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The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchical clustering separated ameloblastomas and KCOTs into 2 distinct groups. The gene set enrichment analysis based on 303 dental genes showed a similar separation of ameloblastomas and KCOTs. Early dental epithelial markers PITX2, MSX2, DLX2, RUNX1, and ISL1 were differentially overexpressed in ameloblastoma, indicating its dental identity. Also, PTHLH, a hormone involved in tooth eruption and invasive growth, was one of the most differentially upregulated genes in ameloblastoma. The most differentially overexpressed genes in KCOT were squamous epithelial differentiation markers SPRR1A, KRTDAP, and KRT4, as well as DSG1, a component of desmosomal cell-cell junctions. Additonally, the epithelial stem cell marker SOX2 was significantly upregulated in KCOT when compared with ameloblastoma. Taken together, the gene expression profile of ameloblastoma reflects differentiation from dental lamina toward the cap/bell stage of tooth development, as indicated by dental epithelium-specific transcription factors. In contrast, gene expression of KCOT indicates differentiation toward keratinocytes. [ABSTRACT FROM PUBLISHER]

Di Palma S, Skálová A, Vanìèek T, Simpson R H W, Stárek I&Leivo I(2005)Histopathology46,144–152Non-invasive (intracapsular) carcinoma ex pleomorphic adenoma: recognition of focal carcinoma by HER-2/ neuand MIB1 immunohistochemistry: Non-invasive carcinoma ex pleomorphic adenoma is defined as a carcinoma arising within the boundaries of a pleomorphic adenoma (PA), but which fails to display invasion beyond the capsule of host PA. Alternative names are intracapsular,in situ, or focal carcinoma. The true nature of non-invasive carcinoma ex-PA is still controversial; for example, it is not clear whether it represents early but genuine carcinomatous changes with the genetic make-up of malignant cells, or simply cytological, possibly metaplastic or‘bizarre’ changes in PA. Strong overexpression and amplification of HER-2/ neuprotein has recently been demonstrated in invasive carcinoma ex-PA. In addition, data from breast cancer studies suggest that amplification of HER-2/neuand overexpression of its gene product is mainly involved in the initiation of breast oncogenesis. We sought to establish whether this method could help to demonstrate that what is described as non-invasive carcinoma ex-PA is really a genuine malignancy, albeit in an early phase.: Eleven cases of non-invasive carcinoma (in situ) ex-PA were studied for HER-2/ neustatus using immunohistochemistry and fluorescentin-situhybridization (FISH). Cells of focal non-invasive carcinoma ex-PA were strongly positive for HER-2/ neuprotein, while the cells of the maternal PA were always negative. Two cases of low-grade non-invasive myoepithelial carcinoma ex-PA were negative. In four cases out of a total of six tumours studied by FISH, we detected amplification ofHER-2/neugene signals in tumour cells of focal, non-invasive, carcinoma.: The current data suggest that non-invasive carcinoma ex PA is a genuine carcinoma within a PA. However, the presence of cyto-nuclear atypia is not sufficient to make a definite diagnosis of malignant change, which requires a combination of morphology and immunohistochemistry. [ABSTRACT FROM AUTHOR]

CONCLUSION: In this material consisting of various salivary gland carcinomas, stage I, male gender and age were the most powerful predictors of patient outcome. OBJECTIVES: To retrieve the records of all salivary gland cancer (SGC) patients diagnosed in Finland between 1991 and 1996 and to evaluate the incidence, histological type and location of SGC, the treatment given and the outcome. MATERIAL AND METHODS: The records for all SGCs (n =286) diagnosed in Finland between 1991 and 1996 and reported to the Finnish Cancer Registry were retrieved. The histological re-evaluation and retrospective study involved 237 SGC patients. RESULTS: The study population consisted of 125 males and 112 females. The mean age was 59 years (males 61 years, females 58 years). Follow-up was at least 5 years. The commonest tumor location was the parotid gland (n = 152; 64%), followed by the minor salivary glands (n =46; 19%), the submandibular gland (n =38; 16%) and the sublingual gland (n = 1; 0.4%). The most frequent histological types of SGC were adenoid cystic carcinoma (n =65; 27%), mucoepidermoid carcinoma (n =45; 19%) and acinic cell carcinoma (n =41; 17%). Surgery, either alone or in combination with other treatment modalities, was used in 209 cases (88%). Radiotherapy was given to 136 patients (57%), 13 of whom (5%) did not undergo surgery. The 5-year overall survival rate was 56.5%, and for stages I-IV it was 78%, 25%, 21% and 23%, respectively (p <0.001; log-rank test). Of the commonest tumor types, the best 5-year relative survival rate was for patients with acinic cell carcinoma (96%), followed by those with mucoepidermoid (79%) and adenoid cystic carcinoma (74%). [ABSTRACT FROM AUTHOR]

