Reydson Alcides de Lima-Souza

Purpose: The WHO classification of head and neck tumors over the past five decades were reviewed, highlighting the major conceptual and taxonomic changes that have shaped contemporary head and neck pathology. Methods: Major WHO classifications of head and neck tumors were reviewed, with a focus on changes in diagnostic concepts and taxonomic principles rather than individual additions or removals of tumor entities. Results: WHO classifications have evolved from morphology-based, site-specific systems to an integrated clinicopathological and molecular taxonomy. Early editions emphasized histomorphology and presumed tissue of origin. Subsequent classifications, however, increasingly incorporated immunophenotypic and molecular findings. The recognition of virus-associated neoplasms and recurrent molecular alterations has contributed to defining new entities and refining existing categories. The fifth edition further standardized tumor taxonomy by introducing essential and desirable diagnostic criteria, reflecting a biology-driven approach to classification. Conclusion: The evolution of WHO classifications reflects major advances in tumor biology and has substantially influenced diagnostic practice and clinical interpretation. Future classifications will likely incorporate increasingly sophisticated molecular, digital, and computational approaches while maintaining standardized, reproducible, and clinically meaningful diagnostic criteria.

Highlights ■ Immunohistochemistry distinguishes Warthin-like mucoepidermoid carcinoma from metaplastic Warthin tumor. ■ CK7, mitochondrial patterns, and double-layer epithelium suggest metaplastic Warthin tumor. ■ Basal CK14, CK5/6, and p63 distinguish metaplastic Warthin tumor from Warthin-like mucoepidermoid carcinoma. ABSTRACT Objective: This study aimed to analyze the clinicopathological and immunohistochemical profiles of unconventional Warthin tumors and mucoepidermoid carcinomas. Methods: Eleven low-grade salivary gland tumors with Warthin-like features were analyzed. Group A (n=6) showed a double-layered oncocytic epithelium in less than 50% of the

Background: Pleomorphic adenoma (PA) is the most common salivary gland tumor, and a subset may recur as recurrent PA (RPA) or progress to carcinoma ex pleomorphic adenoma (CXPA). However, comparative evaluations of their biological behavior and prognostic factors remain limited. Objective: To characterize and compare the clinical features, pathological patterns, treatment outcomes, and prognostic factors of PA, RPA, and CXPA over a 20‐year period at a Brazilian tertiary referral center. Materials and Methods: A retrospective review of 234 cases (148 PA, 23 RPA, 63 CXPA) diagnosed between 2004 and 2024. Analyses included Fisher's exact test and chi‐square test for group comparisons and Cox proportional hazards models for overall (OS) and disease‐specific survival (DSS). Results: PA and RPA mainly affected younger females and presented smaller tumors and shorter clinical evolution than CXPA ( p < 0.01). In CXPA, perineural invasion, angiolymphatic invasion, necrosis, recurrence, symptomatology, distant metastasis, and capsular invasion pattern were associated with reduced OS and DSS ( p < 0.05). Conclusion: This retrospective study demonstrates distinct clinical and pathological profiles across PA, RPA, and CXPA. In CXPA, clinical and histological factors strongly predict survival and should guide risk stratification, therapeutic decisions, and follow‐up strategies.

Background/Objectives: Premalignant laryngeal lesions carry a variable risk of malignant transformation to squamous cell carcinoma. Identifying reliable biomarkers that predict malignant transformation could improve patient management and surveillance strategies. The objective of this work is to perform a systematic review of the literature on biomarkers that predict malignant transformation of premalignant laryngeal lesions. Methods: We conducted a systematic review following PRISMA 2020 guidelines. The PubMed, Scopus and Embase databases, and Google Scholar were searched for studies published between January 2011 and November 2025. Studies investigating biomarkers that predict malignant transformation of histopathologically confirmed premalignant laryngeal lesions were included. Risk of bias was assessed using the ROBINS-I tool. Results: From 166 initially identified records, 11 studies met the inclusion criteria, including 730 patients. These studies investigated diverse biomarker categories such as protein markers (cortactin, FAK, NANOG, SOX2, CSPG4), immune markers (tumor-infiltrating lymphocytes, immune gene signatures), microRNAs (miR-183-5p, miR-155-5p, miR-106b-3p), and genetic markers (chromosomal instability, PIK3CA amplification and mutations, FGFR3 mutations). Five studies provided adequate follow-up data on transformation outcomes. Most studies showed a moderate to serious risk of bias primarily due to limited confounder control and incomplete reporting. Conclusions: While several promising biomarker candidates have been identified, the evidence base remains limited due to small sample sizes, heterogeneous methodologies, and inadequate follow-up data. Cortactin/FAK protein expression and immune signatures are the most promising but require validation in larger, well-designed prospective cohorts.

