Factors and management techniques in odontogenic keratocysts: a systematic review.

OBJECTIVES: Odontogenic keratocysts exhibit frequent recurrence, distinctive histopathological traits, a tendency towards aggressive clinical behavior, and a potential linkage to the nevoid basal cell carcinoma syndrome. The aim of this systematic review is to compile insights concerning the control of this condition and assess the effectiveness of various treatment approaches in reducing the likelihood of recurrence. MATERIALS AND METHODS: The following systematic review adhered to the PRISMA guidelines. The systematic revision was registered on PROSPERO and  structured around the questions related to the population, intervention, control, outcome and study design (PICOS). RESULTS: After conducting a search on the PubMed database, we initially identified 944 records. After using end-note software to remove duplicate entries, results totally with 462 distinct records. A thorough review of the titles and abstracts of these articles led to the selection of 50 papers for in-depth examination. Ultimately, following the application of our eligibility criteria, we incorporated 11 articles into our primary outcome analysis. CONCLUSION: Among the studies examined, the most common location for these lesions was found to be in the area of the mandibular ramus and the posterior region of the mandible. In cases where the exact location wasn't specified, the mandible emerged as the predominant site. When we considered the characteristics of these lesions in studies that mentioned locularity, most were described as unilocular in two studies, while in two other studies, the prevalence of multilocular lesions was observed. Risk factors associated with keratocyst recurrence include younger patient age, the presence of multilocular lesions, larger lesion size, and a longer anteroposterior dimension. Certain treatment methods have demonstrated a lack of relapses. These include the use of 5-fluorouracil, marsupialization, enucleation with peripheral ostectomy or resection, enucleation and curettage, as well as resection without creating continuity defects. However, it is important to note that further research is essential. Prospective studies and randomized trials are needed to collect more comprehensive evidence regarding the effectiveness of various treatment approaches and follow-up protocols for managing odontogenic keratocysts. CLINICAL RELEVANCE: Odontogenic keratocysts still enter into differential diagnoses with other lesions that affect the jaw bones such as ameloblastama and other tumor forms, furthermore it is not free from recurrence, therefore the therapeutic approach to the lesion aimed at its elimination can influence both the possible recurrence and complications, knowledge of the surgical methods that offer the most predictable and clinically relevant result for the management of follow-up and recurrences.

Challenging Differential Diagnosis of Mandible Angle Metastasis from Breast Cancer.

Breast cancer is the most common cancer in women and the second leading cause of cancer-related death. Breast cancer manifestations in the head and neck are relatively rare, and they are mostly bony metastasis to the mandible and maxilla. In this paper, we present a case report of a metastatic tumor in the mandibular angle originating from breast carcinoma. A 32-year-old female patient with a paresthesia/anesthesia in the left mandibular area was referred to us to aid in the differential diagnosis between osteonecrosis and metastasis. Her medical history revealed a radical bimastectomy 3 years ago for invasive lobular carcinoma of the breasts. Additionally, she received chemotherapy and radiotherapy 3 years ago, and intravenous zoledronic acid was administered every 3 weeks. Intraoral examination did not reveal any mucosal ulcer or fistula, and there was no radiological evidence of cyst. The patient demonstrated good oral hygiene. Palpable regional left submandibular lymph nodes and a few swellings on the lateral angular mandibular surface were observed. Cone-beam computed tomography (CBCT) and positron emission tomography (PET) were performed. CBCT showed small poorly diffused radiopacity in proximity to the mandibular angle on both medial and lateral surfaces. PET showed fluoro-2-deoxy-D-glucose uptake in the mandible in the left angle surface area. Based on the patient's clinical history, signs, symptoms, and tomographic evidence, we were able to diagnose mandibular metastasis. This case also highlights the importance of proficiency in reading tomographic examinations, which can be carried out in dental clinics for various purposes. In the absence of symptoms, misdiagnosis can occur, underscoring the significance of accurate interpretation and diagnosis.

Dietary Polyphenols against Oxidative Stress in Head and Neck Cancer: What's New, What's Next.