Twenty oncocytic myoepitheliomas (MEs) and pleomorphic adenomas (PAs) were composed of interlacing fascicles of swollen spindle-shaped or/and epithelioid oncocytic myoepithelial cells showing intense finely granular immunoreactivity with anti-mitochondrial antibody. Focal vacuolation of the cytoplasm of oncocytic myoepithelial cells and their gradual transition into sebaceous metaplasia were observed in 3 cases. Another unusual feature found in 5 cases was the presence of slit-like adenomatoid spaces lined with double-layered oncocytic myoepithelium closely resembling Warthin's tumour. The nuclei of oncocytic cells were characterized by enlargement, hyperchromasia and polymorphism, which should not be confused with malignancy. Oncocytic change in myoepithelial cells in MEs and PAs can cause pitfalls in the differential diagnosis of salivary gland tumours. We describe some unusual histological features associated with onococytic metaplasia in benign myoepithelial cell-derived salivary gland tumours, hoping to help to avoid the overdiagnosis of malignancy. [ABSTRACT FROM AUTHOR]

Presents abstracts from the 2001 Annual Meeting of the Scandinavian Society for Head and Neck Oncology in Stockholm, Sweden. Human Papilloma Virus, protein p53, TP53 mutations and outcome in stage I squamous cell carcinomas of the oral tongue; ACE-inhibition with Ramipril improves after thoracic irradiation in mice; Treatment in a team of patients with carcinoma of the oral cavity.

Canalicular tumors of the salivary glands have recently emerged as an entity characterized by distinct morphology and recurrent HMGA2 gene rearrangement. In this study, we analyzed 40 cases intending to elucidate their features further. The monophasic or biphasic tumors exhibited a growth pattern of interconnected anastomosing trabeculae and canaliculi, accompanied by a classical pleomorphic adenoma in one-third of the cases. Invasive growth into surrounding adipose tissue was revealed in one case which was, therefore, diagnosed as epithelial-myoepithelial carcinoma. Although the tumor cells uniformly expressed HMGA2 protein in all cases, cytokeratin 7, S100 protein, and SOX10 displayed either diffuse positivity or highlighted the luminal and abluminal cell populations, respectively. Areas with morphological oncocytoid change and AR-immunopositivity of luminal cells were seen in 13/14 (93%) of tested biphasic cases. HMGA2 rearrangement was detected by RNA-sequencing in 30 cases. The most common alteration was an HMGA1::WIF1 fusion, but several novel or rare fusion partners were identified, including ARID2, FHIT, MSRB3 and its antisense variant MSRB3-AS1, IFNG-AS1, and the long intergenic region LINC02389. In addition, FISH revealed HGMA2 break-apart in the remaining 10 cases where targeted sequencing failed to detect any alteration or where RNA sequencing could not be performed. Notably, the loss of the 3'-untranslated region of HMGA2 emerges as the common denominator for the described rearrangements, possibly disrupting its negative regulation by small regulatory RNAs. Awareness of this lesion ensures appropriate diagnosis and clinical management, especially with regard to the possibility of malignant transformation described in this and previous studies., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB , or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3 , and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases) , NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1 , PDGFRA , each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC., Competing Interests: Conflicts of Interest and Source of Funding: This study was supported by study grant SVV 260652 from the Ministry of Education of the Czech Republic (N.K.), the Cooperatio Program—research area SURG from the Charles University, Czech Republic (N.K., M.B., A.S.), the project National Institute for Cancer Research—NICR (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next