Salivary duct carcinoma (SDC) is an aggressive neoplasm that typically involves the major salivary glands. This rapidly growing tumor is known to recur and metastasize to the neck nodes and to distant sites. Given its poor prognosis, researchers have focused on identifying factors and driver genomic alterations that may account for its behavior, ultimately yielding potential therapeutic targets. This review summarizes the growing body of knowledge on SDC since the publication of the latest WHO Classification of Tumors of the Head and Neck. Updates on emerging subtypes, immunohistochemical profiles, molecular alterations, and potential therapeutic targets are succinctly presented. Findings from studies on tumor immune microenvironment (TIME), which may have implications for the treatment and prognosis of SDC, are also discussed in this narrative review.

Carcinomas of the larynx encompass a heterogeneous group of tumors with markedly different biological behaviors. Conventional squamous cell carcinoma (SCC) accounts for most cases; however, less common non-SCC histologies, including salivary-type tumors, neuroendocrine carcinomas (NEC), and NUT carcinoma, exhibit distinct biological behaviors and survival outcomes. Despite these differences, most clinical reports and epidemiological datasets aggregate all laryngeal cancers together, which limit prognostic discrimination and may hinder treatment optimization. This narrative review summarizes current evidence regarding the impact of the histologic type on treatment strategies and prognosis in laryngeal carcinomas, highlighting the clinical implications of tumor biology. The survival varies substantially across histologic subtypes, ranging from approximately 95

Parallel to and after publication of the WHO 2024 classification of head and neck tumors, several developments concerning known existing salivary gland tumor entities, but also proposing new evolving tumor entities have been published. This review article describes the most important new developments in salivary gland pathology published through 2022–2025, that were not included in the 5th edition of the WHO Classification of Head and Neck Tumours 2024. This review summarizes these recent developments in both the benign and the malignant tumor categories. Among the recently proposed entities are palisading adenocarcinoma, microcribriform adenocarcinoma, fenestrating adenocarcinoma and skin-analogue poroid carcinoma. Developments in existing carcinoma entities include recognition of mucoacinar carcinoma as subtype of mucoepidermoid carcinoma (MAML2-fused), mucoepidermoid carcinoma without squamous cell differentiation, metatypical adenoid cystic carcinoma, and adenoid cystic carcinoma with prominent tubular hypereosinophilia. In the benign tumor category, recognition of pleomorphic adenoma with canalicular/trabecular phenotype driven by HMGA2 fusions, triphasic basal cell adenoma with S100 protein-positive "stroma", characterized by CTNNB1 mutations, metaplastic Warthin tumor with KRAS mutations and delineation of thymus-like phenotype in non-sebaceous lymphadenoma with recurrent CYLD mutations are the main highlights. Emerging concepts include benign tumor with ductal and papillary morphology (sialadenopapillary ductal tumor). Finally, new grading schemes have been developed/ proposed for acinic cell carcinoma and secretory carcinoma.

DNA methylation of tumour suppressor genes is the most well-studied epigenetic alterations in head and neck cancer. The tumour suppressor genes CDKN2A, RASSF1, and TIMP3 are the most frequently investigated, but the methylation status has been analysed in more than another dozen genes, for example MGMT. In oral squamous cell carcinoma (OSCC) methylation of MGMT, DAPK, and CDKN2A are promising biomarkers of prognostic value. Inhibition of LSD1, encoding a histone demethylase, attenuates the development and growth of OSCC. Methylation of TIMP3 in sinonasal adenocarcinoma (intestinal type) is associated with a significant worse survival, an association not seen in sinonasal squamous cell carcinoma. Olfactory neuroblastoma can be distinguished into four unique subgroups by methylation profiling. Methylation of RASSF1 is seen in NUT carcinoma, and significantly higher RASSF1 methylation is found in SMARCB1/INI1-deficient tumours compared to the less aggressive SMARCB1/INI-proficient tumours. Genome-wide methylation profiling in combination with IDH2 mutation status suggests that tumours with undifferentiable SNUC morphology can be classified into for subgroups. Most salivary gland carcinoma subtypes have specific epigenetic signatures. Four of the most common subtypes, adenoid cystic carcinoma (ADCC), mucoepidermoid carcinoma (MEC), acinic cell carcinoma (ACC), and carcinoma ex pleomorphic adenoma (CXPA) have all methylation of RASSF1A, two (MEC and ADCC) also of TIMP3 and two (MEC and CXPA) of p16INK4a. A methylation landscape of 20 salivary gland tumours (SGTs) is nowadays available.