Head and neck cancers (HNC) are a worldwide health problem, accounting for over 5% of all types of cancers. Their varied nature makes it sometimes difficult to find clear explanations for the molecular mechanisms that underline their onset and development. While chemio- and radiotherapy are clearly not to be dismissed, we cannot undervalue the effect that polyphenols - especially dietary polyphenols - can have in helping us to cope with this medical emergency. By influencing several different proteins involved in numerous different metabolic pathways, polyphenols can have a broad spectrum of biological action and can hopefully act synergistically to tackle down head and neck cancer. Moreover, being natural molecules, polyphenols does not present any side effects and can even enhance drugs efficacy, making our clinical therapy against head and neck cancer more and more effective. Certainly, oxidative stress plays an important role, altering several molecular pathways, lowering the body's defenses, and ultimately helping to create a microenvironment conducive to the appearance and development of the tumor. In this regard, the regular and constant intake of foods rich in polyphenols can help counteract the onset of oxidative stress, improving the health of the general population. In this review, we highlight the role of polyphenols in managing oxidative stress, with such positive effects that they can be considered new tools to use in our anti-head and neck cancer strategy.

Anti-LGALS3BP antibody-drug conjugate treatment induces durable and potent antitumor response in a preclinical model of adenoid cystic carcinoma.

OBJECTIVES: Adenoid cystic carcinoma (ACC) is a rare type of cancer that typically arises from glandular tissues, most commonly in the salivary glands. Although relatively rare, it represents a serious clinical issue as the management of the disease is highly complex being the only therapeutic options represented by invasive surgery and/or radiotherapy. In the present study, we have explored the potential of galectin-3 binding protein (LGALS3BP) as a novel target for antibody-drug conjugate (ADC) therapy in ACC. MATERIALS AND METHODS: RNAseq was conducted on a panel of 10 ACC patient-derived xenografts (PDX)s tissues and 6 normal salivary glands to analyze LGALS3BP gene expression. Protein expression was assessed in ACC PDX and primary tumor tissues using immunohistochemistry. Anti-LGALS3BP ADC named 1959-sss/DM4, was tested in high LGALS3BP expressing ACC PDX model ST1502B. RESULTS: RNAseq analysis revealed that LGALS3BP expression was highly expressed in ACC PDX tissues compared to normal salivary gland tissues. As evaluated by immunohistochemical analysis, LGALS3BP protein was found to be heterogeneously expressed in 10 ACC PDX and in tumor tissues derived from a cohort of 37 ACC patients. Further, treatment with 1959-sss/DM4 ADC led to durable tumor growth inhibition (TGI) in 100% of animals without observed toxicity. CONCLUSIONS: Our study provides strong evidence that LGALS3BP is a promising therapeutic target for ACC, warranting further expedited preclinical and clinical investigation.

Treatment of Mandibular Impacted Canine in a Patient with Class II Division 1 Malocclusion with "Reverse Pin": A Case Report.

This case report presents an orthodontic treatment conducted on a 13-year-old girl with bilateral Class II malocclusion and a mandibular impacted canine. The presence of an impacted tooth necessitates careful consideration of the timing of orthodontic treatment, the appropriate surgical procedure to expose the tooth, the specific orthodontic mechanics involved, and the potential problems that may arise, all of which depend on the type and location of the canine impaction in the jaw. The treatment plan included a surgical procedure to expose the impacted tooth and orthodontic traction to guide it into position. Correction of the Class II Division 1 malocclusion utilized a specialized technique called the "reverse pin", reducing vertical side effects. The revised version maintains clarity and key information about the case report and treatment.

The Potential microRNA Prognostic Signature in HNSCCs: A Systematic Review.

Head and neck squamous cell carcinomas (HNSCCs) are often diagnosed at advanced stages, incurring significant high mortality and morbidity. Several microRNAs (miRs) have been identified as pivotal players in the onset and advancement of HNSCCs, operating as either oncogenes or tumor suppressors. Distinctive miR patterns identified in tumor samples, as well as in serum, plasma, or saliva, from patients have significant clinical potential for use in the diagnosis and prognosis of HNSCCs and as potential therapeutic targets. The aim of this study was to identify previous systematic reviews with meta-analysis data and clinical trials that showed the most promising miRs in HNSCCs, enclosing them into a biomolecular signature to test the prognostic value on a cohort of HNSCC patients according to The Cancer Genome Atlas (TCGA). Three electronic databases (PubMed, Scopus, and Science Direct) and one registry (the Cochrane Library) were investigated, and a combination of keywords such as "signature microRNA OR miR" AND "HNSCC OR LSCC OR OSCC OR oral cancer" were searched. In total, 15 systematic literature reviews and 76 prognostic clinical reports were identified for the study design and inclusion process. All survival index data were extracted, and the three miRs (miR-21, miR-155, and miR-375) most investigated and presenting the largest number of patients included in the studies were selected in a molecular biosignature. The difference between high and low tissue expression levels of miR-21, miR-155, and miR-375 for OS had an HR = 1.28, with 95% CI: [0.95, 1.72]. In conclusion, the current evidence suggests that miRNAs have potential prognostic value to serve as screening tools for clinical practice in HNSCC follow-up and treatment. Further large-scale cohort studies focusing on these miRNAs are recommended to verify the clinical utility of these markers individually and/or in combination.