Generation EU (A.S. and M.B.), and the Finnish Cancer Society, Finska Läkaresällskapet, the Turku University Hospital Fund, and the Maritza and Reino Salonen Foundation, Finland (I.L.). For the remaining authors none were declared., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: 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., Methods: Papers published from January 1, 2000, to August 25, 2024, describing cases of laryngeal G3, DD, and MY CS were included., Results: 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% of patients were followed by loco-regional recurrence., Conclusions: Aggressive subtypes of CS require a radical approach because of the higher rate of loco-regional and distant recurrences compared to low-grade CS. TL with radical intent is the most common treatment, and adjuvant therapy should be considered after careful multidisciplinary discussion., Competing Interests: Declarations. Conflict of Interest: Alfio Ferlito is an Editorial Board member of Oncology and Therapy. Alfio Ferlito was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Cesare Piazza, Claudia Montenegro, Michele Tomasoni, Ilmo Leivo, Göran Stenman, Abbas Agaimy, Roderick H. W. Simpson, and Nina Zidar have nothing to disclose. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

The pathology of reactive, dysplastic, and neoplastic sinonasal seromucinous glands is complex, and their contribution to tumorigenesis of sinonasal carcinomas remains controversial. In our practice, we have observed the presence of respiratory epithelial adenomatoid hamartomas (REAH) and seromucinous hamartomas (SH) associated with adenoid cystic carcinomas (AdCC) in a subset of cases. In many of these cases, genuine atypical features and dysplastic characteristics of the glands were noted at the interface of SH and AdCC. To investigate this phenomenon further, 88 sinonasal AdCC cases were selected from the authors' files and analyzed histologically, immunohistochemically, and genetically searching for MYB/MYBL1 and NFIB gene fusions. HPV testing was also performed. Univariate statistical analysis was conducted on our cohort. Thirty-one cases (35%) showed features of atypical sinonasal glands arising in SH (ASGSH) at the SH-AdCC interface, characterized by bilayered epithelium, architectural disarray, mild nuclear polymorphism, and atypia, sometimes with colloid-like material in the lumen. The MYB immunomarker was negative in 14 ASGSHs (with a positive internal control in AdCC cells), while only two cases showed faint and moderate to weak expression of the antibody in ASGSH glands. In 12 cases, the immunostaining of ASGSH could not be properly assessed, while AdCC cells were negative. The immunostaining was not performed in five cases. Our findings suggest that a subset of sinonasal AdCC may originate in a multistep dysplastic process within SH, consistent with an SH-ASGSH-AdCC progression sequence., Competing Interests: Declarations. Ethics approval: Sample was used in accordance with ethical guidelines. Informed consent was not required for the study. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Current guidelines recommend p16 immunohistochemistry (IHC) for testing human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC). The need for additional HPV-DNA testing is debated., Aims/objectives: We evaluated the prognostic value of HPV-DNA in situ hybridization (ISH) as an adjunct to p16., Material and Methods: A population-based cohort of 1,033 head and neck squamous cell carcinoma patients was used, to identify 124 OPSCC patients treated with a curative intent., Results: Of the p16-positive patients, 17.9% did not show evidence for presence of HPV-DNA in ISH. Both p16 and HPV-DNA ISH were significant prognostic factors for overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) when used independently. When combining information from p16 IHC and HPV-DNA ISH, survival of the p16+/ISH- discordant patients was intermediate compared to the p16+/ISH+ and p16-/ISH- groups. In the discordant group, smoking was a strong prognostic determinator, with non-smokers having an outstanding prognosis., Conclusions and Significance: Both p16 IHC and HPV-DNA ISH perform well as separate prognostic biomarkers for OS, DSS, and DFS on a population level. However, a discordant group does exist. Limiting HPV-DNA testing for p16-positive patients who smoke by the time of diagnosis may be a cost-efficient and justified solution.

