Etiology of Oral Potentially Malignant Disorders and Squamous Cell Carcinoma Based on Cellular Stress Regulation and Matrix Stiffness.

The oral cavity serves as the initial segment of the digestive system and is responsible for both nutritional supplementation and the mechanical breakdown of food. It comprises distinct hard and soft tissues; the oral mucosa is subject to mechanical stress and interaction with microbiota. In oral cancer, tumors exhibit abnormal cellular networks and aberrant cell-cell interactions arising from complex interplays between environmental and genetic factors. This presents a challenge for clinicians and researchers, impeding the understanding of mechanisms driving oral cancer development and treatment strategies. Lesions with dysplastic features are categorized under oral potentially malignant disorders, including oral leukoplakia, erythroplakia, oral submucous fibrosis, and proliferative verrucous leukoplakia, carrying a high malignancy risk. In this review, we discuss oral cancer cell characteristics and the stiffness of the surrounding matrix. We also discuss the significance of stiffness equilibrium in oral potentially malignant disorders, particularly oral submucous fibrosis, possibly triggered by mechanical stress such as betel quid chewing.

Spectrum of Liver Pathology in Dyskeratosis Congenita.

Dyskeratosis congenita (DC) is a rare multisystemic disorder associated with defective telomere maintenance. Frequent clinical manifestations of DC include reticular skin pigmentation, dystrophic nails, oral leukoplakia, and bone marrow failure. Hepatic disturbances are reported to occur in 7% of DC patients. This study aimed to evaluate the histopathologic spectrum of hepatic involvement in this disorder. DC patients with liver tissue in the pathology database at Boston Children's Hospital from 1995 to 2022 were identified. Clinical and pathologic information was documented. Thirteen specimens from 11 DC patients were included (M:F = 7:4; median age at the time of liver tissue evaluation: 18 y). DC-associated gene mutations were identified in 9 patients; TERF1-interacting nuclear factor 2 ( TINF2) was the most frequently represented gene mutation, seen in 4 patients. All patients had bone marrow failure, whereas dystrophic nails, cutaneous abnormal pigmentation, and oral leukoplakia were noted in 73%, 64%, and 55% of patients, respectively. Seven patients underwent bone marrow transplants before biopsy/autopsy (median interval of 45 mo). Histologically, 3 of 4 patients who presented with portal hypertension showed noncirrhotic changes (nodular regenerative hyperplasia and/or obliterative portal venopathy), whereas prominent central and sinusoidal fibrosis was noted in patients with intrahepatic shunting and those showing features of chronic passive congestion. All cases showed hepatocyte anisonucleosis. One patient developed hepatic angiosarcoma, and another 1 had colorectal adenocarcinoma metastatic to the liver. DC patients show heterogeneous histologic findings in their liver. The findings of noncirrhotic portal hypertension, intrahepatic shunting, and angiosarcoma suggest vascular functional/structural pathology as a possible unifying etiology of hepatic manifestations of DC.

Reactive and Nonreactive White Lesions of the Oral Mucosa.

White lesions in the oral cavity may be diverse in etiology and may present with significant clinical and sometimes histologic overlap between categories, making accurate diagnosis difficult at times. Although white lesions of immune and infectious etiology are covered in another article, this article discusses the differential diagnosis between developmental, reactive, idiopathic, premalignant, and malignant white lesions focusing on clinical features of each category.

Phenotype and genotype features of Vietnamese children with pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). PC is an extremely rare condition. To our knowledge, this is the largest genotype-phenotype study of PC in a Vietnamese population to date. MATERIALS AND METHODS: We investigated keratin gene mutations and clinical features of seven Vietnamese children with PC. RESULTS: The seven Vietnamese patients were from six different families (two patients in the same family) from across Northern, Central, and Southern Vietnam. All children displayed PC symptoms before 1 year of age, but diagnosis was delayed in 4/7 patients. Thick fingernails, thick toenails, oral leukokeratosis, and follicular hyperkeratosis were the most common features recorded by all seven patients. Plantar keratoderma and thick fingernails were the clinical features associated with the most significant effect on daily function. All patients had mutations in KRT6A (PC-K6a) focused on the 1A and 2B domains. We found three distinct types of mutations (K6a R466P, K6a N171K, and K6a N172del). One mutation (N172del) was common to 5/7 (71.4%) of the patients. CONCLUSIONS: Individuals displaying nail dystrophy, oral leukokeratosis, follicular hyperkeratosis, and plantar keratoderma should be referred for genetic testing given the high likelihood of a PC-K6a-related mutation in patients with this constellation of clinical signs.

