Association of oral lichen planus with hepatic disorders and hepatocellular carcinoma: systematic review and meta-analysis.

BACKGROUND: Oral lichen planus (OLP) is a prevalent autoimmune chronic inflammatory disease of unknown etiology. The importance of the association between hepatic disease and OLP lies in the fact that many of these disorders (HC, HB, cirrhosis, hepatic steatosis) behave as risk factors for hepatocellular carcinoma. MATERIAL AND METHODS: We searched PubMed, Embase, Web of Science, and Scopus for studies published before January 2022. We evaluated the quality of studies (Joanna Briggs Institute tool). We performed meta-analyses, investigated the heterogeneity between studies, and we also carried out subgroups, meta-regression, and small-study effects analyses. 146 studies (21,187 patients) were included in this study. Our study aims to evaluate current evidence on the prevalence and magnitude of association between hepatic diseases (especially those with risk of malignancy), hepatocellular carcinoma and OLP. RESULTS: Our results suggest that patients with OLP present a significant tendency to the development of hepatitis B (OR=1.62, 95%CI=1.01-2.40, p=0.02), hepatitis C (OR=4.09, 95%CI=2.77-6.03, p<0.001), cirrhosis (OR=5.58, 95%CI=1.83-16.96, p=0.002), hepatic steatosis (OR=5.71, 95%CI=0.97-33.60, p=0.05) and hepatocellular carcinoma (OR=3.10,95%CI=1.14-8.43, p=0.03). CONCLUSIONS: Patients with OLP should be investigated to rule out the presence of hepatic disease, which can lead to hepatocellular carcinoma, allowing an early diagnosis that would help to a better approach to liver disease and a notable improvement in prognosis in terms of both progression and severity.

Dysplasia in oral lichen planus: relevance, controversies and challenges. A position paper.

BACKGROUND: Patients with oral lichen planus (OLP) have an increased risk of oral cancer. For this reason, OLP is classified as an oral potentially malignant disorder. However, the precise personal (or individual) risk is unknown. Recent meta-analytical studies have reported that dysplastic OLP may transform to cancer in around 6% of cases, while the rate of transformation is lower (<1.5%) in non-dysplastic cases. The presence of epithelial dysplasia has emerged as the most powerful indicator for assessing cancer risk in oral potentially malignant disorders in routine practice. However, the general acceptance of epithelial dysplasia as an accompanying histologic feature in OLP is subject to great controversy. Many pathologists consider the presence of dysplasia as a criterion to exclude OLP when routinely reporting on this disease. This practice, widespread among oral pathology professionals, has resulted in the underestimation of the potential for malignancy of OLP. MATERIAL AND METHODS: A review of the literature was carried out in order to critically analyze the relevance, controversies and challenges encountered across the diagnosis of epithelial dysplasia in OLP. RESULTS: 12 studies have been published examining dysplastic changes in OLP, reporting figures ranging from 0.54% to 25% of cases with dysplasia in the first diagnostic biopsy. The diagnosis of dysplasia in the OLP poses an additional difficulty due to the fact that the affected oral epithelium per se develops changes related to autoimmune aggression. Among the most frequent histological features of OLP that develops dysplasia are basal cell hyperplasia with basaloid appearance, loss of basal cells polarity, cellular and nuclear pleomorphism and irregular stratification. CONCLUSIONS: Epithelial dysplasia should not be considered an exclusion criterion for OLP; its evaluation requires experienced pathologists in this field.

Significance of cytoplasmic cyclin D1 expression in oral oncogenesis.

OBJECTIVES: To examine cytoplasmic cyclin D1 expression levels in oral carcinogenesis and evaluate their possible oncogenic significance and their clinicopathological and prognostic implications. MATERIALS AND METHODS: Immunohistochemical analysis of 69 oral squamous cell carcinomas (OSCCs) was performed, revealing 23 with cytoplasmic cyclin D1 expression. We analyzed the association of the percentage of cyclin D1-positive cells and the intensity of expression with TNM classification, tumor stage, differentiation degree, cell morphology, and Ki-67 expression. RESULTS: Cytoplasmic cyclin D1 expression was associated with advanced tumor stage, poor differentiation, elevated Ki-67 expression, and the presence of invasive cell morphology, indicators of a poor prognosis. An association was observed between nuclear and cytoplasmic expressions of cyclin D1. CONCLUSIONS: Cytoplasmic expression of cyclin D1 appears to possess functions related to increased cell migration and invasion in OSCC.