Background: Tertiary lymphoid structures (TLSs) associate with prognosis of many malignancies. However, the clinical significance of TLSs is not well-elucidated in nasopharyngeal carcinoma (NPC) patients., Material and Methods: In this whole population-based multicenter study, a total of 115 patients treated for NPC were included. The patients were treated at the five Finnish university hospitals. TLSs were assessed in routine hematoxylin and eosin (HE)-stained sections., Results: Presence of TLSs associates significantly with improved survival in NPC. Absence of TLSs had a significant association with a poor disease-specific survival of NPC with a hazard ratio (HR) of 1.96 (95 % CI 1.09-3.53, P = 0.025) in the multivariable analysis. Similarly, absence of TLSs associated with worse overall survival with a HR of 1.68 (95 % CI 1.02-2.75, P = 0.040)., Conclusion: TLSs seem to be associated with prognosis of NPC patients. Having TLSs in NPC tumors correlates with good survival. The assessment of TLSs could aid in understanding the clinical behavior and in planning the treatment of NPC., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Evaluation of the prognostic impact of tumor microenvironment (TME) has received attention in recent years. We introduce a TME-based risk stratification for oropharyngeal squamous cell carcinoma (OPSCC)., Material and Methods: A total of 182 patients treated for OPSCC at the Helsinki University Hospital were included. TME-based risk stratification was designed combining tumor-stroma ratio and stromal tumor-infiltrating lymphocytes assessed in hematoxylin and eosin-stained sections., Results: In multivariable analysis, TME-based risk stratification associated with poor disease-free survival with a hazard ratio (HR) of 2.68 (95% CI 1.11-6.48, p = 0.029). In addition, the proposed risk stratification was associated with poor disease-specific survival (HR 2.687, 95% CI 1.28-5.66, p = 0.009) and poor overall survival (HR 2.21, 95% CI 1.23-3.99, p = 0.008)., Conclusion: Our TME-based risk stratification provides a powerful prognostic tool that can be used in daily treatment planning of OPSCC together with tumor-related prognostic markers., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Background: There is lack of knowledge on the utility of prognostic histopathologic characteristics in adenoid cystic carcinoma (ACC) of the head and neck. We evaluated the prognostic value of tumor and stroma-related histopathologic features in ACC., Materials and Methods: A total of 65 cases of ACC from minor and major salivary glands were included in this study. We evaluated tumor budding, tumor-infiltrating lymphocytes (TILs), and tumor-stroma ratio (TSR) in hematoxylin and eosin (HE) stained sections., Results: Stroma-rich ACCs recurred more frequently (p = 0.029) during follow-up and associated with distant metastasis (p = 0.038). In multivariable analysis, stroma-rich tumors associated with poorer disease-specific survival with a hazard ratio of 3.76 (95% CI 1.10-12.83, p = 0.034). ACCs commonly showed a low infiltration of TILs as 89% of the tumors was characterized by an immune desert pattern. Low infiltration of TILs associated significantly with increased tumor budding (p = 0.039)., Conclusion: Adverse features of TSR and tumor budding are widely expressed in ACC, and stroma-rich tumors are associated with poor prognosis. Low number of TILs in ACC tissue indicates a weak immune response by the host and illustrates the nature of ACC as a relentless malignancy., (© 2024 The Author(s). Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

Background: There is a lack of prognosticators of overall survival (OS) for Oral Squamous Cell Carcinoma (OSCC)., Objectives: We examined collaborative machine learning (cML) in estimating the OS of OSCC patients. The prognostic significance of the clinicopathological parameters was examined., Methodology: Altogether, 9439 OSCC patients were extracted from the Surveillance, Epidemiology, and End Results database (US). Five ML models - voting ensemble, stacked ensemble, extreme gradient boosting, light boosting, and logistic regression were used to predict OS. Three of these ML algorithms were combined to form a cluster of cML models. The performance of the cML was compared with the best performing individual ML algorithm following model training., Results: The performance accuracy of the voting ensemble, stacked ensemble, extreme gradient boosting, light boosting, and logistic regression models was 70.2%, 69.9%, 69.1%, 69.4%, and 69.5% respectively, following model training. When the voting ensemble model was compared with cML using temporal validation, the cML showed a comparable performance accuracy. The most significant prognostic factors were age of the patient at diagnosis, T stage, tumor grade, marital status, gender, primary site, surgery, N stage, radiotherapy, ethnicity, chemotherapy, and M stage., Conclusions: cML appears to give reliability to the final prediction and thereby may mark a paradigm shift from model individualism to a more cooperative paradigm. This approach may aid in determining an enhanced individualized treatment for OSCC patients.