Background: Adenoid cystic carcinoma (ACC) demonstrates marked clinical heterogeneity that is inadequately explained by conventional histopathologic and staging systems alone. Recent studies have identified two molecular subtypes based on transcriptomic profiling and MYC/TP63 expression (ACC I: MYC-high/TP63-low; ACC II: MYC-low/TP63-high) with potential prognostic significance. However, the magnitude and consistency of their survival impact remain uncertain. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Embase, and PubMed Central were searched through January 2026 for studies reporting overall survival in ACC stratified by MYC/TP63 molecular subtype. Hazard ratios (HRs) were pooled using random-effects models. Heterogeneity, subgroup analyses by classification method, sensitivity analyses, cumulative meta-analysis, influence diagnostics, and publication bias assessment were performed. Results: Five independent cohorts from two publications comprising 247 patients (90 ACC I, 157 ACC II) were included. ACC I was associated with significantly worse overall survival compared with ACC II, with a pooled HR of 3.88 (95% CI: 2.55-5.90; p < 0.001). No statistical heterogeneity was observed (I2 = 0%). Prognostic separation was consistent across RNA sequencing and immunohistochemistry-based classification methods. Conclusions: Transcriptomic and MYC/TP63-based molecular subtyping provides strong and reproducible prognostic stratification in ACC. ACC I tumors confer an approximately four-fold higher mortality risk compared with ACC II tumors. Incorporation of molecular subtype into routine diagnostic and clinical decision-making may improve risk stratification, surveillance strategies, and future trial design in ACC.

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.

Laryngeal chondrosarcoma (CS) is a rare indolent malignant tumor. High-grade (G3), dedifferentiated (DD), and myxoid (MY) CSs are considered more aggressive subtypes due to their metastatic potential and relatively poor outcomes. The aim of this systematic review is to evaluate treatment modalities and survival outcomes in patients affected by these rarer CS subtypes. Papers published from January 1, 2000, to August 25, 2024, describing cases of laryngeal G3, DD, and MY CS were included. A total of 38 patients (15 G3, 13 DD, and 10 MY) were selected. Cricoid cartilage was the most common site of origin. Total laryngectomy (TL) was often performed. Primary conservative approaches in 42.8

Objective: To evaluate the impact of postoperative radiotherapy (PORT) on oncological outcomes in node-negative early-stage oral squamous cell carcinoma (OSCC) with perineural invasion (PNI). Methods: A systematic review and meta-analysis was conducted using the PubMed, EMBASE, and Scopus databases for the period from 2000 to 2024. Studies comparing PORT versus observation in pN0 early-stage OSCC with PNI were included. Oncological outcomes assessed included overall survival (OS), disease-free survival (DFS), and local control (LC). A random-effects model was used to calculate log odds ratios, and heterogeneity was assessed using tau2, chi2, and I2 statistics. Results: Seven retrospective studies comprising 522 patients (281 PORT, 241 no-PORT) were included. The 3-year overall survival (OS) was 86.3% in the PORT group compared to 71.1% in the no-PORT group (logOR = −1.03, p = 0.0012), while the 5-year OS was 88.1% versus 77.3% (logOR = −0.97, p = 0.0061). Disease-free survival (DFS) also favored PORT, with 3-year DFS at 86.3% versus 58.1% (logOR = −1.19, p < 0.001) and 5-year DFS at 86.3% versus 55% (logOR = −0.78, p = 0.003). Local control (LC) was higher in the PORT group, with 3-year LC rates of 89% compared to 72.2% in the no-PORT group (logOR = −1.13, p = 0.025). Conclusions: PORT significantly improves OS, DFS, and LC in node-negative early-stage OSCC with PNI as the sole adverse feature.