Outcomes of oral lichen planus and oral lichenoid lesions treated with topical corticosteroid.

OBJECTIVE: To determine corticosteroid treatment effectiveness in patients with oral lichen planus/oral lichenoid lesions (OLP/OLL). MATERIAL AND METHODS: Twenty-one patients with OLP and eighty-one patients with OLL received 0.05% clobetasol propionate (CP) or 0.05% triamcinolone acetonide (TA) in aqueous solution (AS) or orabase (OB), evaluating responses to treatment and follow-up compliance. RESULTS: Lesions were atrophic (72 of 102; 70.6%), extensive (58 of 100; 58%), producing eating difficulties (62 of 102; 60.8%), and spontaneous pain (30 of 102; 29.4%); 50 patients (49%) received CP-AS. The mean ± SD percentage of follow-ups attended was 43 ± 32%. Symptom remission was achieved in 46% of patients receiving CP-AS, 36.36% of those receiving TA-AS, 20% of those receiving CP-OB, and 25% of those receiving TA-OB. Follow-up compliance was poor in 66.7% of patients. Among 51 patients with continuous symptoms, 64.7% evidenced total remission at treatment completion; among 33 with intermittent symptoms, 73.1% had outbreaks 2-3 times/year and 51.5% controlled outbreaks with <6 corticosteroid applications. Adverse effects were observed in seven patients (6.8%) (moon face, hirsutism, capillary fragility) in induction stage, subsiding with dose; among 15 patients under maintenance treatment for >6 months, one showed hypothalamic-pituitary-adrenal (HPA) axis inhibition but not adrenal insufficiency. CONCLUSIONS: Our treatment proved highly effective and safe. Recall programs are desirable to enhance follow-up compliance.

Is oral cancer incidence among patients with oral lichen planus/oral lichenoid lesions underestimated?

BACKGROUND: Oral lichen planus (OLP) and oral lichenoid lesions (OLL) are considered potentially malignant disorders with a cancer incidence of around 1% of cases, although this estimation is controversial. The aim of this study was to analyze the cancer incidence in a case series of patients with OLP and OLL and to explore clinicopathological aspects that may cause underestimation of the cancer incidence in these diseases. METHODS: A retrospective study was conducted of 102 patients diagnosed with OLP (n = 21, 20.58%) or OLL (n = 81) between January 2006 and January 2016. Patients were informed of the risk of malignization and followed up annually. The number of sessions programmed for each patient was compared with the number actually attended. Follow-up was classified as complete (100% attendance), good (75-99%), moderate (25-74%), or poor (<25% attendance) compliance. RESULTS: Cancer was developed by four patients (3.9%), three males and one male. One of these developed three carcinomas, which were diagnosed at the follow-up visit (two in lower gingiva, one in floor of mouth); one had OLL and the other three had OLP. The carcinoma developed in mucosal areas with no OLP or OLL involvement in three of these patients, while OLP and cancer were diagnosed simultaneously in the fourth. Of the six carcinomas diagnosed, five (83.3%) were T1 and one (16.7%) T2. None were N+, and all patients remain alive and disease-free. CONCLUSIONS: The cancer incidence in OLP and OLL appears to be underestimated due to the strict exclusion criteria usually imposed.

An update on the implications of cyclin D1 in oral carcinogenesis.

Cyclin D1 promotes cell cycle progression during G1 phase, a key event in G1-S transition. The protein is encoded by gene CCND1, located in chromosomal band 11q13. Cyclin D1 plays key roles in cell biology, including cell proliferation and growth regulation, mitochondrial activity modulation, DNA repair, and cell migration control. CCND1 gene and its protein cyclin D1 are frequently altered by different molecular mechanisms, including amplification, chromosomal translocations, mutations, and activation of the pathways involved in cyclin D1 expression, alterations which appear to be essential in the development of human cancers, including oral carcinoma. This is the first published review of the specific features of cyclin D1 overexpression in oral oncogenesis. Starting with the physiological regulation of cyclin D1, there is an evaluation of its functions, overexpression mechanisms, and the implications of the oncogenic activation of CCND1/cyclin D1 in oral squamous cell carcinoma. The potential diagnostic and prognostic value of cyclin D1 is reviewed. The influence of CCND1/cyclin D1 on tumor size and clinical stage is reported, and an update is provided on the utilization of cyclin D1 as therapeutic target and on the combination of cyclin D1 inhibitors with cytotoxic agents. Future research lines in this field are also proposed.

