Rosario Serpico

Oral Manifestations of Celiac Disease

Introduction Contrary to early beliefs, celiac disease (CD) is relatively common; however, it still remains underdiagnosed since most cases are atypical, with few or no gastrointestinal symptoms and predominance of extraintestinal manifestations. As a consequence, the diagnosis of the disorder often requires a multidisciplinary approach. Also some oral ailments have been described in celiac patients. In this study, we review the papers that have reported oral manifestations in subjects with CD. Methods A comprehensive literature search was conducted in Medline and Embase databases using appropriate key words. Additional papers were selected by cross-referencing from the retrieved articles. Results Dental enamel defects are the oral lesions most closely related to CD. There are conflicting data on the association between CD and recurrent aphthous stomatitis. A correlation of CD with atrophic glossitis has been reported, although robust evidence in support of it is lacking. Patients with CD have caries indexes seemingly lower than healthy individuals, but they may experience delay in tooth eruption. Occurrence of other oral mucosal lesions in CD subjects is likely occasional. Conclusions Patients with systematic dental enamel defects should be screened for CD even in the absence of gastrointestinal symptoms. CD screening tests for patients with oral aphthae or idiopathic atrophic glossitis should be selectively considered during a medical evaluation that focuses on all aspects of the patients status.

WNT pathway in oral cancer: Epigenetic inactivation of WNT-inhibitors

Epigenetic DNA methylations plays an important role in oral carcinogenesis. The soluble frizzled receptor protein (SFRP) family together with WIF-1 and DKK-3 encodes antagonists of the WNT pathway. Silencing of these genes leads to constitutive WNT signalling. Because aberrant expression of beta-catenin might be associated with the epigenetic inactivation of WNT inhibitors, we analyzed, in a collection of primary OSCC with matched normal oral mucosa, the methylation status of a complete panel of genes, SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3, that are involved directly and indirectly in WNT pathway, in order to demonstrate WNT-pathway activation in the absence of beta-catenin and/or APC/Axin mutations during oral carcinogenesis. Methylation-specific PCR (MSP) was performed to study inactivation of SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 genes in 37 cases of paraffin embedded oral cancer. This study showed that the methylation is an important epigenetic alteration in oral cancer. In particular, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 revealed methylation status of their promoter in OSCC, whereas SFRP-1 showed demethylation in cancer. Fishers exact test revealed statistically significant results (p<0.05) for all genes. The Wald test confirmed the statistically significant association between SFRP2-4-5 gene methylation and OSCC (p<0.05). SFRP-1 was also characterized by a different statistically significant epigenetic behaviour, because of it was demethylated in cancer (p<0.05). Statistical regression test showed high levels of sensitivity, specificity and accuracy for SFRP genes, while WIF-1 and DKK-3 have reportedly high specificity, moderate accuracy but low sensitivity. This study suggests that a cause of catenin delocalization in oral cancer could be due to WNT pathway activation, by epigenetic alterations of SFRP, WIF-1 and DKK-3 genes.

Cyclooxygenase-2 expression in oral squamous cell carcinoma

Cyclooxygenase (COX), the key enzyme in prostaglandin cascade, is expressed in two isoforms: the constitutive COX-1 and the inducible COX-2. Hyper-expression of COX-2 has been implicated in the pathogenesis of colon-rectal cancer in humans but it appears to play a significant role as a tumour progression factor also in other forms of human cancer, including oral cancer. The aim of this study was to analyze the expression of COX-2, at the protein level, in 45 cases of oral squamous cell carcinoma. Standard immunohistochemical streptavidin-biotin peroxidase analysis was carried out with a highly specific antibody against human COX-2 and cell specific markers, in 45 oral squamous cell carcinomas. Our study revealed a moderate to high COX-2 expression in 35 out of the 45 oral squamous cell carcinoma specimens (77.8%). COX-2 expression appeared particularly abundant in the superficial ulcerated layers of relatively well differentiated carcinomas. However, we were unable to assess any statistically significant association between COX-2 hyper-expression and tumor site, tumor grading, tumor size, presence of lymph node metastases, tumor stage and age at onset, respectively. Interestingly, COX-2 expression was detected not only in areas of epithelial dysplasia adjacent to the primary layers (86% of the cases) but also in normal-appearing epithelium at the boundaries of squamous cell carcinomas (77%), indicating a possible involvement in tumour progression by the apparently normal tissue surrounding the lesion. Moreover, intense COX-2 staining was observed in endothelial cells of intra-tumour vessels and extra-tumour vessels adjacent to the tumour nests, in a high proportion of cases (82%). COX-2 positivity was associated with CD34 and VEGF positivity, indicating that these vessels were probably neo-formed. From this study, as well as from other works, it appears that COX-2 is over-expressed in this important human malignancy. However, further studies are necessary to understand the exact magnitude of this over-expression and, mostly, the possible role of COX-2 in the pathogenesis and progression of oral cancer.