BACKGROUND:Adenoid cystic carcinoma (ACC) is an aggressive therapy-resistant head and neck cancer with a high frequency of local recurrences and distant metastases. Activation of the MYB gene, encoding an oncogenic master transcription factor, is the key genomic hallmark of ACC and a potential therapeutic target. Here, we have investigated the clinical significance of alternative MYB promoter (MYB TSS2) activation in primary ACCs. METHODS:MYB TSS2 activity was studied in 28 ACCs using MYB exon-specific qPCR assays. Overall survival (OS) and risk analyses were done to estimate the outcomes of MYB TSS2 high and low cases, respectively. The genomic and transcriptomic profiles of the ACCs were also analyzed in relation to MYB TSS2 activity. RESULTS:OS was significantly shorter among patients in the MYB TSS2 high group compared to the MYB TSS2 low group (p = 0.02). Multivariate analysis indicated that MYB TSS2 activity was a significant prognostic biomarker for OS (p = 0.03) that was independent of tumor grade and NOTCH1 mutation status. There was markedly higher MYB TSS2 activity in ACCs with 6q deletions compared to those without deletions (p = 0.04). Moreover, MYB TSS2 high tumors had an increased expression of cell cycle genes and known MYB target genes. CONCLUSION:The study demonstrates that alternative MYB promoter activity is a new potential prognostic biomarker for ACC and further strengthens the relevance of MYB-targeted therapy. Our findings indicate that MYB TSS2 high primary tumors are more aggressive and have a worse prognosis than MYB TSS2 low tumors.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) represent a distinct subgroup of head and neck squamous cell carcinoma (HNSCC) characterized by better prognosis and increased radiosensitivity compared to HPV-negative OPSCC. However, current diagnostic and monitoring methods, including tissue biopsies and imaging, are insufficient for precise risk stratification and early detection of recurrence, leading to challenges in treatment de-escalation and surveillance strategies. Circulating tumor HPV DNA (ctHPV-DNA) has emerged as a promising minimally invasive biomarker that offers tumor-specific detection and monitoring capabilities, potentially transforming the management of HPV-related OPSCC through early disease detection, treatment response assessment, recurrence surveillance stratification, and disease monitoring. Despite encouraging results from early clinical studies, current use is limited to trial settings. Large-scale prospective studies are needed to validate its clinical utility and determine whether early ctHPV-DNA testing can improve patient outcome while reducing treatment related morbidity. This review outlines the biological rationale, technological approaches, and current clinical evidence for ctHPV-DNA in HPV-related OPSCC, emphasizing its potential role in treatment monitoring and surveillance.

Pleomorphic adenoma (PA) is the most common salivary gland tumor. PAs are characterized by chromosomal rearrangements of 8q12 and 12q14-15, leading to gene fusions involving the PLAG1 and HMGA2 oncogenes. Here, we performed the first comprehensive study of the transcriptomic and gene fusion landscape of 38 cytogenetically characterized PAs. RNA-seq identified PLAG1 or HMGA2 fusions in 33/38 cases (87%), of which 15 were novel fusions. Fusions were found also in tumors with normal karyotype, demonstrating that they are generated by cryptic rearrangements. PLAG1 was mainly activated by promoter swapping and HMGA2 by truncation of its 3'-part. RNA-seq revealed upregulation of genes involved in extracellular matrix production, WNT-signaling, and epithelial-mesenchymal transition in PA compared to normal salivary tissue. Principal component analysis identified two PA subclusters characterized by PLAG1- and HMGA2-activation, respectively, that differed in expression of genes involved in the immune system, cell adhesion, and microenvironment remodeling. Moreover, comparative analyses of PA and salivary carcinomas revealed that PA resembles myoepithelial carcinoma. Our study reveals new oncogenic gene fusions and expands our knowledge about the molecular underpinnings of PA.

Benign and malignant head and neck tumors are common worldwide and cause mortality and morbidity with variations in population prevalence [...]

Despite decades of progress, laryngeal squamous cell carcinoma (SCC) is still associated with significant morbidity and mortality worldwide. Additional biomarkers are needed to apply precision medicine and predict the clinical course. We reviewed and summarised routinely reported histopathologic features (e.g. subtypes of laryngeal SCC) along with promising potential biomarkers not yet routinely assessed using international guidelines. These include extra- vs intratumoural vascular and perineural invasion, tumour budding, depth of invasion, and tumour-infiltrating lymphocytes. We also address the problem of specimen quality and type (open approach vs endoscopic surgery) and the related limitations. High-risk human papillomavirus infection is another controversial issue to be discussed, being rare in laryngeal SCC, with an indeterminate prognostic significance and less reliable p16 overexpression as a surrogate marker of HPV infection. Further studies are warranted to address the applicability and to see which of the described parameters may help to better stratify patients with laryngeal SCC and should therefore be included in the pathology report.