The Immune Cells in the Development of Oral Squamous Cell Carcinoma.

A still unresolved issue surrounding tumor formation concerns the role that the immune system plays in preventing the formation and progression of neoplasia, including oral squamous cell carcinoma (OSCC). Antitumor immunity has historically been seen as a critical barrier for cancer cells to develop, grow and spread, and this can be modulated using immunotherapies to achieve antitumor clinical responses. However, it has recently become clear that tumor-associated immunity, particularly the inflammatory microenvironment, has the paradoxical effect of enhancing tumorigenesis and progression. In this review, we discuss the multifaceted function of infiltrating immune cells in suppressing or promoting premalignancy and cancer. In particular, we report on the evidence supporting a role for T lymphocytes, dendritic cells, macrophages, and neutrophils in the development and progression of oral potentially malignant disorders (OPMD) and OSCC. We also draw attention to the clinical relevance of immune cell phenotypes and associated molecules for use as biomarkers and to the translatability of current research findings to improve classification systems and precision medicine in patients with OSCC.

LGALS3BP is a potential target of antibody-drug conjugates in oral squamous cell carcinoma.

OBJECTIVE: The aim of the present study was to evaluate the expression of intracellular and vesicular LGALS3BP in oral squamous cell carcinoma (OSCC) patients and available cell lines to explore its potential as a target for antibody-drug conjugate (ADC) therapy. METHODS: Free and vesicular LGALS3BP expression levels were evaluated in cancer tissues from a cohort of OSCC patients as well as in a panel of OSCC cell lines through immunohistochemistry, qRT-PCR, Western Blot analysis, and ELISA. RESULTS: LGALS3BP resulted in being highly expressed in the cytoplasm of tumour cells in OSCC patient tissues. A strong correlation was found between high LGALS3BP expression levels and aggressive histological features of OSCC. Biochemistry analysis performed on OSCC cell lines showed that LGALS3BP is expressed in all the tested cell lines and highly enriched in cancer-derived extracellular vesicles. Moreover, LGALS3BP high-expressing HOC621 and CAL27 OSCC cell lines showed high sensitivity to the ADC-payload DM4, with an IC50 around 0.3 nM. CONCLUSIONS: The present study highlights that LGALS3BP is highly expressed in OSCC suggesting a role as a potential diagnostic biomarker and therapeutic target for ADC-based therapy.

COVID-19 and Oral Lichen Planus: Between an "Intriguing Plot" and the "Fata Morgana Effect".

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant morbidity and mortality worldwide since its declaration as a global pandemic in March 2020. Alongside the typical respiratory symptoms, unusual clinical manifestations such as oral lichen planus (OLP) have been observed. OLP is a chronic inflammatory mucocutaneous dermatosis that results from a cell-mediated reaction, and its pathogenesis involves the loss of immunological tolerance. OLP has been associated with several triggering factors, such as certain drugs, stress, smoking, and even some viruses. Exposure to the spike protein antigen of SARS-CoV-2 during an infection can trigger autoimmune reactions and lead to the onset or flare of OLP. The E3 protein ligase TRIM21, which is identified in the lamina propria of OLP lesions, is overexpressed in COVID-19 patients and plays a critical role in autoimmune pathologies. Furthermore, the psychological stress of the lockdown and quarantine can be a trigger for the onset or exacerbation of OLP. However, the diagnosis of OLP is complex and requires a biopsy in order to confirm a clinical diagnosis, rule out other pathologies, and establish the most appropriate therapeutic procedure. Further research is needed to understand the potential link between Co-19 and OLP.