Epstein-Barr virus oral shedding and viremia and their association with oral hairy leukoplakia in HIV+ individuals.

OBJECTIVE: To assess the oral shedding and viremia of Epstein-Barr virus (EBV) in HIV-positive patients and their relationship with oral hairy leukoplakia (OHL). METHODOLOGY: A total of 94 HIV-positive patients were included in the study, in which blood and saliva samples were collected for EBV quantification. Data on gender, age, time of HIV seropositivity, combined antiretroviral therapy (cART), CD4+ T-cell counts, and HIV viral load were collected. OHL diagnosis was based on histopathological examination and EBV in situ hybridization. RESULTS: The EBV load in the 94 HIV-positive patients was higher in saliva than in blood (2.4 and 1.6, respectively), and there was a positive correlation between EBV oral shedding and viremia (p = 0.001). Twenty (21.27%) patients had OHL and also a higher EBV load in saliva (mean log10  = 3.11) compared to those who had no OHL (p = 0.045). Presence of OHL was only associated with age (p = 0.030). CONCLUSION: In HIV-positive patients, the presence of OHL was associated with EBV oral shedding but not with viremia, regardless of the amount of circulating CD4+ T cells.

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita.

Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.

Liver Transplant for Management of Hepatic Complications of Dyskeratosis Congenita: A Case Report.

Dyskeratosis congenita, a rare genetic disorder typified by progressive bone marrow failure, is classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; however, it is a multisystem disease. Although hepatic involvement occurs in about 7% of patients with dyskeratosis congenita, end-stage liver disease is rare. Treatment of dyskeratosis congenita generally involves hematopoietic stem cell transplant. For patients with hepatic failure, liver transplant can be an option. Here, we describe a case of a patient with dyskeratosis congenita who presented with liver failure and pulmonary failure, precluding him from hematopoietic stem cell transplant. After liver transplant, the patient had significant improvements in pulmonary function and transfusion requirements, allowing the patient to qualify for hematopoietic stem cell transplant. Although hematopoietic stem cell transplant is typically the first step in the management of dyskeratosis congenita, for patients with severe hepatic manifestations of the disease, a liver transplant first approach may result in better disease management.

Malignant transformation of oral leukoplakia: a multicentric retrospective study in Brazilian population / Transformación maligna de la leucoplasia oral: un estudio retrospectivo multicéntrico en población brasileña

Background: Among the oral potentially malignant disorders, leukoplakia stands out as the most prevalent. Thepurpose of this study was to analyse the clinical-pathological features of oral leukoplakia in groups of patientsfrom three major pathology centers in two different regions of Brazil, in order to determine which factors wouldbe associated to the clinical risk of malignant transformation.Material and Methods: A total of 148 patients was analyzed, and data regarding gender, age, site, classification ofthe clinical subtype, harmful habits such as use of tobacco and alcohol, time of evolution and presence of dyspla-sia were collected. The association between risk factors and malignant transformation was investigated using thechi-square test and Fischer's exact test for correlation of variables. A significance level of 5% (p≤0.05) was used.Results: The mean age of the patients was 60 years, and 56% were female. Most of the lesions (34,5%) were lo-cated in the lateral and ventral regions of the tongue. Of the 148 patients, ninety had clinical follow-up. Malignanttransformation occurred in 13 patients (8.8%), with an average of 44 months of follow up.Conclusions: Non-smoker, nonhomogeneous clinical presentation, location at the tongue, and the presence of highdegree of dysplasia were statistically relevant factors associated with a higher risk of transformation transformation.(AU)

Annual malignant transformation rate of oral leukoplakia remains consistent: A long-term follow-up study.