Background: Many histopathologic prognostic markers, identified by routine hematoxylin and eosin (HE) staining, have been proposed for predicting the survival of patients with oral squamous cell carcinoma (OSCC). Subsequently, several meta-analyses have been conducted on these prognostic markers. We sought to analyze the accumulated evidence from these meta-analyses., Methods: An electronic database search of PubMed, Scopus, Ovid Medline, Web of Science, and Cochrane Library was conducted to retrieve all meta-analysis articles published on histopathologic prognostic markers of OSCC. The risk of bias of the included studies was analyzed using the Risk of Bias in Systematic Reviews (ROBIS) tool. The synthesis of the results was conducted following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)., Results: There were 16 meta-analysis articles published on the histological prognostic markers of OSSC. The accumulated evidence from these meta-analyses highlighted the powerful prognostic value of depth of invasion, tumor thickness, perineural invasion, lymphovascular invasion, worst pattern of invasion, tumor budding, and tumor-stroma ratio. The highest odds ratio (OR) of a relationship between a histopathologic prognostic marker and outcome was for the depth of invasion (OR 10.16, 95% CI 5.05-20.46) and tumor thickness (OR 7.32, 95% CI 5.3-10.1) in predicting lymph node metastasis., Conclusion: The published meta-analyses present robust evidence on the significance of emerging histopathologic markers, namely, worst pattern of invasion, tumor budding, and tumor-stroma ratio. It is time to consider such markers in daily pathology reporting and risk stratification of OSCC., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is a cause of significant mortality and morbidity. The epidemiology of this cancer varies worldwide due to either genetic differences in populations or differences in carcinogen exposure. The application of massive parallel sequencing-based techniques in HNSCC should provide a helpful understanding of the genetic alterations that eventually lead to HNSCC development and progression, and ideally, could be used for personalized therapy. In this review, the reader will find an overview of the mutational profile of conventional HNSCC according to published results on massive parallel sequencing data that confirm the pivotal role of TP53 and the frequent involvement of CDKN2A and PIK3CA. The reader will also find a more detailed description of the genes, such as NOTCH1 and FBXW7, that were not identified in HNSCCs before the development of these techniques, the differences that can be site-specific, such as the different mutational signatures that indicate specific carcinogens for various subsites of the head and neck, and finally, the actionability of these findings that should allow more personalized therapy for patients., Competing Interests: Declarations. Compliance with ethical standards.: N/A Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Sclerosing mucoepidermoid carcinoma (SMEC) of the salivary glands is a rare variant of low-grade mucoepidermoid carcinoma with scanty cellular atypia characterized by marked fibrosis/sclerosis and a rich inflammatory infiltrate. Herein, we report 25 unpublished cases of SMEC, two of them with prominent eosinophilia (2/25; 8%) and three with abundant IgG4-positive plasma cells (3/25; 12%). In our series of salivary SMEC, molecular analysis using fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) provided evidence of MAML2 gene rearrangement in 18 cases of the 21 analyzable cases tested (86%), while this gene locus was intact in 3 cases (14%). This study focuses on the diagnostic criteria of salivary SMEC given its challenge of abundant collagenous stroma, minimal residual neoplastic areas, and inconspicuous mucous cells. Follow-up data of our cases indicate that salivary SMECs have favorable outcomes. Molecular analysis for MAML2 gene rearrangement suggests that SMECs of salivary glands represent a rare variant of conventional low-grade MECs of salivary glands. In contrast, SMECs of the thyroid gland are genetically distinct from salivary-type thyroid MECs., Competing Interests: Declarations Ethics approval The study was approved by the institutional review board of the Faculty of Medicine in Pilsen, Charles University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Informed consent No patient consent was required for this study. Conflict of interest The authors have no relevant financial or non-financial interests to disclose. AA is the Editor-in-Chief of Virchows Archiv. AS serves on the Editorial Board of Virchows Archiv., (© 2024. The Author(s).)

