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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.)

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard -/- mice which lack ASC. Treatment with anti-ASC PYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC 50  ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases., (© 2024. The Author(s).)

Aims: Low-grade non-intestinal-type sinonasal adenocarcinoma (LGSNAC) is a rare heterogeneous and poorly characterised group of tumours, distinct from intestinal- and salivary-type neoplasms. Therefore, further characterisation is needed for clearer biological understanding and classification., Methods and Results: Clinical, histological and molecular characterisation of four cases of biphasic, low-grade adenocarcinomas of the sinonasal tract was performed. All patients were male, aged between 48 and 78 years, who presented with polypoid masses in the nasal cavity. Microscopically, virtually all tumours were dominated by tubulo-glandular biphasic patterns, microcystic, focal (micro)papillary, oncocytic or basaloid features. Immunohistochemical staining confirmed biphasic differentiation with an outer layer of myoepithelial cells. Molecular profiling revealed HRAS (p.G13R, p.Q61R) mutations, and concomitant AKT1 (p.E17K, p.Q79R) mutations in two cases. Two cases showed potential in-situ/precursor lesions adjacent to the tumour. Follow-up periods ranged from 1 to 30 months, with one case relapsing locally after 12 and > 20 years., Conclusion: This study further corroborates a distinct biphasic low-grade neoplasm of the sinonasal tract with seromucinous differentiation. Although morphological and molecular features overlap with salivary gland epithelial-myoepithelial carcinoma, several arguments favour categorising these tumours within the spectrum of LGSNAC., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Adenoid cystic carcinoma (AdCC) is a salivary gland neoplasm that infrequently appears in the sinonasal region. The aim of this study was to evaluate the outcome and clinicopathological parameters of sinonasal AdCC. A retrospective analysis was conducted on all cases of AdCC affecting the nasal cavity or paranasal sinuses between 2000 and 2018 at the University Hospital Zurich. Tumor material was examined for morphological features and analyzed for molecular alterations. A total of 14 patients were included. Mean age at presentation was 57.7 years. Sequencing revealed MYB::NFIB gene fusion in 11/12 analyzable cases. Poor prognostic factors were solid variant (p < 0.001), histopathological high-grade transformation (p < 0.001), and tumor involvement of the sphenoid sinus (p = 0.02). The median recurrence-free survival (RFS) and OS were 5.2 years and 11.3 years. The RFS rates at 1-, 5-, and 10-year were 100%, 53.8%, and 23.1%. The OS rates at 1-, 5-, and 10- years were 100%, 91.7%, and 62.9%, respectively. In Conclusion, the solid variant (solid portion > 30%), high-grade transformation, and sphenoid sinus involvement are negative prognostic factors for sinonasal AdCC. A high prevalence of MYB::NFIB gene fusion may help to correctly classify diagnostically challenging (e.g. metatypical) cases., (© 2024. The Author(s).)

Prostate-Specific Antigen (PSA) based screening of prostate cancer (PCa) needs refinement. The aim of this study was the identification of urinary biomarkers to predict the Prostate Imaging-Reporting and Data System (PI-RADS) score and the presence of PCa prior to prostate biopsy. Urine samples from patients with elevated PSA were collected prior to prostate biopsy (cohort = 99). The re-analysis of mass spectrometry data from 45 samples was performed to identify urinary biomarkers to predict the PI-RADS score and the presence of PCa. The most promising candidates, i.e. SPARC-like protein 1 (SPARCL1), Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), Alpha-1-microglobulin/bikunin precursor (AMBP), keratin 13 (KRT13), cluster of differentiation 99 (CD99) and hornerin (HRNR), were quantified by ELISA and validated in an independent cohort of 54 samples. Various biomarker combinations showed the ability to predict the PI-RADS score (AUC = 0.79). In combination with the PI-RADS score, the biomarkers improve the detection of prostate carcinoma-free men (AUC = 0.89) and of those with clinically significant PCa (AUC = 0.93). We have uncovered the potential of urinary biomarkers for a test that allows a more stringent prioritization of mpMRI use and improves the decision criteria for prostate biopsy, minimizing patient burden by decreasing the number of unnecessary prostate biopsies., (© 2024. The Author(s).)