OBJECTIVES: Numerous clinical and histopathological characteristics have been associated with malignant transformation (MT) of oral leukoplakia (OL), including classic and differentiated epithelial dysplasia, but MT predictions remain suboptimal. The objective of this study was to determine the annual MT rate of OL and to identify clinicopathological risk factors associated with MT. PATIENTS AND METHODS: 170 patients with OL were included in this retrospective cohort study, 117 females and 53 males. Follow-up ranged from 12 to 219 months (median 54). The analyzed variables included age, gender, smoking habits, clinical presentation, subsite, size and treatment. In a subgroup of 140 patients, histopathological diagnoses were reviewed with regard to the presence of dysplasia, discerning both classic dysplasia and differentiated dysplasia. RESULTS: MT occurred in 23% of the patients, resulting in an annual MT rate of 4.9% (95% CI: 3.5 - 6.6) which remained consistent. High-risk subsite (tongue and floor of mouth) was the only clinical predictor for MT (Hazard Ratio = 2.7, 95% CI: 1.3 - 5.5, p = 0.007). In 140 patients, classic dysplasia (Hazard Ratio = 7.2, 95% CI: 1.6 - 33.1, p = 0.012) and differentiated dysplasia (Hazard Ratio = 6.6, 95% CI: 1.2 - 25.4, p = 0.026) were predictors for MT. Binary grading between dysplasia and no dysplasia was significant for predicting MT (Hazard Ratio = 6.4, 95% CI: 1.5 - 27.5, p = 0.013). CONCLUSION: Since annual MT rate of OL remains stable during follow-up, regular long-term or even life-long follow-up is advocated. Specific oral subsites and epithelial dysplasia are predictors for MT of OL.

Second primary tumors in proliferative verrucous leukoplakia: a series of 33 cases.

OBJECTIVES: To describe the number of second primary malignancies in a series of 33 patients with proliferative verrucous leukoplakia (PVL), detailing the mean time between primary malignancies and their clinical characteristics. MATERIALS AND METHODS: Two groups of patients were included in this study: group 1 comprised 33 PVL patients who had developed ≥ 2 oral squamous cell carcinoma (OSCC) and group 2 comprised 48 PVL patients without malignant degeneration. We compared the groups with regard to age, gender, oral location, and number of oral sites affected. For patients in group 1, we determined the locations, clinical forms, and TNM stages of oral cancers. We also recorded the intervals of time between instances of oral cancer for all patients. RESULTS: The groups did not differ significantly in age; however, group 1 included more women (p < 0.05). The follow-up period and number of oral PVL locations were greater in group 1 (p < 0.01). Moreover, in group 1, as the number of OSCCs increased, the intervals between them became shorter. The gingiva was the most common site. The mean number of cancers in group 1 was 3.15; five second primary tumors were diagnosed in one patient. CONCLUSIONS: Multiple cancers in PVL patients were more frequently located on the gingiva in the form of erythroleukoplastic areas. In addition, the interval between new cancers decreased over time. CLINICAL RELEVANCE: This is the series with the highest number of cases described with second primary tumors in PVL.

Role of the human papillomavirus in malignant transformation of oral leukoplakia distinct from oropharyngeal squamous cell carcinoma: A study of 76 patients with internal-control specimens.

OBJECTIVE: This study sought to investigate the role of human papillomavirus (HPV) in the carcinogenesis of oral leukoplakia (OLK), with the oral cavity as the site of interest. STUDY DESIGN: A total of 76 patients (152 specimens) were enrolled in the study. The patients were divided into 2 groups: the malignant transformation of OLK (OLK-MT) group and the non-malignant transformation of OLK (OLK-non-MT) group. HPV reverse dot blot analysis, HPV DNA polymerase chain reaction (PCR), and p16INK4A immunohistochemistry (IHC) were used to determine HPV infection status. RESULTS: Transformation of OLK commonly occurred in the lateral/ventral tongue, buccal mucosa, and gingiva. On the basis of the initial analysis of specimens, only 5.3% (4 of 76) of patients were found to be HPV-16 positive, and these patients' final specimens yielded negative results. Overexpression of p16INK4A in the dysplastic stage was associated with the transformation of OLK (P = .013; odds ratio = 3.544). CONCLUSIONS: Transformation of OLK was common in patients who are elderly, in females, and in nonsmokers/nondrinkers; lesions were located in the lateral/ventral tongue, with dysplasia and overexpressed p16INK4A seen during the initial stage. HPV may be an opportunistic infection in the oral cavity and may not be a cause of malignant transformation of OLK. p16INK4A expression, which initially increases and then diminishes or disappears, may be an early predictor of malignant transformation.

