Salivary Biomarkers for Oral Squamous Cell Carcinoma Diagnosis and Follow-Up: Current Status and Perspectives

Oral cancer is the sixth most common cancer type in the world, and 90% of it is represented by oral squamous cell carcinoma (OSCC). Despite progress in preventive and therapeutic strategies, delay in OSCC diagnosis remains one of the major causes of high morbidity and mortality; indeed the majority of OSCC has been lately identified in the advanced clinical stage (i.e., III or IV). Moreover, after primary treatment, recurrences and/or metastases are found in more than half of the patients (80% of cases within the first 2 years) and the 5-year survival rate is still lower than 50%, resulting in a serious issue for public health. Currently, histological investigation represents the “gold standard” of OSCC diagnosis; however, recent studies have evaluated the potential use of non-invasive methods, such as “liquid biopsy,” for the detection of diagnostic and prognostic biomarkers in body fluids of oral cancer patients. Saliva is a biofluid containing factors such as cytokines, DNA and RNA molecules, circulating and tissue- derived cells, and extracellular vesicles (EVs) that may be used as biomarkers; their analysis may give us useful information to do early diagnosis of OSCC and improve the prognosis. Therefore, the aim of this review is reporting the most recent data on saliva biomarker detection in saliva liquid biopsy from oral cancer patients, with particular attention to circulating tumor DNA (ctDNA), EVs, and microRNAs (miRNAs). Our results highlight that saliva liquid biopsy has several promising clinical uses in OSCC management; it is painless, accessible, and low cost and represents a very helpful source of diagnostic and prognostic biomarker detection. Even if standardized protocols for isolation, characterization, and evaluation are needed, recent data suggest that saliva may be successfully included in future clinical diagnostic processes, with a considerable impact on early treatment strategies and a favorable outcome

Commonalities between ENT Specialists and Oral Medicine Experts: Old HPV Diseases and New Oral HPV-Cancer along the Borders

A human papillomavirus (HPV) infection is globally one of the most common causes of sexually transmitted infections of the mucous membranes (genital, anal and oral). Over the last decade, an increasing number of young patients have been infected due to the changes in sexual habits in the general population. The majority of the lesions are benign; however, substantial scientific evidence has suggested a role for the HPV family in the carcinogenesis of squamous cell carcinoma (SCC). It is proposed that dentists, in addition to ENT specialists, should apply standardized management protocols in order to construct a well-defined pathway in terms of diagnosis, which is based on a PCR diagnostic technique and the management of those lesions

Proteomic identification of salivary biomarkers in 20 patients with Oral Squamous Cell Carcinoma

Objectives. Saliva has been proposed as a potential diagnostic fluid combined with proteomic analysis. The aim of this study is to assess the proteomic salivary profile using SELDI-TOF-MS technology in patients with Oral Squamous Cell Carcinoma (OSCC), grouped in relation to the TNM staging and compared with healthy subjects. Methods. In this secondary hospital based case-control study, patients with confirmed histopathological diagnosis of primary untreated OSCC as “cases” and healthy age- and sex-matched subjects as “controls” were consecutively enrolled, after informed consent. Saliva (5 mL) was collected by spitting directly into a clean 15 mL conical tube, aliquoted and stored at -80°C until use. SELDI-TOF Q10 ProteinChip system was used to screen for differentially expressed proteins in the saliva samples according to the manufacturer’s instructions (BioRad Inc). Univariate statistics and Roc plot were used for data analysis. Results. Twenty cases (6 M, 14 F, middle age 66.8 yy) and 20 controls (8 M, 12 F, middle age 61.9 yy) were included. In cases, seven were early-EsOSCC (3 stage I and 4 stage II) and 13 were late-LsOSCC (7 stage III and 6 stage IV). Proteomic analysis showed significant statistical differences in peptide profile in control vs OSCC and in EsOSCC vs LsOSCC samples (p<0.05). The differentiated pattern between overall OSCC and controls consisted of one peptide peak (8940-ROC:1), between EsOSCC and controls of four peptide peaks (7096-ROC 0.93; 12712–ROC:0.89; 8086 – ROC: 0.93 and 11002 – ROC:0.93) and between LsOSCC and EsOSCC of one peptide peak (6026-ROC 0.80). Conclusions. Although with limitation of the small sample size, this first study suggests that saliva contains proteomic signatures that could serve as biomarkers for OSCC at different stages. Once validated on a large clinical cohort, oral fluid proteomic based on SELDI-TOF-MS technology may be extensively used as a promising new non-invasive tool for early diagnosis in oral cancer patients