Purpose: TMPRSS2:ERG gene fusion negatively regulates PSMA expression in prostate adenocarcinoma (PCa) cell lines. Therefore, immunohistochemical (IHC) ERG expression, a surrogate for an underlying ERG rearrangement, and PSMA expression patterns in radical prostatectomy (RPE) specimens of primary PCa, including corresponding PSMA-PET scans were investigated., Methods: Two cohorts of RPE samples (total n=148): In cohort #1 (n=62 patients) with available RPE and preoperative [ 68 Ga]Ga-PSMA-11 PET, WHO/ISUP grade groups, IHC-ERG (positive vs. negative) and IHC-PSMA expression (% PSMA-negative tumour area, PSMA %neg ) were correlated with the corresponding SUV max . In the second cohort #2 (n=86 patients) including RPE only, same histopathological parameters were evaluated., Results: Cohort #1: PCa with IHC-ERG expression (35.5%) showed significantly lower IHC-PSMA expression and lower SUV max values on the corresponding PET scans. Eight of 9 PCa with negative PSMA-PET scans had IHC-ERG positivity, and confirmed TMPRSS2::ERG rearrangement. In IHC-PSMA positive PCa, IHC-ERG positivity was significantly associated with lower SUV max values. In cohort #2, findings of higher IHC-PSMA %neg and IHC-ERG expression was confirmed with only 0-10% PSMA %neg tumour areas in IHC-ERG-negative PCa., Conclusion: IHC-ERG expression is significantly associated with more heterogeneous and lower IHC-PSMA tissue expression in two independent RPE cohorts. There is a strong association of ERG positivity in RPE tissue with lower [ 68 Ga]Ga-PSMA-11 uptake on corresponding PET scans. Results may serve as a base for future biomarker development to enable tumour-tailored, individualized imaging approaches., (© 2024. The Author(s).)