Oral cancer associated with chronic mechanical irritation of the oral mucosa

Background: Most of the studies dealing with Chronic Mechanical Irritation (CMI) and Oral Cancer (OC) only considered prosthetic and dental variables separately, and CMI functional factors are not registered. Thus, the aim of this study was to assess OC risk in individuals with dental, prosthetic and functional CMI. Also, we examined CMI presence in relation to tumor size. Material and methods: a case-control study was carried out from 2009 to 2013. Study group were squamous cell carcinoma cases; control group was patients seeking dental treatment in the same institution. Results: 153 patients were studied (Study group n=53, Control group n=100). CMI reproducibility displayed a correlation coefficient of 1 (p< 0.0001). Bivariate analysis showed statistically significant associations for all variables (age, gender, tobacco and alcohol consumption and CMI). Multivariate analysis exhibited statistical significance for age, alcohol, and CMI, but not for gender or tobacco. Relationship of CMI with tumor size showed no statistically significant differences. Conclusions: CMI could be regarded as a risk factor for oral cancer. In individuals with other OC risk factors, proper treatment of the mechanical injuring factors (dental, prosthetic and functional) could be an important measure to reduce the risk of oral cancer (AU)

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Leucoplasia verrucosa proliferativa de la lengua / Proliferative verrucous leukoplakia of the tongue

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Oral leukoplakia and oral cavity squamous cell carcinoma.

Oral leukoplakia is defined as a white oral lesion not related to another disease process. These lesions are largely asymptomatic, and the clinical relevance of oral leukoplakia is primarily tied to its association with oral cavity squamous cell carcinoma. Timely workup and effective management of these lesions can reduce the risk of malignant transformation and promote early diagnosis of invasive tumors. A biopsy should be performed promptly of any persistent or suspicious leukoplakia with subsequent management dictated by histologic findings. Benign lesions can be observed or treated with topical therapy, and dysplastic lesions should be excised. Some risk of malignant transformation remains even after treatment, and close follow-up is required. Oral cavity squamous cell carcinoma is an aggressive malignancy that can result from malignant conversion of oral leukoplakia or occur de novo. These tumors are primarily treated with surgical resection and adjuvant radiation or chemoradiation as dictated by histopathologic findings.

Reduced CX3CL1 Secretion Contributes to the Susceptibility of Oral Leukoplakia-Associated Fibroblasts to Candida albicans.

Candida leukoplakia (OLK) is a kind of oral leukoplakia combined with chronic candidal infection, which plays an important role in the malignant transformation of OLK. However, little is known about the etiology, including susceptibility of leukoplakia to candidal adhesion, invasion and infection. Some antimicrobial peptides secreted by oral epithelial cells or fibroblasts potentially have antifungal activities against Candida albicans (C. albicans). In this study, we established three co-culture models to simulate different C. albicans-fibroblasts interactions during progression of candida leukoplakia. The susceptibility of oral leukoplakia-associated fibroblasts (LKAFs) to C. albicans and its underlying mechanism were determined. Samples of 14 LKAFs and 10 normal fibroblasts (NFs) were collected. The co-culture models showed that LKAFs had promoted the adhesion, invasion, and survival of C. albicans compared with NFs. CX3CL1, a chemokine with antifungal activity, was less abundant in LKAFs than NFs. Overexpression of CX3CL1 via transfection in LKAFs could partly restore the resistance to C. albicans. We also showed that inhibition of ERK could suppress CX3CL1 secretion. While phosphor-ERK was inhibited in LKAFs compared with NFs. Besides, the mRNA expression of a shedding enzyme for CX3CL1, disintegrin and metalloproteinase domain (ADAM) 17 was decreased in LKAFs than NFs. In conclusion, LKAFs produced and secreted less CX3CL1 by inhibiting the ERK signaling pathway, thereby contributing to impaired cell resistance to C. albicans.