Background: xCT, also known as SLC7A11 (solute carrier Family 7 Member 11), is a cystine/glutamate antiporter protein that mediates regulated cell death and antioxidant defense. The aim of this study was to investigate the effect of xCT on the outcome of patients diagnosed with new head and neck squamous cell carcinoma (HNSCC)., Methods: This retrospective cohort study utilized a population-based dataset, comprising all patients (n = 1033) diagnosed with new HNSCC during 2005-2015 in a population of 697,000 people. All patients (n = 585) with a tumor tissue sample available for immunohistochemical (IHC) staining were included. The follow-up rates were 97% and 81% at 3 and 5 years, respectively. Also, the specificity of the anti-xCT antibody was validated., Results: The expression level and prognostic significance of xCT were strongly dependent on tumor location. In oropharyngeal squamous cell carcinoma (OPSCC) patients, xCT expression was a significant prognostic factor for 5-year overall survival (OAS) (HR: 2.71; 95% CI 1.67-4.39; p < 0.001), disease-specific survival (DSS) (HR: 2.58; 95% CI 1.47-4.54; p = 0.001), and disease-free survival (DFS) (HR: 2.69; 95% CI 1.55-4.64; p < 0.001). Five-year survival rates for OPSCC patients with high and low levels of xCT were OAS 34% versus 62%; DSS 51% versus 73%; DFS 43% versus 73%, respectively. According to a multivariate model adjusted for age, T-class, nodal positivity, and tobacco consumption, xCT was an independent prognostic factor for 3-year survival, in which it outperformed p16 IHC. Similar associations were not observed in squamous cell carcinomas of oral cavity or larynx. Regarding treatment modalities, xCT was most predictive in HNSCC patients who received radiotherapy., Conclusions: High xCT expression was associated with poor prognosis in OPSCC. Our findings suggest that joint analysis of xCT and p16 may add significant value in OPSCC treatment stratification., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive epithelial and/or myoepithelial neoplasm that arises in association with a pleomorphic adenoma (PA). Its etiopathogenesis remains poorly understood, but it is believed that the development of this tumor is due to the accumulation of genetic, protein, metabolic, and epigenetic alterations in a PA. A retrospective review of the Salivary Gland Tumor Registry in Pilsen yielded 84 CXPA, namely 25/84 salivary duct carcinoma (SDC), 15/84 myoepithelial carcinoma (MC), 1/84 epithelial-myoepithelial carcinoma (EMC), and 1/84 adenoid cystic carcinoma (AdCC). All 84 CXPA cases were analyzed by next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH). Forty-three tumors originally diagnosed as CXPA (43/84, 51.2%) showed some molecular alteration. Fusion transcripts were identified in 12/16 (75%) CXPA, including LIFR::PLAG1, CTNNB1::PLAG1, FGFR1::PLAG1, and a novel fusion, HMGA2::LINC02389. Most of the fusions were confirmed by FISH using PLAG1 (6/11) and HMGA2 (1/1) gene break probes. Split signals indicating gene break were identified by FISH for PLAG1 (12/17), HMGA2 (3/4), EWSR1 (7/22), and MYB (2/7). Concerning pathogenic mutations, only CXPA with epithelial differentiation (SDC) presented these alterations, including HRAS mutation (2/4), TP53 (1/4), PTEN (1/4), and ATK1 (1/4). In addition, amplifications in ERBB2 (17/35), MDM2 (1/4), and EWSR1 (1/7) were detected. A novel finding was the discovery of an HMGA2::LINC02389 fusion in 1 patient with EMC ex-PA. The present results indicate that molecular profiling of CXPA with myoepithelial differentiation (MC) tends to reveal chromosomal fusion events, whereas CXPA with epithelial differentiation (SDC) tends to have a higher frequency of pathogenic mutations and gene amplifications., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs in all major and minor salivary gland and seromucous gland sites. AdCCs of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost consistent presence of fusion genes MYB::NFIB, or less commonly MYBL1::NFIB. We collected a cohort of 95 cases of AdCC, which were largely characterized by canonical fusions MYB::NFIB (49 cases) or MYBL1::NFIB (9 cases). In additional 11 cases of AdCC, rearrangements in MYB or NFIB genes were detected by FISH. In addition, NGS revealed novel noncanonical fusion transcripts EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, MYB::TULP4, and ACTN4::MYB, each of them in 1 case. The tumors that showed noncanonical fusions had features of metatypical AdCC with a diverse architecture, lobulated multinodular growth pattern, and hypercellular peripheral palisading of nuclei (2 cases), tubular hypereosinophilia (2 cases), and pale eosinophilic to vacuolated (bubbly) cytoplasm (3 cases). Our study documented 3 cases of AdCC of salivary glands harboring novel gene fusions TULP4::MYB, ACTN4::MYB, and ACTB::MYB, in 1 case each, which have not been described before. A rare EWSR1::MYB fusion was detected in 1 case. Moreover, 1 case of sinonasal metatypical AdCC showed EWSR1 rearrangement detected by FISH. Also, 1 case with an ESRRG::DNM3 fusion of unknown significance is described in this study. These discoveries illustrate how broad molecular profiling will expand understanding of changes in known entities., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352&#95;374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival., (© 2023. The Author(s).)