Background: Diagnosis of salivary gland neoplasms is challenging, especially on cytological specimens acquired by fine-needle aspiration. The recently implemented standardized Milan system for reporting salivary gland cytopathology provides an estimated risk of malignancy (ROM); yet, for two of the categories, the diagnosis of the lesion remains unclear. However, a precise diagnosis is desirable for optimal patient management, including planning of surgery and imaging procedures., Methods: Cytological specimens (n = 106) were subjected to molecular analysis using the SalvGlandDx panel. The risk of malignancy was calculated for each detected alteration based on the diagnosis of the resection specimen. By taking into account the molecular alterations, their associated ROM, the clinical and cytological features, and the current literature, the Milan category was evaluated., Results: Of n = 63 technically valid cases, 76% revealed a molecular alteration. A total of 94% of these molecularly altered cases could be assigned to a different Milan category when additionally taking molecular results into account. In only 2% of the salivary gland neoplasms of uncertain malignant potential, in which a molecular alteration was detected, the classification remained salivary gland neoplasms of uncertain malignant potential., Conclusion: Molecular analysis of cytological specimens provides a benefit in classifying salivary gland neoplasms on fine-needle aspiration. It can improve the ROM estimation and thus help to assign cases of formerly unknown malignant potential to clearly benign or malignant categories., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Two benign adenomatous lesions are commonly recognized within the sinonasal tract, namely respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH). We present 10 hitherto unrecognized benign polypoid nasal and sinonasal tumoriform lesions having in average 3.6 cm in largest dimension, which are histogenetically related to SH and REAH. In addition to typical structures of REAH and SH, these lesions contained an additional characteristic and slightly atypical adenomatous component, which we termed atypical sinonasal glands arising in SH (ASGSH). ASGSH often produced deep red colored secretion with peripheral clearing similar to that seen in thyroid follicles. In contrast to SH, ASGSH was endowed by both secretory and myoepithelial layers and had mostly angulated shapes with snout-like protrusions into the lumens. Both layers were formed by an irregular, disorganized, and often incomplete cell lining, which had slightly atypical cytological features without mitoses. In 3 cases, ASGSHs revealed sebaceous differentiation, and in 3 cases the stroma produced a well-differentiated cartilage. Neoplastic nature of ASGSH was supported by finding of various mutations as revealed by next generation sequencing in five cases. In two cases each, we found identical mutations in BRAF gene (Val600Glu), and RET gene (Arg912Trp), respectively and in one case FAT1 gene alteration (Pro1665Leu)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: For minimally invasive surgery of parathyroid adenomas, exact localization diagnostics are essential. Main imaging modalities used for diagnostics are sonography, SPECT with/without CT (traditional imaging) and 18 F-choline-PET. The aim of our study was to identify predictors for inconclusive SPECT imaging and subsequently determine in which cases 18 F-choline-PET is needed., Methods: Retrospective analysis of 138 patients with histologically confirmed primary hyperparathyroidism (pHPT). After sonography, patients underwent SPECT or SPECT/CT imaging, with subsequent 18 F-choline-PET in cases of disconcordant results. Logistic regression analysis was used to identify clinical and laboratory factors predictive for negative SPECT results., Results: Sensitivity rates for sonography, SPECT, SPECT/CT, and choline-PET were 47 %, 49 %, 71.7 %, and 97 %, respectively. Logistic regression revealed lower PTH levels (p < 0.001), presence of structural thyroid disease (p = 0.018), and negative sonography (p < 0.001) as predictive of negative/equivocal SPECT outcome. An additional traditional imaging CT scan to a SPECT enhanced detection odds, as did greater adenoma weight. Urolithiasis, osteoporosis, and calcium values as measurement of activity and duration of disease showed no significant association with the detection rate. Furthermore, our study demonstrated that 18 F-choline-PET exhibited remarkable sensitivity in detecting adenomas among patients with negative/equivocal SPECT results., Conclusion: Our study reveals potential predictive factors for a negative/equivocal SPECT outcome in pHPT. Identifying these factors might allow minimizing futile SPECT examinations and perhaps encourage timely utilization of 18 F-choline-PET imaging. Our study reinforces the clinical significance of 18 F-choline-PET, especially in complex cases with disconcordant results by conventional parathyroid imaging methods., Competing Interests: Declaration of competing interest M.W.H. received grants and speaker honoraria from GE Healthcare, a fund by the Alfred and Annemarie von Sick legacy and a grant from the clinical research priority program (CRPP) Artificial Intelligence in Oncological Imaging Network of the University of Zurich. Otherwise this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate inter-reader agreement, and diagnostic performance of the Prostate Imaging after Focal Ablation (PI-FAB) score applied to multiparametric MRI (mpMRI) in patients who underwent focal high-intensity focused ultrasound (HIFU) therapy for localized prostate cancer., Methods: In this retrospective, IRB-approved, single-center study, 73 men, who underwent focal HIFU treatment and received follow-up mpMRIs with subsequent prostate biopsies, were included. The PI-FAB score was applied to follow-up MRIs at 6, 12, and 36 months post-HIFU by two radiologists with different experience levels. Inter-reader agreement was assessed using Gwet's AC1, and the diagnostic performance of the PI-FAB score was assessed in relation to histopathologic results of subsequent prostate biopsies for each reader., Results: PI-FAB scores showed substantial to almost perfect inter-reader agreement (AC1: 0.80-0.95) and demonstrated high specificity (Reader 1: 90-98 %, Reader 2: 87-98 %) and NPVs (Reader 1: 91-100 %, Reader 2: 88-97 %) in ruling out residual or recurrent in-field prostate cancer post-HIFU. Sensitivity (Reader 1: ≥43 %, Reader 2: ≥14 %) and PPVs (Reader 1: ≥33 %, Reader 2: ≥14 %) were mostly relatively lower, with notable disparities between the two readers, indicating the potential influence of radiologist experience., Conclusions: The PI-FAB score provides a consistent and reliable tool for post-HIFU monitoring of prostate cancer using mpMRI. It demonstrates substantial to almost perfect inter-reader agreement and is particularly effective in excluding in-field residual or recurrent prostate cancer post-HIFU treatment. Its application can potentially enhance post-treatment patient care, emphasizing its value as a non-invasive MRI-based monitoring approach after focal ablative therapy of the prostate., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Cytological specimens play a pivotal role in head and neck nodule/mass work up and diagnoses. The specimens´ importance has grown with the onset of personalized medicine and the routine use of molecular markers in the diagnostic work up. The Updates in Head and Neck Cytopathology Short Course ran during the 35th European Congress of Pathology held in Dublin, Ireland, in 2023 and brought together experts in cytopathology, pathology, and related fields to share their expertise and experience in the field of head and neck cytopathology and its future directions. Topics such as a one-stop clinic, the Milan System for Reporting Salivary Gland Cytopathology, next generation sequencing, and human papilloma virus detection in the head and neck area were covered during the short course. These topics are briefly summarized in the present review., (© 2024 The Authors. Cytopathology published by John Wiley & Sons Ltd.)