Asymmetrical proliferative pattern loss linked to cyclin D1 overexpression during malignant transformation of the lip epithelium.

BACKGROUND: There is inadequate knowledge on the involvement of oncogenic mechanisms linked to the cyclin (CCND1) gene in lip squamous cell carcinoma (LSCC). OBJECTIVE: The aim of this study was to analyse the implication of cyclin D1 in the malignant transformation of lip lesions. METHODS: We immunohistochemically studied 45 actinic cheilitis cases (15 mild dysplasia, 15 moderate dysplasia, 15 severe dysplasia/carcinoma in situ), 30 LSCC cases with adjacent non-tumour epithelium and 15 normal oral epithelium samples for detection of cyclin D1, ß-catenin and Ki-67. RESULTS: Cyclin D1 and Ki-67 expressions were significantly increased in the basal layer of premalignant epithelia and peripheral layers of tumour nests vs. CONTROLS: Premalignant epithelia had lost their asymmetrical proliferative pattern. CONCLUSION: Lip carcinogenesis was associated with loss of the asymmetrical proliferative pattern, a preventive mechanism against lip oncogenesis, and with cyclin D1 overexpression.

Asymmetrical proliferative pattern loss during malignant transformation of the oral mucosa.

OBJECTIVES: The aim of this study was to study the loss of asymmetrical proliferation in oral tumorigenesis. MATERIALS AND METHODS: Samples: 92 oral squamous cell carcinomas (OSCC) with associated non-tumor epithelia (NTE). NTE and tumor were classified as distant from or close to the invasion point. Immunohistochemistry was performed using Mib-1 antibody. Ki-67 was assessed in basal, parabasal layer, medium and upper third, counting total and positive cells. Proliferative patterns were classified according to the ki-67 expression: 1 = expression in parabasal layers of well-differentiated tumor nest (WDTN); 2 = expression in parabasal and basal layers of WDTN; 3 = ki-67 expression in <20% cells in tumor tissue without WDTN; 4 = ki-67 expression in ≥20% of cells in tumor tissue without WDTN; and 5 = ki-67 expression exclusively found in basal layers of WDTN. RESULTS: Ki-67 expression was highest in parabasal layers of both close and distant NTE (39.7 ± 27.6 and 30.1 ± 20) and was also elevated in the close (43.4 ± 21.3) and distant (48.8 ± 21.9) tumor tissue samples. Close tumors largely corresponded to proliferation patterns 2 and 4, while distant tumors generally followed pattern 4. Of the 92 close NTE samples, 23 showed reduced basal proliferation with increased parabasal proliferation. Tumors derived from these epithelia followed patterns 2 (52%, 12/23 cases) or 4 (30.4%, 7/23 cases). Parabasal proliferation in distant NTE was significantly increased in patients with multiple vs. single tumors (36.7% vs. 25.4%; P = 0.032). CONCLUSION: The change from asymmetrical to symmetrical division appears to be an oncogenic mechanism in oral carcinogenesis.

Atraumatic restorative treatment and Carisolv use for root caries in the elderly: 2-year follow-up randomized clinical trial.

