1 in oral squamous cell carcinoma and oral leukoplakia is associated with disease progress and CD8+ tumor-infiltrating lymphocytes.

OBJECTIVE: In recent years, monoclonal antibodies targeting programmed cell death-ligand 1 (PD-L1) have become a promising cancer immunotherapy. However, the role of PD-L1 in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs), including oral leukoplakia (OLK), remains controversial. The aim of the present study was to investigate the expression level of PD-L1 in OSCC and OPMDs, and examine its relationship with CD8 expression and different clinicopathological features. METHOD: Expression of PD-L1 and CD8 were conducted in 41 OSCC, 21 OLK, and 25 normal mucosa samples by immunohistochemistry. Then, the density of PD-L1 expression was measured, and its correlation with CD8 expression and different clinicopathological features was analyzed. RESULTS: PD-L1 protein was detected in 97.6% of OSCC, 61.9% of OLK, and 0% of normal tissues. PD-L1 was highly expressed in human OSCC tissue (P < 0.0001), when compared to both OLK and control tissues. PD-L1 positivity was significantly associated with CD8 density (P < 0.0001, r = 0.8491). The PD-L1 high expression OSCC group displayed a trend for improved overall survival (OS) and disease-free survival (DFS) compared to the low expression group, although the differences were not significant. Moreover, the expression level of PD-L1 in OSCC was positively correlated with the pathological grade (P < 0.0001), but it was independent of age, gender, smoking, drinking, tumor size, lymph node status, or recurrence (P > 0.05). Also, there was a significant upregulation of PD-L1 expression observed in the OLK group compared to the control group (P < 0.0001). PD-L1 positivity in OLK patients was associated with gender and smoking habits (P < 0.05), but it did not correlate with age, drinking, or dysplasia (P > 0.05). CONCLUSION: The upregulation of PD-L1 may be associated with disease progress and CD8+ tumor-infiltrating lymphocytes in oral premalignant and malignant lesions.

Survival study of leukoplakia malignant transformation in a region of northern Spain

BACKGROUND: Oral leukoplakia is the most common potentially malignant disorder (PMD) of the oral cavity. The objectives of this study are to determine the clinicopathologic features in a group of patients with oral leukoplakia of Northern Spain (Galicia), determining the factors associated to clinical risk and analyzing the malignant transformation of these patients. MATERIAL AND METHODS: We included 85 patients. We recorded sex and age, habits like alcohol and tobacco, size, clinical appearance, site, number of lesions, and presence or absence of dysplasia. We assess the association between risk factors and transformation and developed a logistic regression analysis. Finally we used the Kaplan-Meier and log-rank test for the survival analysis. RESULTS: 7 patients (8.2%) had malignant transformation. The mean follow-up of the patients was 4.13 years versus 5.58 years of those who developed carcinoma. Only location and initial dysplasia have a statistically significant relationship with malignant transformation, but when applied the long rank test only the presence of dysplasia remains statistically significant (P<0,026). Oral Cancer Free Survival was 81.9% (0.150) at 11 years for the group without dysplasia. CONCLUSIONS: We found that the presence of dysplasia is the only risk factor that is statistically related to the development of a carcinoma

Survival study of leukoplakia malignant transformation in a region of northern Spain.

BACKGROUND: Oral leukoplakia is the most common potentially malignant disorder (PMD) of the oral cavity. The objectives of this study are to determine the clinicopathologic features in a group of patients with oral leukoplakia of Northern Spain (Galicia), determining the factors associated to clinical risk and analyzing the malignant transformation of these patients. MATERIAL AND METHODS: We included 85 patients. We recorded sex and age, habits like alcohol and tobacco, size, clinical appearance, site, number of lesions, and presence or absence of dysplasia. We assess the association between risk factors and transformation and developed a logistic regression analysis. Finally we used the Kaplan-Meier and log-rank test for the survival analysis. RESULTS: 7 patients (8.2%) had malignant transformation. The mean follow-up of the patients was 4.13 years versus 5.58 years of those who developed carcinoma. Only location and initial dysplasia have a statistically significant relationship with malignant transformation, but when applied the long rank test only the presence of dysplasia remains statistically significant(P<0,026). Oral Cancer Free Survival was 81.9% (0.150) at 11 years for the group without dysplasia. CONCLUSIONS: We found that the presence of dysplasia is the only risk factor that is statistically related to the development of a carcinoma.

Cytogenetic biomonitoring in oral leukoplakia patients with mild dysplasia.