High-risk TP53 mutations predict poor primary treatment response of patients with head and neck squamous cell carcinoma.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) poses a diagnostic and therapeutic challenge worldwide and is associated with a poor survival rate. Due to the variability in the efficacy of treatments for HNSCC, new predictive biomarkers of therapy outcomes are needed. Recently, we developed an algorithm that employs the mutational profile of TP53 as an independent prognostic factor in HNSCC. In this study, we investigated its role as a predictive biomarker of treatment outcomes in HNSCC patients. We also tested the usefulness of two classification systems for TP53 mutational landscapes. MATERIALS AND METHODS: Clinical and genomic data were retrieved from The Cancer Genome Atlas database. We built a multivariate stepwise backward binary regression model to assess the role of TP53 mutations in predicting therapeutic outcomes. RESULTS: Cases harbouring high-risk-of-death mutations reported an odds ratio of 3.301 for stable or progressive disease compared to wild-type cases, while no significant difference in treatment outcomes was found between cases with low-risk-of-death mutations and wild-type TP53. Our analysis found that older patients with a history of alcohol consumption had a higher risk of stable/progressive disease. CONCLUSIONS: This study improves current evidence on the role of TP53 mutations in treatment response in HNSCC patients.

Mandibular Reconstruction after Resection of Ameloblastoma by Custom-Made CAD/CAM Mandibular Titanium Prosthesis: Two Case Reports, Finite Element Analysis and Discussion of the Technique.

Virtual surgical planning for CAD/CAM mandibular reconstruction by titanium prosthesis was recently reported for resected cases. Even if some advantages are evident, difficulties that may arise for TMJ function after reconstruction originate from prosthesis contamination through oral mucosa dehiscence. In these two cases reported of mandibular reconstruction after resection of ameloblastoma by custom-made CAD/CAM titanium prosthesis, the procedures were aimed to preserve the TMJ glenoid cavity and articular disc avoiding functional problems for hemi-mandibular resections that included the condyle (as in case #1) or with condylar preservation (as in case #2) and avoiding intraoral incisions in both cases. The entire surgical planning and prosthetic fabrication were explained with specifications and the sequence of the surgical procedure. Finite elements analysis (FEA) was performed to check the force distribution and efficacy of the prosthetic device (case 1 with hemi-mandibular resection and rehabilitation). Although successful in these two cases, surgical reconstruction of the mandibular defect after resection by a CAD-CAM custom-made prosthesis still shows some drawbacks and failure risks. Several advantages of this technique and the surgical success in these two cases were presented, but limitations and side effects must be considered when cases are selected.

Location and Gender Differences in Osteonecrosis of the Jaws in Patients Treated with Antiresorptive and Antineoplastic Drugs Undergoing Dentoalveolar Surgical, Systematic Review with Meta-Analysis and Trial Sequential Analysis.

In the treatment and prevention of osteoporosis and more generally of neoplastic and metabolic pathologies affecting bone tissues, antiresorption drugs such as bisphosphonates and monoclonal antibody are used. Bisphosphonates have been linked to cases of osteonecrosis of the jaws since 2003 by Marx, with more and more evidence over the next two decades; together with bisphosphonate drugs, cases relating to the use of monoclonal drugs have been subsequently added. Among the main independent risk factors, we have extraction procedures in oral surgery that can affect both the mandible and the maxilla and the anterior or posterior sectors. The incidence of MRONJ treated with oral bisphosphonates ranges from 0.5% to 3% according to studies; this incidence would appear to be higher in patients treated with antiresorptive agents with neoplastic diseases. Many pathologies including those in which antiresorptive drugs are used show differences in prevalence in relation to sex; similarly, there could be differences in the incidence of cases of osteonecrosis based on gender in patients undergoing dentoalveolar surgery. Therefore, the objective of this systematic review and trial sequential analysis was to identify and quantify whether there is a proportionally greater risk of MRONJ in male or female subjects and whether there is evidence of greater involvement of osteonecrosis at several extraction sites, differentiating them into mandibular or maxilla and in the anterior or posterior sector. The revision protocol followed the indications of the Cochrane Handbook, and were recorded in Prospero, while the drafting of the manuscript was based on PRISMA. The results of the systematic review, after the study identification and selection process, included a total of 24 studies. The results of the meta-analysis reports: odds ratio (random effects model): 1.476 (0.684, 3.184) between male and female; odds ratio (random effects model): 1.390 (0.801, 2.412) between mandible and maxillary, and an odds ratio value of 0.730 (0.250, 2.137) between the anterior and posterior extraction sites. In conclusion, we can see that there was a trend in the onset of MRONJ as a complication of dentoalveolar surgical procedures, which proportionally mostly involved the male sex and the posterior mandibular sectors, however, this trend must be further confirmed by additional studies.