Oro-dental manifestations in Hallopeau-Siemens-type recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa of Hallopeau‐Siemens (RDEB‐HS) is a rare genetic disorder characterized by trauma‐induced blisters, milia, acral pseudosyndactyly, and scarring. RDEB‐HS patients present with a distinct pattern of oral involvement consisting of microstomia, ankyloglossia, vestibule obliteration and dental caries. In this review, we describe the orodental manifestations of RDEB‐HS and present our experience in a cohort of six new cases of RDEB‐HS in children aged 6–10 years, documenting the presence of microstomia, ankyloglossia and vestibule obliteration in childhood. We also show that compared with unaffected control children, RDEB‐HS subjects have a greater risk of developing high caries indices with early onset, both for permanent or deciduous teeth, and a worse oral hygiene index (scored as OHI). Tooth malpositions and the cross‐bite relationship between maxilla and mandible could play a major role in promoting these events. We propose that dental management of RDEB‐HS subjects should commence as soon as tooth eruption begins.

Angiosarcoma of the head and neck with intra-oral presentation. A clinico-pathological study of four cases

Angiosarcoma of the head and neck is a rare malignant tumour that most commonly involves the skin and subcutis, particularly of the scalp. It has been reported in intra-oral locations very rarely. This study reports on the clinico-pathological features of four such cases, in elderly patients and manifesting an aggressive course. All patients were admitted for rapidly enlarging masses involving the hard palate, alveolar crest and retromolar trigone and displaying bone destruction in three cases. Morphologically, three cases were composed by bundles of spindle cells admixed with variably sized abortive vascular channels which only showed slit-like spaces separating large clusters of epithelioid cells. In all instances, intra-cytoplasmic vacuoles containing intact or fragmented red blood cells were distinctly evident. All neoplasms showed consistent CD 31 immunoreactivity and variable degrees of CD 34 and Factor VIII related antigen positivity and were responsible for the death of the patients, for local progression or lung metastases, within 6 months from the original diagnosis. Due to their rarity, angiosarcomas with intra-oral presentation may be diagnosed with difficulty, especially on small incisional biopsies. and their differentiation from spindle cell carcinoma, malignant melanoma, anaplastic lymphoma, malignant myoepithelioma and other sarcomas that more commonly arise at this site should be based on accurate immunohistochemical characterisation.

Use of Lugol’s iodine in oral cancer diagnosis: An overview

Early diagnosis of oral squamous cell carcinoma (OSCC) still represents an important challenge for clinicians and patients. Vital staining such as toluidine blue and Lugols iodine solution, are routinely used in the OSCC detection but few data exist about the last one. A literature review is made to evaluate the effectiveness and safety of Lugols iodine solution in OSCC detection and in its margins demarcation. A review was made of the studies published between 1990 and 2010 in relation to the application of Lugols iodine for OSCC detection and a better definition of its margins. Data obtained point to the utility and the safety of Lugols iodine when employed for detection and margins delineation of OSCC and dysplasia. All the studies consulted found the Lugols iodine to be effective, cheap and easy to use and they emphasized its importance in clinical practice. There is need for larger controlled, randomized studies with carefully selected and standardized outcome measures and patients.

pEGFR-Tyr 845 expression as prognostic factors in oral squamous cell carcinoma: A tissue-microarray study with clinic-pathological correlations

The EGFR (epidermal growth factor receptor) a member of the family of transmembrane protein kinase receptors known as the erbB family shows a significant correlation with the presence of metastases and poorly differentiated oral cancer. Aim of the present work is to define the key-role of EGFR in oral cancer prognosis. We have analyzed the EGFR expression on 149 cases of oral squamous cell cancers (OSCC) and we have found that it was poorly expressed in normal oral epithelium, but its expression was significantly increased in OSCCs. Moreover, we have recorded that both pEGFR-Tyr 845 and pEGFR-Tyr 1068 were mainly distributed in high histological grading and in advanced stages. Western blotting has confirmed the total absence of EGFR phosphorylation in normal oral epithelium and the higher level of protein phosphorylation in representative cases of OSCCs. The EGF-R amplification was found by fluorescence in situ hybridization (FISH) in 14% of OSCC; interestingly, EGF-R amplification was mainly observed in OSCC with higher histological grading (G2 and G3) and advanced stage (pT4) sub-groups. Kaplan-Meyer survival analysis suggested that patients with positive pEGFR-Tyr 845 tumors had a worse prognosis and were bad responders to chemotherapy. These results confirm the central role of EGF-R activation status as a prognostic biomarker in OSCC.