OBJECTIVE: A study is made of DNA damage and apoptosis in a group of patients with oral leukoplakia (OL) with mild dysplasia. MATERIALS AND METHODS: The study comprised 30 patients with a clinicopathological diagnosis of OL with mild dysplasia and 30 controls. Both samples were similar in terms of age and gender distribution. Brush samples of lesion epithelial cells were collected, followed by cell centrifugation, preparation of the slides, fixation and staining, and analysis under the fluorescent light microscope. The exfoliated cells were examined to detect micronuclei (MN), nuclear buds, binucleated cells, condensed chromatin, pyknosis, and cells with karyorrhexis and karyolysis. RESULTS: The patients with OL with mild dysplasia showed a greater frequency of MN (P < 0.001), nuclear buds (P = 0.018), and binucleated cells (P = 0.008). CONCLUSIONS: Cytogenetic biomonitoring is a simple and scantly invasive technique allowing clinicians to assess DNA damage and apoptosis in patients with OL. CLINICAL RELEVANCE: Oral cancer should be detected and controlled in its precancerous stages in order to increase survival rates. Leukoplakia lesions must be biomonitorized periodically. Biomonitorization offers sensibility, no morbidity, speed, and low cost.

Predictive value of dysplasia grading and DNA ploidy in malignant transformation of oral potentially malignant disorders.

Dysplasia grading is widely used to assess risk of transformation in oral potentially malignant disorders despite limited data on predictive value. DNA ploidy analysis has been proposed as an alternative. This study examines the prognostic value for both tests used in a routine diagnostic setting to inform clinical management. A retrospective study of conventional dysplasia grading was conducted on 1,401 patients. DNA ploidy analysis was conducted on a subset of 273 patients and results correlated with clinical information, pathologic diagnosis, and outcome over 5 to 15 years. Malignant transformation occurred in 32 of 273 patients (12%) and, of these, 20 (63%) of preexisting index lesions were aneuploid. Of 241 patients not developing carcinoma, only 39 (16%) of index lesions were aneuploid. Epithelial dysplasia correlated with DNA ploidy status (P < 0.001). The overall positive predictive value for malignant transformation by DNA aneuploidy was 38.5% (sensitivity 65.2% and specificity 75%) and by severe dysplasia grade 39.5% (sensitivity 30% and specificity 98%). DNA diploid and tetraploid status had negative predictive value of 90% to 96%. Combining DNA ploidy analysis with dysplasia grading gives a higher predictive value than either technique alone. Each of three traditional dysplasia grades predicts a significantly different risk of carcinoma development and time to transformation. DNA ploidy analysis had equivalent predictive value and also detected additional risk lesions in the absence of dysplasia.

Preoperative circulating C-reactive protein levels predict pathological aggressiveness in oral squamous cell carcinoma: a retrospective clinical study.

OBJECTIVES: Previous studies have demonstrated a relationship between elevated serum C-reactive protein (CRP) levels and shorter survival in cancer patients. Few studies, however, have investigated the role of serum CRP levels in oral squamous cell carcinoma. The present study was conducted to analyze the relationship between preoperative CRP levels, clinicopathologic factors, and prognosis in oral squamous cell carcinoma patients. DESIGN: Retrospective clinical study. SETTING: University teaching hospital. PARTICIPANTS: Eighteen oral cavity leukoplakia and 59 oral squamous cell carcinoma patients between November 2006 and November 2009 from the Chang Gung Memorial Hospital. OUTCOME MEASURES: Clinicopathologic parameters, disease-free survival and overall survival were correlated with CRP levels. METHODS: Serum CRP levels were measured preoperatively, and all oral cavity cancer patients underwent curative intent radical surgery with or without postoperative adjuvant therapy. RESULTS: The CRP levels in leukoplakia patients were used to analyze if factors (including diabetes and liver cirrhosis, smoking, alcohol drinking and areca quid chewing) influence CRP levels, and the results demonstrated they were not associated with CRP elevation (> 5.0 mg/L) (P > 0.05). In oral cancer patients, elevated CRP levels were associated with tumor status (P = 0.005), tumor stage (P = 0.054), bone invasion (P = 0.033), lymph node metastasis (P = 0.004) and lymph node extra-capsular spread (P = 0.018). Patients with higher CRP levels showed poorer disease-free survival (log rank test, P < 0.001) and overall survival (log rank test, P = 0.013). CONCLUSIONS: Preoperative serum CRP levels are associated with advanced tumor stage, bone invasion, lymph node metastasis, lymph node extra-capsular spread and patients' survival. CRP is thus potentially a prognostic indicator, but studies with longer follow-up will be needed to confirm its reliability.