OBJECTIVES: New preventive and treatment strategies are required to address the high prevalence of caries among the elderly. The main objective of this study was to analyze the effectiveness of Carisolv® gel to improve the clinical behavior of restorations obtained by atraumatic restorative treatment (ART) in root caries of elderly patients. A secondary objective was to determine the factors associated with the failure of ART restorations after a 2-year follow up. MATERIAL AND METHODS: A randomized controlled trial with 2-year follow-up was designed for this purpose. Candidate caries lesions were randomly assigned to an ART group for root caries treatment with the conventional ART technique, filling with glass ionomer, or an ART + Carisolv® gel for the same ART plus the application of a caries solvent (Carisolv®). Evaluations were conducted at 6, 12, and 24 months. RESULTS: A total of 81 restorations were performed, 37 in the ART group and 44 in the ART + Carisolv® gel group, with 22 and 26 restorations, respectively, surviving at the end of the 24-month follow-up. Survival rates at 24 months did not significantly differ between ART (63 %) and ART + Carisolv® gel (62 %) restorations. The best model for predicting the failure of the restorations included the number of tooth-brushings/day, the presence or not of prosthesis, the anterior or posterior location of the tooth, and the baseline plaque level. CONCLUSION: The application of Carisolv does not modify the survival rate of ART restorations in elderly patients. CLINICAL RELEVANCE: The use of Carisolv gel does not improve the outcomes of atraumatic restorative treatment.

Expression of proliferative markers in ameloblastomas and malignant odontogenic tumors.

OBJECTIVE: To compare the proliferative activity in ameloblastoma and malignant odontogenic tumors, as assessed by Ki-67 immunostaining and determine whether expression of substance P (SP) and NK-1 receptor (NK-1R) is related to cell proliferation in these tumors. MATERIALS AND METHODS: Immunohistochemistry was used to evaluate protein expression in 44 benign and malignant odontogenic tumors from 39 patients. Immunohistochemistry was performed with anti-SP, anti-NK-1R, and anti-Ki-67 monoclonal antibodies, and the clinical and pathological data of the patients with odontogenic tumor were evaluated. RESULTS: Expression of Ki-67 in malignant odontogenic tumors was significantly higher than in ameloblastomas (P < 0.001), and the expression level was associated with higher expression of NK-1R. Among the ameloblastomas, there was significantly higher expression of Ki-67 in peripheral ameloblastic-like cells (3.3 ± 4.1) than in stellate reticulum-like cells (2.6 ± 3.7) (P = 0.04). In the majority of tissue locations of the malignant tumors, expression of SP and NK-1R was positively correlated with higher expression of Ki-67. CONCLUSION: These findings show that the expression level of Ki-67 in ameloblastomas was positively correlated with the rate of growth of odontogenic tumors. Overexpression of NK-1R complex in malignant odontogenic tumors could be part of the trigger stimulus that results in higher proliferative activity of the tumor.

Molecular findings in oral premalignant fields: update on their diagnostic and clinical implications.

The development of multiple oral tumours, seen in up to 30% of patients with a primary oral squamous cell carcinoma, is sometimes attributable to the presence of genetically altered premalignant fields and has important prognostic implications. Molecular techniques available for the definitive diagnosis of such a field (loss of heterozygosity analysis of 3p, 9p and 17p and study of TP53 tumour suppressor gene mutation) are expensive, complex and not universally available, hampering their routine application. Nevertheless, molecular diagnosis is essential for modern assessment of the risk of multiple tumours and for decisions on the appropriate preventive and therapeutic approaches. This article reviews current knowledge on molecular findings in premalignant fields in the oral cavity and oropharynx and provides an update on criteria for their identification, discussing the clinical and therapeutic implications.

Cell apoptosis and proliferation in salivary glands of Sjögren's syndrome.

BACKGROUND: Sjögren's syndrome (SS) occurs associated with parotid neoplasm, non-Hodgkin's B-cell lymphoma, which could impair the condition or be life-threatening for patients. The aim of this work was to analyze cell proliferation and apoptosis modifications in acinar, ductal and inflammatory infiltrate in salivary glands (SG) in patients with Sjögren Syndrome, keratoconjunctivitis, or stomatitis sicca or in healthy subjects, to establish parameters that indicate the likelihood of malignancy of the disease in populations at risk. METHODS: A study was performed with n = 58 histological samples of lower lip SG from patients diagnosed with SS, keratoconjunctivitis, or stomatitis sicca (SICCA) and from healthy subjects (C). Ki67 and caspase-3 immunolabeling were performed. RESULTS: The most important result was significant differences between the three study groups in Ki67 and caspase-3 markers (P < 0.0001) in infiltrated lymphocytes. CONCLUSION: The results of this work are indicative of a high degree of proliferation (85%) in infiltrated lymphocytes (IL) associated with SS which, according the literature, could be considered a risk. Furthermore, the markers used in this work are widely known and represent a lower cost than others and can be used to determine risk groups within the population of SS patients, enabling their follow-up.