Oral lichen planus in children: An Italian case series.

Oral lichen planus usually occurs in adults; there are no clear data regarding the incidence and the clinical features of oral lichen planus in children. This paper reports clinical findings, treatments, and outcomes of 13 Italian patients with oral lichen planus in childhood diagnosed between 2001 and 2021. The most common finding was keratotic lesions with reticular or papular/plaque-like patterns, confined to the tongue in seven patients. Although oral lichen planus in childhood is rare and the malignant transformation index is unknown, specialists must be aware of its characteristics and oral mucosal lesions must be correctly diagnosed and managed.

Is the Non-Coding RNA miR-195 a Biodynamic Marker in the Pathogenesis of Head and Neck Squamous Cell Carcinoma? A Prognostic Meta-Analysis.

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of neoplasms whose histological derivation comes from the mucous membranes lining the epithelium: the oral cavity, the larynx, the hypopharynx, the nasopharynx, and the oropharynx. The etiopathogenetic mechanisms involving tumor genesis including the alteration of cell proliferation, apoptosis, invasion, migration, and death may involve alterations in the expression of microRNA (miR). To date there have been no systematic reviews with meta-analysis conducted specifically on the role of miR-195 in HNSCC; therefore, our hypothesis was to evaluate if the aberrant expression of miR-195 in HNSCC tissues may represent a prognostic biomarker of survival through the hazard ratio (HR) and relative risk (RR) analysis. The systematic review was designed according to the PRISMA indications; in total, three electronic databases were consulted (PubMed, Scopus, Cochrane Central Trial) including Google Scholar and the gray literature, and a combination of keywords was used such as miR-195 AND HNSCC, microRNA AND HNSCC and miR-195. The meta-analysis and trial sequential analysis were performed using RevMan 5.41 software and TSA software (Cochrane Collaboration, Copenhagen, Denmark). This search identified 1592 articles and, at the end of the selection process, three articles were included. The results of the meta-analysis reported an aggregated risk ratio for overall survival (OS) between the expression of miR-195 at the highest and lowest of 0.36 and 6, respectively, 95% CI: [0.25, 0.51]. Heterogeneity was evaluated through Chi2 = 0.05 df = 2 (p = 0.98) and the Higgins index I2 = 0%. The test for the overall effect was Z = 5.77 (p < 0.00001). The forest plot was in favor of higher OS in patients with high miR-195 expression.

Neurosensory Alterations and Interleukins Cascade in SARS-CoV-2 Infection - Results from a Retrospective Cohort of COVID-19 Inpatients.

OBJECTIVES: The aim of this study was to relate IL-6 and IL-1ß serum levels with the severity of olfactory disorders and with the type of unperceived odors. METHODS: 82 inpatients (45 men aged 62.3 ± 14.2 and 37 women aged 57.1 ± 12.8) with only smell dysfunctions were divided into two groups. The evaluation of the smell disorder was carried out with a questionnaire to define which sensitivity is most compromised in COVID-19 patients. Cytokine levels were measured with chemiluminescence and ELISA assay. Statistical analyses were performed with the Wilcoxon Rank test, Welch's T-test, and Mann-Whitney test (p < 0.05). RESULTS: Statistically significant differences in IL-6 and IL-1 ß levels were found in moderate disease patients when there was an impairment of trigeminal sensitivity (p <0.05) and trigeminal and olfactory sensitivity. CONCLUSIONS: The results obtained showed that in COVID-19 patients the impairment of trigeminal sensitivity in association with olfactory sensitivity was more prevalent in moderate than in mild forms.

Guided Dental Implant Surgery: Systematic Review.

Among the common procedures in clinical practice in the field of dentistry is prosthetic rehabilitation through the insertion of dental implants. In order to obtain the best aesthetic and functional results, the oral surgeon who deals with implantology must be able to position the dental implants correctly; a crucial role is therefore played by the diagnostic and treatment planning phases, where attention must be paid to anatomical constraints and prosthetic constraints in the alveolar bone site. The parameters, such as bone quality, bone volume, and anatomical restrictions, can be processed and simulated using implant planning software. The simulation of the virtual positioning of the implant can lead to the construction of a three-dimensional model of the implant positioning guide, which can be used during the implant surgery. The aim of this systematic review is to evaluate survival rates, early and late failure rates, peri-implant bone remodeling, and possible implant-prosthetic complications related to implants placed using digitally designed surgical guides. This systematic review was written following the indications of PRISMA and envisaged the use of 3 databases: Scopus, PubMed, and Cochrane Library. Results: Only 9 of the 2001 records were included, including 2 retrospective studies and 7 prospective studies. Conclusion: On the basis of the studies selected in this review, it can be seen that the implant survival obtained with the use of guided implant surgery shows high percentages. Many recorded failures occurred early, due to a lack of osseointegration, and the variables that come into play in the survival of the implants are many.