Background: Radiomics is a rapidly growing field used to leverage medical radiological images by extracting quantitative features. These are supposed to characterize a patient's phenotype, and when combined with artificial intelligence techniques, to improve the accuracy of diagnostic models and clinical outcome prediction., Objectives: This review aims at examining the application areas of artificial intelligence-based radiomics (AI-based radiomics) for the management of head and neck cancer (HNC). It further explores the workflow of AI-based radiomics for personalized and precision oncology in HNC. Finally, it examines the current challenges of AI-based radiomics in daily clinical oncology and offers possible solutions to these challenges., Methods: Comprehensive electronic databases (PubMed, Medline via Ovid, Scopus, Web of Science, CINAHL, and Cochrane Library) were searched following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The quality of included studies and their risk of biases were evaluated using the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD)and Prediction Model Risk of Bias Assessment Tool (PROBAST)., Results: Out of the 659 search hits retrieved, 45 fulfilled the inclusion criteria. Our review revealed that the application of AI-based radiomics model as an ancillary tool for improved decision-making in HNC management includes radiomics-based cancer diagnosis and radiomics-based cancer prognosis. The radiomics-based cancer diagnosis includes tumor staging, tumor grading, and classification of malignant and benign tumors. Similarly, radiomics-based cancer prognosis includes prediction for treatment response, recurrence, metastasis, and survival. In addition, the challenges in the implementation of these models for clinical evaluations include data imbalance, feature engineering (extraction and selection), model generalizability, multi-modal fusion, and model interpretability., Conclusion: Considering the highly subjective and interobserver variability that is peculiar to the interpretation of medical images by expert clinicians, AI-based radiomics seeks to offer potentially useful quantitative information, which is not visible to the human eye or unintentionally often remain ignored during clinical imaging practice. By enabling the extraction of this type of information, AI-based radiomics has the potential to revolutionize HNC oncology, providing a platform for more personalized, higher quality, and cost-effective care for HNC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s).)

Malignant tumors derived from the epithelium lining the nasal cavity region are termed sinonasal cancers, a highly heterogeneous group of rare tumors accounting for 3 - 5 % of all head and neck cancers. Progress with next-generation molecular profiling has improved our understanding of the complexity of sinonasal cancers and resulted in the identification of an increasing number of distinct tumor entities. Despite these significant developments, the treatment of sinonasal cancers has hardly evolved since the 1980s, and an advanced sinonasal cancer presents a poor prognosis as targeted therapies are usually not available. To gain insights into potential targeted therapeutic opportunities, we performed a multiomics profiling of patient-derived functional tumor models to identify molecular characteristics associated with pharmacological responses in the different subtypes of sinonasal cancer., Methods: Patient-derived ex vivo tumor models representing four distinct sinonasal cancer subtypes: sinonasal intestinal-type adenocarcinoma, sinonasal neuroendocrine carcinoma, sinonasal undifferentiated carcinoma and SMARCB1 deficient sinonasal carcinoma were included in the analyses. Results of functional drug screens of 160 anti-cancer therapies were integrated with gene panel sequencing and histological analyses of the tumor tissues and the ex vivo cell cultures to establish associations between drug sensitivity and molecular characteristics including driver mutations., Results: The different sinonasal cancer subtypes display considerable differential drug sensitivity. Underlying the drug sensitivity profiles, each subtype was associated with unique molecular features. The therapeutic vulnerabilities correlating with specific genomic background were extended and validated with in silico analyses of cancer cell lines representing different human cancers and with reported case studies of sinonasal cancers treated with targeted therapies., Conclusion: The results demonstrate the importance of understanding the differential biology and the molecular features associated with the different subtypes of sinonasal cancers. Patient-derived ex vivo tumor models can be a powerful tool for investigating these rare cancers and prioritizing targeted therapeutic strategies for future clinical development and personalized medicine., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Juha K. Rantala is the founder of Misvik Biology Oy, and Noora Lehtinen, Janne Suhonen, Kiesha Rice and Eetu Välimäki are employees of Misvik Biology Oy., (Copyright © 2024. Published by Elsevier Inc.)