Recently, significant advances in the molecular characterization of salivary gland neoplasms have facilitated the classification and diagnosis of specific diagnostic entities. In the highly challenging diagnostic scenario of salivary malignancies, molecular testing is increasingly being adopted in routine practice to refine the cytological diagnosis of salivary lesions. Here, we reviewed the most recent evidence in the field of salivary glands molecular cytopathology., (© 2024 The Authors. Cytopathology published by John Wiley & Sons Ltd.)

Defining the exact histological features of salivary gland malignancies before treatment remains an unsolved problem that compromises the ability to tailor further therapeutic steps individually. Radiomics, a new methodology to extract quantitative information from medical images, could contribute to characterizing the individual cancer phenotype already before treatment in a fast and non-invasive way. Consequently, the standardization and implementation of radiomic analysis in the clinical routine work to predict histology of salivary gland cancer (SGC) could also provide improvements in clinical decision-making. In this study, we aimed to investigate the potential of radiomic features as imaging biomarker to distinguish between high grade and low-grade salivary gland malignancies. We have also investigated the effect of image and feature level harmonization on the performance of radiomic models. For this study, our dual center cohort consisted of 126 patients, with histologically proven SGC, who underwent curative-intent treatment in two tertiary oncology centers. We extracted and analyzed the radiomics features of 120 pre-therapeutic MRI images with gadolinium (T1 sequences), and correlated those with the definitive post-operative histology. In our study the best radiomic model achieved average AUC of 0.66 and balanced accuracy of 0.63. According to the results, there is significant difference between the performance of models based on MRI intensity normalized images + harmonized features and other models (p value < 0.05) which indicates that in case of dealing with heterogeneous dataset, applying the harmonization methods is beneficial. Among radiomic features minimum intensity from first order, and gray level-variance from texture category were frequently selected during multivariate analysis which indicate the potential of these features as being used as imaging biomarker. The present bicentric study presents for the first time the feasibility of implementing MR-based, handcrafted radiomics, based on T1 contrast-enhanced sequences and the ComBat harmonization method in an effort to predict the formal grading of salivary gland carcinoma with satisfactory performance., (© 2024. The Author(s).)

Objective: To assess the oncological and functional outcomes of focal high-intensity focused ultrasound (HIFU) in treating localised prostate cancer (PCa), a 3-year prospective study was undertaken using periodic post-ablation saturation biopsies., Patients and Methods: Men with two or fewer lesions of grade group (GG) ≤3 PCa were eligible for participation. Additional criteria included a prostate-specific antigen (PSA) level of ≤15 ng/mL, clinical T1c-T2, and a life expectancy of ≥10 years. The primary endpoint was failure-free survival (FFS), defined as absence of clinically significant PCa (csPCa) in- or out-of-field on protocol-mandated saturation biopsy, no whole-gland or systemic salvage treatment, PCa metastasis, or PCa-related death. Results are reported using two distinct definitions of csPCa: (i) the presence of any GG ≥2 and (ii) any GG ≥3 or core involvement of ≥6 mm. Secondary endpoints were functional patient-reported outcome measures addressing urinary, sexual, and bowel function., Results: A total of 91 patients were included: six (7%) with GG1 and 85 (93%) with GG ≥2. In all, 83 (91%) underwent at least one follow-up biopsy. Biopsy attendance at 6, 12, and 36 months was 84%, 67%, and 51%, respectively. The FFS at these time points for any GG ≥2 PCa was 79% (95% confidence interval [CI] 80-88%), 57% (95% CI 48-69%) and 44% (95% CI 34-56%), respectively. Using the second definition, FFS were 88% (95% CI 81-95%), 70% (95% CI 61-81%) and 65% (95% CI 55-77%), respectively. The 3-year cancer-specific survival was 100%, and freedom from metastasis was 99%. Magnetic resonance imaging (MRI) (negative predictive value of up to 89%, 95% CI 84-93%) and relative decrease of PSA values (P = 0.4) performed poorly in detecting residual disease. Urinary and bowel assessment returned to baseline questionnaire scores within 3 months. In all, 17 (21%) patients reported meaningful worsening in erectile function. A significant decrease of PCa related anxiety was observed., Conclusions: Focal HIFU treatment for localised PCa shows excellent functional outcomes with half of the patients remaining cancer-free after 3 years. Whole-gland treatment was avoided in 81%. Early follow-up biopsies are crucial to change or continue the treatment modality at the right time, while the use of MRI and PSA in detecting PCa recurrence is uncertain., (© 2023 BJU International.)