Background: Given the rarity and aggressive nature of osteosarcomas (OS) in the oral and maxillofacial region, understanding their molecular alterations is essential to improve diagnosis, prognosis, and guide targeted therapies. This study aimed to map molecular alterations associated with oral and maxillofacial OS, providing an overview of the genetic mechanisms involved in their development and progression. Methods: A scoping review was performed following the PRISMA‐ScR guidelines. Studies included observational research, case reports, and systematic reviews focusing on molecular alterations in oral and maxillofacial OS. A comprehensive search was conducted across four databases, and findings were synthesized and categorized by molecular characteristics. Results: A total of 20 studies involving 68 maxillofacial OS cases were included. The average patient age was 39.4 years, with a slight male predominance. The mandible was the most commonly affected site, and chondroblastic OS was the most frequent histological subtype. Genetic alterations were predominantly observed in the TP53 gene, along with alterations in MDM2 , CDK4 , and other genes. Treatment primarily involved surgery, with or without chemotherapy. Local recurrence occurred in 11.1% of cases, and distant metastases in 16%. At the final follow‐up, 69.7% of patients were alive. Conclusion: This study emphasizes the value of molecular techniques in improving the diagnosis and management of maxillofacial OS. However, further research is needed to fully understand the molecular complexity and optimize therapeutic strategies.

Diagnosing salivary gland tumors remains challenging due to their clinical and biological complexity, histopathologic diversity, and overlapping morphology. Over the last few years, molecular profiling has emerged as a key tool for improving tumor classification, shedding light on the cellular and molecular mechanisms underlying tumors pathogenesis. This review provides a comprehensive exploration of the clinical application of molecular profiling in the decision to indicate targeted therapy for salivary gland neoplasm. The increasing adoption of innovative biological markers associated with Next-Generation Sequencing highlights the potential of molecular diagnostic approaches as well as the prediction of therapeutic response. While immunohistochemistry remains a reliable and widely accessible ancillary tool for characterizing specific salivary gland tumors subtypes, additional validation using in situ hybridization, reverse transcription polymerase chain reaction or Next-Generation Sequencing may enhance diagnostic accuracy and facilitate the identification of actionable molecular alterations in the appropriate clinical and morphological context. This integrated diagnostic approach strengthens clinical decision-making and opens new avenues for precision-targeted therapy in the management of salivary gland tumors. As molecular insights continue to expand, the integration of traditional and modern tools will be critical to improving diagnostic accuracy, prognostic stratification, and treatment outcomes for patients with salivary gland tumors.

Pleomorphic adenoma (PA) is the most common salivary gland tumor. Although it is benign, PA may recur, metastasize, and undergo malignant transformation into carcinoma ex pleomorphic adenoma (CXPA). The mechanisms underlying this transformation are unclear, but it is believed that they involve the accumulation of molecular alterations. This study aimed to analyze the metabolomic profile associated with the acquisition of the malignant phenotype in PA and to identify the metabolic pathways involved in this process. A retrospective analysis was conducted using our institutional Salivary Gland Tumor Registry, which comprises 15 cases each of normal salivary gland (NSG), PA, recurrent PA (RPA), and CXPA. Metabolomic profiling was performed on formalin-fixed, paraffin-embedded tissue samples. Selected CXPA cases underwent genetic sequencing to investigate potential molecular alterations. The analysis revealed changes in carbohydrate, amino acid, and lipid metabolism. Notably, alterations in lipid-related pathways, particularly those involving fatty acids, appeared to play a significanat role in the acquisition of the malignant phenotype. Genetic analysis identified a novel NTF3::ITPR2 fusion in one CXPA case. Additionally, variants were detected in ARID1A, NSD1, XPO1, FOXA1, TP53, GATA2, LZTR1, PIK3CA, IRF4, and CHEK1, with allele frequencies ranging from 10% to 84%, indicating substantial genetic heterogeneity among CXPA cases. This study provides the first comprehensive metabolomic snapshot of malignant phenotype acquisition in PA. Identifying lipid metabolic dysregulation and a novel NTF3::ITPR2 gene fusion highlights potential diagnostic biomarkers and unveils actionable pathways that could be translated into targeted and personalized therapies for salivary gland tumors. Graphical Abstract

Objective: This study aimed to systematically review primary sarcomas in the oral and maxillofacial region, focusing on patient demographics and sarcoma‐specific characteristics, including clinical presentation, histopathology, treatment approaches, outcomes, and survival rates. Materials and Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines and based on the PECOS framework, including observational studies on primary oral and maxillofacial sarcomas. An electronic search in five databases identified eligible studies, and outcomes were analyzed via Kaplan–Meier and Cox regression. Results: The review included 35 studies comprising 687 cases of sarcomas in the oral and maxillofacial region. The mean patient age was 35.26 years, with a slight male predominance. Lesions predominantly involved the mandible, with osteosarcoma being the most common histological subtype. Multimodal treatment was most frequent. Of 616 patients with survival data, 58.1% were alive at analysis. The overall 5‐year survival and disease‐free survival rates were 54.3% and 60.4%, respectively. Factors such as age, histological type, T classification, stage grouping, surgical margins, local recurrence, and distant metastases significantly influenced survival ( p < 0.05). Conclusion: This study provides a comprehensive review of oral and maxillofacial sarcomas, offering data to understand the clinicopathological characteristics of these lesions, helping to improve their diagnosis and management.