A Troubling Diagnosis of Verrucous Squamous Cell Carcinoma (“the Bad Kind” of Keratosis) and the Need of Clinical and Pathological Correlations: A Review of the Literature with a Case Report

Verrucous carcinoma (also known as Ackerman tumor) is an uncommon exophytic low-grade well-differentiated variant of squamous cell carcinoma. This neoplasm typically involves the oral cavity, larynx, genitalia, skin, and esophagus. It is well known for its locally aggressiveness and for its clinically slow-growing behaviour with minimal metastatic potential. Verrucous carcinoma of oral cavity is so closely aligned with the use of snuff and chewing tobacco that it has been called the “snuff dippers cancer”. Recent studies have proved the role of HPV. The typical clinical presentation of oral verrucous carcinoma has long been known, as its remarkably innocuous appearance and biological behaviour. In this work, we report a review of the scientific literature and describe a troublesome case of oral verrucous cancer.

Cyclooxygenase isozymes in oral squamous cell carcinoma:a real-time RT-PCR study with clinic pathological correlations.

COX-2 expression in tumour cells has been associated with carcinogenesis in many human neoplasms, including head and neck cancer, while the COX-1 isoform of the cyclooxygenase enzyme is constitutively expressed in normal tissues. We measured COX-1 and COX-2 m-RNA expression in samples of both oral cancer and matched oral mucosa from 22 patients by RealTime RT-PCR; clinic pathological data (grading, TNM staging, inflammation, follow-up) of all patients were available for statistical evaluation. Most of the tumor samples in our study expressed at least one cyclooxygenase enzyme (COX-1 or COX-2 mRNA) more than their matched normal oral mucosa (p<0.05), with no correlation with the entity of inflammation, and a significant inverse relationship was found between COX-1 and COX-2 in each sample. Higher levels of COX-2 expression were associated with poor disease-free survival (p<0.05), but not with overall survival and higher tumor stage and grade. Our results suggest that COX-1 may play a role in oral carcinogenesis, and could be regarded as a potential therapeutic target by chemo preventive drugs; moreover, COX-2 expression might be addressed as a new prognostic tool in the clinical management of OSCC.

P-cadherin expression and survival rate in oral squamous cell carcinoma:an immunohistochemical study

BackgroundP-cadherin (P-cad) is a transmembrane molecule involved in the cell-cell adhesion and similar to E-cadherin (E-cad), but less investigated in oncology, especially in in vivo studies. Aims of the present study were to assess the prevalence of P-cad expression in oral squamous cell carcinoma (OSCC) and to verify whether P-cad can be considered a marker of prognosis in patients with OSCC.MethodsIn a retrospective study, a cohort of 67 OSCC patients was investigated for P-cad expression and its cellular localization by immunohistochemistry; some respective healthy margins of resection were similarly investigated as standard controls. After grouping for P-cad expression, OSCCs were statistically analyzed for the variables age, gender, histological grading (G), TNM, Staging, and overall survival rate. Univariate and multivariate analyses were performed.Results37 cases (55.2%) of OSCC showed membranous/cytoplasmic positivity for P-cad, whereas 30 (44.8 %) were negative. Although with some differences in membranous vs cytoplasmic localization of P-cad in OSCC with different G, no statistical association was found between P-cad expression and any variables considered at baseline. In terms of prognostic significance, P-cad non expression was found to have an independent association with poorer overall survival rate than P-cad expressing group (P = 0.056); moreover, among P-cad +ve patients the best prognosis was for those OSCC with membranous (P < 0.0001) than those with cytoplasmic P-cad expression.ConclusionOn the basis of these results, it is possible to suggest P-cad as an early marker of poor prognosis. The abnormal or lack of P-cad expression could constitute an hallmark of aggressive biological behavior in OSCC