The application of molecular profiling has made substantial impact on the classification of urogenital tumors. Therefore, the 2022 World Health Organization incorporated the concept of molecularly defined renal tumor entities into its classification, including succinate dehydrogenase-deficient renal cell carcinoma (RCC), FH-deficient RCC, TFE3-rearranged RCC, TFEB-altered RCC, ALK-rearranged RCC, ELOC-mutated RCC, and renal medullary RCC, which are characterized by SMARCB1-deficiency. This review aims to provide an overview of the most important molecular alterations in renal cancer, with a specific focus on the diagnostic value of characteristic genomic aberrations, their chromosomal localization, and associations with renal tumor subtypes. It may not yet be the time to completely shift to a molecular RCC classification, but undoubtedly, the application of molecular profiling will enhance the accuracy of renal cancer diagnosis, and ultimately guide personalized treatment strategies for patients., (© 2023. The Author(s).)

Purpose: To identify predictors of prostate cancer (PCa) and clinically significant prostate cancer (csPCa) in men with prior false-negative multiparametric MRI (mpMRI), focusing on image quality scoring systems and clinical parameters., Methods: In this IRB-approved retrospective single-center study, patients with a negative mpMRI (PI-RADS score ≤2) and subsequent prostate biopsies were included. Histopathological results served as reference standard. Welch's t-Test was conducted to identify significant differences in image quality scores (PI-QUAL and PSHS) between patients with and without PCa/csPCA. In addition, clinical parameters (age, BMI, PSA density) and image quality scores (PI-QUAL and PSHS) were examined as potential predictors of PCa/csPCa detection after a false-negative mpMRI in uni- and multivariate analyses., Results: Among 96 patients with negative mpMRI results, 44.8 % had PCa and 16.7 % had csPCa upon biopsy with histopathological confirmation. PI-QUAL scores were significantly lower in patients with PCa (p = 0.03) and csPCa (p = 0.005). PSHS scores were lower in patients with csPCa, but the difference was not statistically significant (p = 0.1). Higher age (p = 0.035) and a lower PI-QUAL score (p < 0.004) were predictors of subsequent csPCa detection upon biopsy, however, a lower PI-QUAL score was the only independent predictor of missed csPCa in false-negative mpMRIs., Conclusions: Lower image quality scores were associated with missed PCa/csPCa in patients with false-negative mpMRIs, with PI-QUAL being an independent predictor of failed csPCa detection. This highlights the importance of image quality for prostate MRI and advocats the inclusion of its measurement into the standardized report., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Gleason grading is an important prognostic indicator for prostate adenocarcinoma and is crucial for patient treatment decisions. However, intermediate-risk patients diagnosed in the Gleason grade group (GG) 2 and GG3 can harbour either aggressive or non-aggressive disease, resulting in under- or overtreatment of a significant number of patients. Here, we performed proteomic, differential expression, machine learning, and survival analyses for 1,348 matched tumour and benign sample runs from 278 patients. Three proteins (F5, TMEM126B, and EARS2) were identified as candidate biomarkers in patients with biochemical recurrence. Multivariate Cox regression yielded 18 proteins, from which a risk score was constructed to dichotomize prostate cancer patients into low- and high-risk groups. This 18-protein signature is prognostic for the risk of biochemical recurrence and completely independent of the intermediate GG. Our results suggest that markers generated by computational proteomic profiling have the potential for clinical applications including integration into prostate cancer management., (© 2023 Zhong et al.)