Cervical lymph node metastasis significantly influence prognosis in oral squamous cell carcinoma (OSCC), guiding staging, treatment decisions, and overall survival. Sentinel lymph node biopsy (SLNB) offers a minimally invasive approach for early detection of subclinical nodal metastasis, including micrometastases (0.2–2 mm) and isolated tumor cells (ITCs, < 0.2 mm). Despite its success in melanoma and breast cancer, the clinical relevance of micrometastases and ITCs in OSCC remains incompletely defined. This narrative review explores the biological significance, diagnostic challenges, and emerging strategies for detecting micrometastasis and ITCs in OSCC, aiming to inform their potential role in refining staging systems and treatment algorithms. We performed a comprehensive literature review of SLNB in OSCC, examining data on histopathological detection techniques, molecular markers, artificial intelligence (AI), and radiomics-based tools that enhance diagnostic sensitivity and specificity for occult metastases. While current guidelines in some countries endorse SLNB for early-stage OSCC, integration of micrometastasis and ITC data into staging remains inconsistent. Studies suggest that ITCs represent early metastatic events with variable prognostic significance. Advanced techniques such as step-serial sectioning, immunohistochemistry, and molecular diagnostics—including ctDNA, gene-expression profiling, and AI-assisted pathology—have shown promise in improving detection accuracy. However, robust prospective data are lacking, and a consensus on the management of minimal nodal disease is yet to be reached. Accurate identification and interpretation of micrometastasis and ITCs in OSCC represent an evolving frontier in head and neck oncology. Future staging systems should incorporate these elements supported by standardized protocols and high-level evidence. The integration of AI, molecular diagnostics, and radiomics holds the potential to enhance risk stratification and personalize surgical decision-making, reducing overtreatment while ensuring oncologic safety.

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.

Adenoid cystic carcinoma (ACC) is a head and neck cancer that frequently originates in salivary glands, but can also strike other exocrine glands such as the breast. A key molecular alteration found in the majority of ACC cases is MYB gene rearrangements, leading to activation of the oncogenic transcription factor MYB. In this study, we used immortalised breast epithelial cells and an inducible MYB transgene as a model of ACC. Molecular profiling confirmed that MYB-driven gene expression causes a transition into an ACC-like state. Using this new cell model, we identified BUB1 as a targetable kinase directly controlled by MYB, whose pharmacological inhibition caused MYB-dependent synthetic lethality, growth arrest and apoptosis of patient-derived cells and organoids.

Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.

ObjectiveAdenoid cystic carcinoma (ACC) is a head and neck cancer with a poor long-term prognosis that shows frequent local recurrences and distant metastases. The tumors are characterized by MYB oncogene activation and are notoriously unresponsive to systemic therapies. The biological underpinnings behind therapy resistance of disseminated ACC are largely unknown. Here, we have studied the molecular and clinical significance of MYB alternative promoter (TSS2) usage in ACC metastases.Materials and methodsMYB TSS2 activity was investigated in primary tumors and metastases from 26 ACC patients using RNA-sequencing and quantitative real-time PCR analysis. Differences in global gene expression between MYB TSS2 high and low cases were studied, and pathway analyses were performed.ResultsMYB TSS2 activity was significantly higher in ACC metastases than in primary tumors (median activity 15.1 vs 3.0, P = 0.0003). MYB TSS2 high ACC metastases showed a specific gene expression signature, including increased expression of multi-drug resistance genes and canonical MYB target genes, and suppression of the p53 and NOTCH pathways.ConclusionsCollectively, our findings indicate that elevated MYB TSS2 activity is associated with metastases, potential drug resistance, and augmented MYB-driven gene expression in ACC. Our study advocates the need for new therapies that specifically target MYB and drug resistance mechanisms in disseminated ACC.

Background: This study assessed the diagnostic yield of high-throughput sequencing methods in a cohort of craniosynostosis (CS) patients not presenting causal variants identified through previous targeted analysis.Methods: Whole-genome or whole-exome sequencing (WGS/WES) was performed in a cohort of 59 patients (from 57 families) assessed by retrospective phenotyping as having syndromic or nonsyndromic CS.Results: A syndromic form was identified in 51% of the unrelated cases. A genetic cause was identified in 38% of syndromic cases, with novel variants detected in FGFR2 (a rare Alu insertion), TWIST1, TCF12, KIAA0586, HDAC9, FOXP1, and NSD2. Additionally, we report two patients with rare recurrent variants in KAT6A and YY1 as well as two patients with structural genomic aberrations: one with a 22q13 duplication and one with a complex rearrangement involving chromosome 2 (2p25 duplication including SOX11 and deletion of 2q22). Moreover, we identified potentially relevant variants in 87% of the remaining families with no previously detected causal variants, including novel variants in ADAMTSL4, ASH1L, ATRX, C2CD3, CHD5, ERF, H4C5, IFT122, IFT140, KDM6B, KMT2D, LTBP1, MAP3K7, NOTCH2, NSD1, SOS1, SPRY1, POLR2A, PRRX1, RECQL4, TAB2, TAOK1, TET3, TGFBR1, TCF20, and ZBTB20.Conclusion: These results confirm WGS/WES as a powerful diagnostic tool capable of either targeted in silico or broad genomic analysis depending on phenotypic presentation (e.g., classical or unusual forms of syndromic CS).