Ki-67 expression in non-tumour epithelium adjacent to oral cancer as risk marker for multiple oral tumours.

OBJECTIVE: The aim of this study was to determine whether the differential assessment of epithelial proliferation is useful to diagnose premalignant fields and assess the risk of multiple tumours. MATERIAL AND METHODS: We analysed 83 oral carcinomas with associated non-tumour epithelium classified as distant or close according to its distance (> or <1 cm) from the invasion point, and as squamous hyperplasia, mild, moderate, severe dysplasia or carcinoma in situ. Twenty-five healthy oral mucosa samples were used as controls. An immunohistochemical technique was applied using Mib-1. Ki-67 in premalignant epithelium was assessed in basal layer, parabasal layer, medium and upper third. RESULTS: Parabasal expression was significantly higher or showed a tendency to be higher in close and distant epithelia with any histological grade than in the controls. Parabasal Ki-67 significantly differed between distant epithelia associated with multiple vs single tumours (P < 0.001) and between distant epithelia associated with multiple tumours vs controls (P < 0.001). This difference was not observed between distant epithelia associated with single tumours and controls (P = 0.175). The cut-off point that differentiated epithelia associated with multiple tumours was >50% of Ki-67 + parabasal cells in distant epithelia, which yielded 0.88 sensitivity and 0.79 specificity. CONCLUSIONS: The concept of a precancerous field may be linked to an increase in the proliferative activity of parabasal cells.

HPA-suppressive effects of aqueous clobetasol propionate in the treatment of patients with oral lichen planus.

BACKGROUND: Oral topical corticosteroids have potential to produce inhibition of the hypothalamus-pituitary-adrenal (HPA) axis. OBJECTIVE: To assess whether clobetasol propionate (CP) in aqueous solution causes HPA inhibition. PATIENTS AND METHODS: Sixty-two patients with oral lichen planus or oral lichenoid lesions presenting with severe lesions were treated with topical oral 0.05% CP plus 100,000 IU/cm(3) nystatin in aqueous solution. Initial treatment of three 5-min mouthwashes (10 mL) daily was reduced, when the response was deemed complete or excellent, to a maintenance treatment of one 5-min mouthwash on alternate days for 6 months; treatment was then withdrawn and patients were followed up for 1 year. HPA function was assessed by plasma cortisol measurement and adrenocorticotropin (ACTH) stimulation at the end of the initial and maintenance treatment regimens. RESULTS: The HPA axis was more frequently inhibited during initial (53/62; 85.5%) vs. maintenance (2/49; 4%) regimens of aqueous CP. LIMITATIONS: In patients with morning plasma cortisol levels between 3 and 18 microg/dL, a normal result for the ACTH stimulation test only moderately reduces the possibility that a patient has secondary adrenal insufficiency. This can be considered a minor limitation in our study, as only three patients required additional assessment with the ACTH stimulation test. CONCLUSIONS: Hypothalamus-pituitary-adrenal inhibition is substantial during initial treatment with aqueous CP three times daily.

Oral ulcers: clinical aspects. A tool for dermatologists. Part I. Acute ulcers.

Oral ulcers are generally painful lesions that are related to various conditions developing within the oral cavity. They can be classified as acute or chronic according to their presentation and progression. Acute oral ulcers are be associated with conditions such as trauma, recurrent aphthous stomatitis, Behçet's disease, bacterial and viral infections, allergic reactions or adverse drug reactions. Chronic oral ulcers are associated with conditions such as oral lichen planus, pemphigus vulgaris, mucosal pemphigoid, lupus erythematosus, mycosis and some bacterial and parasitic diseases. The correct differential diagnosis is necessary to establish the appropriate treatment, taking into account all the possible causes of ulcers in the oral cavity. In the first part of this two-part review, acute oral ulcers are reviewed.

Oral ulcers: clinical aspects. A tool for dermatologists. Part II. Chronic ulcers.