Evidence of field cancerization of oral squamous cell carcinoma: a case report

Objectives. From 1953 (1) the term “field cancerization” has been used to describe an “increased risk of cancer de- velopment in the entire upper aerodigestive tract due to multiple genetic abnormalities in the whole region after pro- longed exposure to carcinogen” (2). This phenomenon implies the occurrence of multiple primary tumors/potentially malignant disorders as results of cell-molecular aberrations in different independent sites (polyclonal theory) or from the same site through widespread expansion or later spread across the mucosa (monoclonal theory). Case report. A 63-year-old female patient referred in June of 2014 for exophytic/ulcerative lesion in the hard palate. At the same time, several teeth (1.5, 1.6 and 3.6) with poor prognosis and an incisional biopsy were per- formed. The histological examination reported a diagnosis of oral squamous cell carcinoma (G1) and the manage- ment (imaging and TNM staging) was scheduled. Unfortunately, 30 days after exodontia, one of alveolar sites (3.6) showed proliferative tissue and not healing. A new biopsy was carried out, revealing an histological diagnosis of “epithelium with marked parakeratosis, acanthosis and papillomatosis associated with areas of moderate dys- plasia (IIC: PanCK)”. Conclusions. The features described in different areas of the oral cavity led us to make a diagnosis of oral field can- cerization. This condition still must be analyzed in order to clarify the onset and development but, most importantly, a protocol for manage these patients have to be developed. Chemoprevention and cessation of smoking and alcohol may impact new tumors. Amelioration of surgery, radiotherapy, chemotherapy and gene therapy may influence the morbidity and mortality of oral cancer patients, even if a short follow up and the secondary prevention may warrant a life-long surveillance

The dental management of patients at risk of medication-related osteonecrosis of the jaw: New paradigm of primary prevention

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents; it is a potentially painful and debilitating condition that can considerably affect the quality of life of patients. Furthermore, even if its epidemiology and pathogenesis have still not been fully clarified, several risk factors related to MRONJ have been recognized in prevention protocols. Three main risk factors are as follows: (i) the type of ONJ-related medications: antiresorptive (e.g., Bisphosphonates, Denosumab) and antiangiogenic drugs (e.g., Bevacizumab, Sunitinib); (ii) the category of patient at MRONJ risk: cancer versus non-cancer patient; (iii) the typologies and timing of dental treatments (e.g., before, during, or after the drug administration). The aim of this paper is to describe the new paradigm by the Italian Society of Oral Pathology and Medicine (SIPMO) on preventive dental management in patients at risk of MRONJ, prior to and during/after the administration of the aforementioned ONJ-related drugs. In reducing the risk of MRONJ, dentists and oral hygienists are key figures in applying a correct protocol of primary prevention for pre-treatment and in-treatment patients. However, the necessity of a multidisciplinary standardized approach, with a sustained dialogue among specialists involved, should be always adopted in order to improve the efficacy of preventive strategies and to ameliorate the patient\u2019s quality of life

Triple simultaneus oral squamous cell carcinoma in a heavy smoker patient: a case report