The development of proliferative verrucous leukoplakia in oral lichen planus. A preliminary study.

BACKGROUND: Was to describe 14 cases of a proliferative verrucous leukoplakia as a clinical evolution of oral lichen planus. MATERIAL AND METHODS: The clinical and histopathological characteristics of 14 cases of OLP that progress towards a plaque-like and verrucous form were indicated, with monitoring over a period of six to 24.3 years. RESULTS: The female/male ratio was 11/3, (78.6 and 21.4%). The mean age when the first biopsy was undertaken was 56.4 years old. None of the patients smoked during the study. As bilateral reticular was clinically diagnostic criterion, the second most frequent clinical form was the plaque form (n=10; 71.4%), followed by the atrophic (n=6; 42.8%), and erosive forms (n=4; 28.5%). Clinically it spread towards attached gingival mucosa and the hard palate. In the histopathologic study, there were a predominance of hyperkeratosis and verrucous epithelial hyperplasia. Three of the cases progressed to a squamous cell carcinoma, and one patient developed two verrucous carcinoma. CONCLUSIONS: Further research is needed to demonstrate if proliferative multifocal oral lichen planus and proliferative multifocal oral leukoplakia are the same disorder but have different behaviour of malignancy for reasons of origin.

Dyskeratosis congenita associated with leukoplakia of the tongue.

Dyskeratosis congenita (DC) is an inherited disease characterized by the triad of skin pigmentation, nail dystrophy, and oral leukoplakia. Among other abnormalities, bone marrow failure and a predisposition to cancer are recognized as the major causes of premature mortality in patients with DC. This disease is associated with short telomeres and mutations in 10 genes associated with telomerase and telomere components. The case of a 35-year-old male patient diagnosed with DC, who presented with leukoplakia of the tongue and had a high degree of hypoplastic marrow, but no haematological abnormalities, is reported here. The diagnosis of DC was confirmed by detection of short telomeres in the blood cells and mutations in the DKC1 gene. This encounter with the case presented suggests that an awareness of the classical forms of DC is important for oral clinicians so that an early diagnosis can be made and the patient can be managed appropriately. Furthermore, genetic analysis is necessary to establish the diagnosis of DC.

Nested PCR for detection of HSV-1 in oral mucosa

BACKGROUND: It has been estimated that 15%-20% of human tumours are driven by infection and inflammation, and viral infections play an important role in malignant transformation. The evidence that herpes simplex virus type 1 (HSV-1) could be involved in the aetiology of oral cancer varies from weak to persuasive. This study aimed to investigate by nested PCR (NPCR) the prevalence of HSV-1 in samples from normal oral mucosa, oral leukoplakia, and oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: We investigated the prevalence of HSV-1 in biopsies obtained from 26 fresh, normal oral mucosa from healthy volunteers as well as 53 oral leukoplakia and 27 OSCC paraffin-embedded samples. DNA was extracted from the specimens and investigated for the presence of HSV-1 by nested polymerase chain reaction (NPCR) and DNA sequencing. RESULTS: HSV-1 was detected in 14 (54%) of the healthy samples, in 19 (36%) of the oral leukoplakia samples, and in 14 (52%) of the OSCC samples. The differences were not statistically significant. CONCLUSIONS: We observed a high incidence of HSV-1 in healthy oral mucosa, oral leukoplakia, and OSCC tissues. Thus, no connection between OSCC development and presence of HSV-1 was detected

Dyschromatosis Universalis Hereditaria with Oral Leukokeratosis--A Case of Mistaken Identity and Review of the Literature.

Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis characterized by reticulated hyper- and hypopigmented macules distributed over the trunk and extremities in otherwise healthy patients. DUH presents in a fashion similar to that of a variety of reticulate and pigmentary dermatoses, some of which are associated with precancerous entities and other comorbidities. It is therefore imperative that the clinician recognize and differentiate these disorders so that appropriate screening and counseling can be offered to the patient. We report a case of DUH in a 13-year-old boy presenting with oral leukokeratosis, with a review of the literature exploring the differential diagnoses.