Oral ulcers are generally painful lesions that are related to various conditions developing within the oral cavity. They can be classified as acute or chronic according to their presentation and progression. Acute oral ulcers are be associated with conditions such as trauma, recurrent aphthous stomatitis, Behçet's disease, bacterial and viral infections, allergic reactions or adverse drug reactions. Chronic oral ulcers are associated with conditions such as oral lichen planus, pemphigus vulgaris, mucosal pemphigoid, lupus erythematosus, mycosis and some bacterial and parasitic diseases. The correct differential diagnosis is necessary to establish the appropriate treatment, taking into account all the possible causes of ulcers in the oral cavity. In this second part of this two-part review, chronic oral ulcers are reviewed.

A role for the substance P/NK-1 receptor complex in cell proliferation and apoptosis in oral lichen planus.

OBJECTIVES: To determine whether substance P (SP) and NK-1 receptor (NK-1R) are expressed in oral lichen planus (OLP) and are related to cell proliferation and apoptosis in this disease. MATERIAL AND METHODS: Tissue samples from 50 OLP patients and 26 healthy controls were studied. Immunohistochemistry was performed with anti-SP, anti-NK-1R, anti-ki-67 and anti-caspase-3 monoclonal antibodies and the clinical and pathological data of the OLP patients were evaluated. RESULTS: With the exception of NK-1R expression in epithelial cell membrane and cytoplasm, all markers were more frequently present in OLP patients than in controls (P < 0.05). Higher cytoplasmatic expression of NK-1R was associated with higher epithelial expression of caspase-3 (P < 0.05). Higher epithelial expression of NK-1R and SP was associated with higher suprabasal and basal epithelial expression of ki-67 (P < 0.05 and P < 0.005, respectively). CONCLUSIONS: Actions of the SP/NK-1R complex may contribute to the immune disorder underlying OLP and trigger stimuli to induce cell proliferation. These results indicate that this complex might play a role in the malignant transformation of OLP.

Differences in the expression of p53 protein in oral lichen planus based on the use of monoclonal antibodies DO7 and pAb 240.

UNLABELLED: A comparison is made of p53 expression in oral lichen planus, detected via monoclonal antibodies pAb240 and DO7, and with cell apoptosis and proliferation markers. An immunohistochemical study was made of 51 cases of oral lichen planus and 26 controls, using monoclonal antibodies DO7 and pAb240, anti-caspase-3 antibody and Mib-1 antibody against Ki-67. The cases showed important p53 expression with D07 (68%, 36 cases), presumably wild p53, and low p53 expression with pAb240 (14.9%, 7 cases), presumably mutated p53. No significant relationship was observed between p53 expression and caspase-3 apoptosis marker, though an association was recorded between p53 expression with DO7 and Ki-67 expression. CONCLUSIONS: In oral lichen planus, p53 protein preferentially activates the cell cycle for DNA repair, this representing a very effective genome vigilance mechanism, in view of the low rate of malignant transformations observed in this disease.

Update on molecular pathology in oral cancer and precancer.

Oral carcinogenesis is a multifactorial process involving numerous genetic events that alter normal functions of oncogenes and tumour suppressor genes. This may increase the production of growth factors or the number of receptors on the cell surface, and/or increase transcription factors or intracellular signal messengers. Together with the loss of tumour suppressor activity, these changes lead to a cell phenotype that can increase cell proliferation, with loss of cell cohesion, and infiltration of adjacent tissue thus causing distant metastasis. Molecular pathology is responsible for defining the molecular mechanisms that underlie the onset of oral precancer and cancer. The aim of this review is to describe recent advances in our understanding of the molecular control of the innumerable pathways related to these processes. These may lead to short- or medium term improvements in the diagnosis and prognosis of oral precancerous and cancerous lesions and to the development of novel therapeutic approaches to this disease.

Oral lichen planus: controversies surrounding malignant transformation.

Studies of the malignant potential of oral lichen planus (OLP) have been hampered by inconsistencies in the diagnostic criteria used for OLP, the criteria adopted to identify a true case of malignant transformation in OLP, the risk factors for malignant transformation and the optimum management of patients to ensure the early diagnosis of transformation. Consensus remains elusive, and leading workers in this field have recently published conflicting reports on the malignant potential of OLP and on the important question of the advisability of excluding patients with epithelial dysplasia or a tobacco habit from studies on this issue. The present review outlines these debates and proposes a possible a molecular basis for the malignant transformation in this disease.