Malignant transformation of oral leukoplakia: a retrospective cohort study of 218 Chinese patients.

BACKGROUND: Oral leukoplakia (OL) is the best-known potentially malignant disorder. A new binary system to grade dysplasia was proposed by WHO, but the biological significance in predicting malignant transformation risk is unknown. The objective of this study is to estimate the rate of malignant transformation in a long-term follow-up cohort, explore the usefulness of the new binary system of grading dysplasia and identify significant risk factors of OL malignant transformation in China. METHODS: A total of 218 patients with clinical and histopathologic diagnosis of OL were retrospectively reviewed. They were selected among all archived files at the Department of Oral Mucosal Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The mean follow-up period was 5.3 years. RESULTS: Among 218 cases, 39 (17.9%) OL patients developed oral cancer, with a mean duration of 5.2 years. Cox regression analysis revealed that dysplasia was an independent risk factor for OL malignant transformation, but age, gender, lesion site, diet habit, smoking and ethanol intake were not risk factors. High-risk dysplastic OL was associated with a 4.57-fold (95% confidence interval, 2.36-8.84; P < 0.001) increased risk of malignant transformation, compared with low-risk dysplasia. Consistent with this result, high-risk dysplastic OL had significantly higher malignant incidence than low-risk dysplasia, particularly during the first 2-3 years of follow-up, by Kaplan-Meier analysis (Log-rank test, P < 0.001). CONCLUSIONS: The new binary system's function in predicting OL malignant transformation risk was investigated in this survey. The utilization of high-risk dysplasia as a significant indicator for evaluating malignant transformation risk in patients with OL was suggested, which may be helpful to guide treatment selection in clinical practice.

Comparison of histological grading and large-scale genomic status (DNA ploidy) as prognostic tools in oral dysplasia.

Approximately one in ten oral white patches (leukoplakia) are histologically classified as dysplasia, with a well-documented potential for developing into oral squamous cell carcinoma (OSCC). Histological grading in oral dysplasia has limited prognostic value, whereas large-scale genomic status (DNA ploidy, nuclear DNA content) is an early marker of malignant transformation in several tissues. Biopsies from 196 patients with oral leukoplakia histologically typed as dysplasia were investigated. Inter-observer agreement among four experienced pathologists performing a simplified grading was assessed by Cohen's kappa values. For 150 of the 196 cases, it was also possible to assess large-scale genomic status and compare its prognostic impact with that of histological grading. Disease-free survival was estimated by life-table methods, with a mean follow-up time of 103 months (range 4-165 months). The primary considered end-point was the subsequent occurrence of OSCC. For grading of the total of 196 cases, kappa values ranged from 0.17 to 0.33 when three grading groups (mild, moderate, and severe dysplasia) were considered, and from 0.21 to 0.32 when two groups (low grade and high grade) were considered (p=0.41). For the 150 cases in which large-scale genomic status was also assessed, kappa values for the histological grading ranged from 0.21 to 0.33 for three grading groups and from 0.27 to 0.34 for two grading groups (p=0.47). In survival analysis, histological grading was without significant prognostic value for any of the four observers (p 0.14-0.44), in contrast to DNA ploidy (p=0.001). It is concluded that DNA ploidy in oral dysplasia has a practical prognostic value, unlike histological grading of the same lesions.

Follow-up of oral leukoplakia after carbon dioxide laser surgery.

We evaluate the 3-year result of 145 oral leukoplakias operated on by outpatient carbon dioxide laser surgery at the Istituto Nazionale Tumori, Milan, Italy. The surgical technique that was used consisted of excision in 140 patients and vaporization in 5 patients. Cancer was found in 14 out of 140 patients who underwent excision (10%). In the analysis of the disease-free survival rate and of the unfavorable pattern of events, only 131 patients with benign postoperative histologic diagnosis were considered. Fifty-eight patients developed unfavorable events. The probabilities of remaining free of disease or of developing local relapses or new lesions at 3-year survival was 0.57, 0.27, and 0.19, respectively. Two patients had oral carcinomas after the operation. Forty patients modified their alcohol or tobacco habits or their teeth and/or prosthesis. Moreover, only two patients modified these factors before the unfavorable events occurred.