Introduction. The presence of multiple malignancies in the aerodigestive tract is a rare disorder defined as multiple primary carcinoma (MPC)1, which lesions must be at different sites separated by normal mucosa and histologically confirmed, and should not be metastatic disease from the index carcinoma2. The reported incidence of MPC in the oral cavity has been reported to be 1.4%. MPC can be simultaneous (diagnosed at the same time as the index tumour), synchronous (additional primaries diagnosed within 6 months of the index tumour), or metachronous (primaries that develop more than 6 months after the index tumour)2. Case report. A 79-year-old edentulous male patient presented 3 different oral lesions: a) an erythro/leukoplasic le- sion on the soft palate and uvula (2,5x1cm), b) a verrucous/ulcerative lesion on the floor of the mouth (1x1cm), c) an exophytic/ulcerative lesion on the edentulus ridge of the 4th sextant (3,5x1cm). Lesions were not associated to any symptoms; the lesions b and c were bleeding and fixed to the underlying tissue. The patient reported no health concerns; he referred a 10-pack-year of cigarettes history followed by 50-pack-year of cigars. All the lesions presented a dark royal blue aspect after the toluidine blue staining3. Incisional biopsies were made and the histological examination reported a diagnosis of “oral squamous cell carcino- ma” in each of the tissue samples. Patient was referred to the Department of Oral Maxillofacial and Plastic Surgery for the TNM staging and the management. Conclusion. The MPC pathogenesis is uncertain involving genetic susceptibility, tumor immunity and environmental factors. Moreover, multiple cancers have a poor prognosis, 3-year survival rate of 50%, underlining that secondary prevention should be promoted and supported in adult heavy smokers, as the early diagnosis of oral carcinoma aris- es the probability of successful treatment

Oral HPV Infection: Current Strategies for Prevention and Therapy

Infection with High Risk (HR) Human Papillomaviruses (HPVs) is the main aetiological agent of Cervical Squamous Cell Carcinoma (CSCC) and also associated in a subgroup of other neoplasms, including Oropharyngeal Squamous cell Carcinoma (OPSCC). HPV infection, in genital as in oral mucosa can also be subclinical or associated with benign proliferative lesions (common warts, condylomas, papillomas) caused mostly by infection with Low Risk (LR)-HPVs. In the last decades, extensive research has resulted in growing knowledge on HPV biology and specifically viral life cycle, biochemical properties of viral proteins and their interaction with the host proteins leading to potential new targets of prophylactic or therapeutic vaccines and therapies for HPV infection. In addition, notable progresses have been made in the field of diagnostics to detect HPV DNA or RNA. The recent epidemiological data suggest the significant changes in HPV endemic, due to the changes in sexual habits especially among young generations (i.e. early sexual debuts, multiple sexual partners, oral and anal sex); this scenario has urged on the need of adequate campaigns of primary (sexual education, vaccination programs) and secondary prevention (diagnostics of HPV-related diseases). Due to the growing interest on HPV infection and HPV related cancers, the authors made a narrative review of the literature on oral HPV infection and oral-genital transmission. After this, in view of the controversies about the strategies of therapy and prevention of HPV infection, the present review focuses on the current state of art about the available tools for the therapeutic and, if any, preventive management of oral HPV infection

Doctoral: A smartphone-based decision support tool for the early detection of oral potentially malignant disorders

Oral potentially malignant disorders can be defined as mucosal lesions and conditions with an increased risk of malignant transformation. Oral potentially malignant disorders are a significant health burden, and they are often diagnosed late due to scant attention to routine dental practice and the low number of specialized oral medicine centres. This report summarizes the DoctOral experience, a research initiative, providing a free smartphone-based decision support tool for the general medical/dental practitioner; the tool is based on the clinical appearance of oral lesions. Captured, oral pictures can be immediately examined via interactive decision trees and constructed on the smartphone. Such decision trees are expressed in standard formats, and they are readily accessible for facilitating the completion of a hypothetical diagnostic path. Since October 2017 the DoctOral mobile app has been downloaded by 10K + users, achieving a score of 4.8 out of 5. DoctOral also supports an unfolding joint initiative, called DoctOralAI: this involves selecting reference images, with which to create an open-source model, and perform a Case-Based Reasoning method, both of which are combined with machine learning. The DoctOral mobile app has revolutionized oral pathology by providing dental students and professionals with an interactive platform for recognizing and diagnosing oral lesions