Evaluation of qualitative and quantitative taste alterations in COVID-19.

A large percentage of coronavirus disease 2019 (COVID-19) patients have taste dysfunction. Interleukin 6 (IL-6) levels in mild and moderate COVID-19 patients with the type (quantitative or qualitative) of taste disorders were compared in this observational study. The 208 COVID-19 patients (118 men and 90 women) revealing only taste dysfunctions as prodromic symptoms were classified as mild and moderate patients. Survey results were used to evaluate the taste disorder. The IL-6 levels were measured using a chemiluminescence assay. Statistical analysis was conducted using the Wilcoxon rank, Welch's, and Mann-Whitney tests. The findings revealed that neither the presence of dysgeusia or phantogeusia nor the perception of sour and salty, differed statistically significantly between moderate and mild patients (P > 0.05). But between moderate and mild patients, there were statistically significant differences in how umami, bitter, sweet, and parageusia were perceived (P < 0.05). There was an impairment of multiple tastes up to ageusia in patients with high IL-6 levels. The findings demonstrated that parageusia and dysfunctions in umami, bitter, and sweet taste perception can be indicators of more severe forms of COVID-19.

Prognostic significance of tumor budding thresholds in oral tongue squamous cell carcinoma.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) represents the most common malignancy of the oral cavity. Tumor budding (TB) is a reliable prognostic factor in OTSCC; however, a standardized scoring system is not still validated. AIMS: The study aims to evaluate the prognostic role of TB in 211 OTSCC patients treated between 1997 and 2018. MATERIALS & METHODS: TB was evaluated on hematoxylin and eosin-stained sections in the hotspot area of the infiltrative front (×200-magnification). It was scored using a two-tier system, a three-tier system, and according to BD-model and revised-Grading system. Univariate and multivariate Cox regression analyses of disease-specific survival (DSS) and disease-free survival (DFS) were performed. A p < 0.05 was considered as statistically significant. RESULTS: The two-tier and three-tier systems resulted an independent prognostic factor of DSS. High-risk patients had a 2.21 and 3.08 times increased probability of poor DSS compared with low-risk group. It is significantly increased even for intermediate-risk group. No significant differences emerged classifying patients according to BD-model and revised-Grading system. DISCUSSION: These data confirm the prognostic value of TB in predicting DSS in OTSCC. Classifying patients into two groups using the 5-bud cutoff significantly discriminates their outcomes. CONCLUSION: Since the established role of DOI and the poor prognostic value of grading, TB could be considered an independent prognostic marker.

Pattern and localization of perineural invasion predict poor survival in oral tongue carcinoma.

BACKGROUND: Survival rate for oral tongue squamous cell carcinoma (OTSCC) is still poor and, despite Tumor-Node-Metastasis staging system has been recently updated, patients included under the same stage still show difference in prognosis. Perineural invasion (PNI) emerged to be an indicator of tumor aggressive behavior and unfortunate events. In this study, we investigate the clinic and prognostic value of PNI in a cohort of OTSCC patients. METHODS: About 200 patients with OTSCC were retrospectively evaluated the presence of PNI. PNI was furtherly descripted as uni-/multifocal and as intra-/peritumoral. Disease-Specific and Relapse-Free Survival (DSS; RFS) were estimated; moreover, we included PNI in the current AJCC 8th Staging System, improving the prognostication model. RESULTS: Perineural invasion was found in 40.5% of patients. Intratumoral PNI predicted patients at high risk of being diagnosed with lymph-node metastasis. Tumors with positive PNI reported a worse DSS (Hazard Ratio=1.878, p-value = 0.008). Moreover, patients exhibiting both multifocal intra- and peritumoral PNI reported poorest DSS (Hazard Ratio = 2.409, p-value = 0.010). Patients were reclassified in a new staging system in case of multifocal PNI, providing better stratification capacity. CONCLUSIONS: Perineural invasion might serve as an additional prognostic factor in OTSCC, and by integrating PNI in the staging system, further improvements in prognostication might be reached.