Background: Lymphoepithelial carcinoma of the salivary glands (LECSG) is a rare disease in the Western hemisphere that is typically associated with an EBV infection. The molecular mechanisms of LECSG tumorigenesis are poorly understood., Results: Here we report a case of EBV-associated LECSG with an unusual immunophenotype. The tumor exhibited bi-morphic histological features with a mutually exclusive expression of HER2 and p16. The p16-positive domain of the tumor immunohistochemically co-expressed late membrane protein 1 (LMP-1), while the HER2 positive domain did not. Both tumor regions expressed SSTR2., Methods: In situ hybridization confirmed the EBV origin of the tumor while extensive immunohistochemical characterization and the recently established RNA-based next generation sequencing panel ("SalvGlandDx" panel) did not reveal evidence for another salivary gland neoplasm. No HPV co-infection was detected by in situ hybridization or PCR-based screenings and no ERBB2 gene amplification was detected by fluorescence in situ hybridization., Conclusion: These findings suggest tumor heterogeneity and lack of genomic aberrations in EBV-associated LECSGs. The heterogenous and unusual immunohistochemical features explain the diagnostic difficulties and simultaneously extend the immunophenotype spectrum of this tumor entity., (© 2023. The Author(s).)

This meta-analysis aims to investigate the outcome of sinonasal adenoid cystic carcinoma (snAdCC). We followed PRISMA guidelines and included studies reporting 5-year overall survival (OS) rates for snAdCC. Eligible studies were identified through a literature search and assessed using JBI critical appraisal checklist. A total of 17 studies were included comprising 2259 patients (mean age: 58.1 years, 52.7% female, 47.3% male). The meta-analysis demonstrated that the 5-year OS, 10-year OS, and 5-year disease-free survival (DFS) were 68%, 40%, and 47.2%, respectively. Descriptive statistics on study level showed high rates of locally advanced tumor stages at diagnosis: 23% cT3, 53% cT4, 3.4% N+, and 4.2% M+. 29.7% of the tumors were in the nasal cavity, 67.6% in the paranasal sinuses. The maxillary, ethmoid, sphenoid, and frontal sinus were affected in 50.9%, 7.2%, 4%, and 0.5%, of cases. A combination of surgery and radiotherapy was used in 45.4% of the patients and 19.3% of patients received surgery only. In conclusion, these findings emphasize the significance of thorough surveillance for individuals with snAdCC to identify any potential recurrence or progression of the disease.

The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without (p = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS., (© 2023. The Author(s).)

Background: In recent years, the list of tumor entities in the sinonasal tract has significantly expanded, requiring advanced diagnostic testing. We report the case of a 32-year-old patient with an unusual NUT carcinoma originating in the maxillary sinus, which showed extensive well-differentiated, papillary squamous morphology, similar to the spectrum of the recently described DEK::AFF2 fusion-associated carcinoma., Methods: We performed immunohistochemical and molecular studies including EBV- and HPV-testing, as well as DNA/RNA next generation sequencing., Results: The tumor showed predominantly exophytic papillary growth with mature squamous differentiation. An additional component harbored atypical, less differentiated basaloid tumor cells with infiltration of the adjacent stroma. Conspicuous inflammation was evident. There was no evidence of HPV DNA or EBV RNA. Next-generation sequencing revealed a NUT::NSD3 gene fusion corresponding to ("speckled-type") immunopositivity of NUT in the tumor cells., Conclusions: We describe a NUT::NSD3 gene fusion-associated NUT carcinoma of the sinonasal tract with a deceptively well-differentiated papillary growth pattern, thus expanding the morphological spectrum of this typically poorly differentiated neoplasm., (© 2023. The Author(s).)

Background: In head and neck squamous cell carcinoma (HNSCC), salvage neck dissection (ND) is required after primary chemoradiation in case of residual nodal disease. Upon histopathological examination, viability of tumor cells is assessed but little is known about other prognostic histopathological features. In particular, the presence of swirled keratin debris and its prognostic value is controversial. The aim of this study is to examine histopathological parameters in ND specimens and correlate them with patient outcome to determine the relevant parameters for histopathological reporting., Materials and Methods: Salvage ND specimen from a cohort of n = 75 HNSCC (oropharynx, larynx, hypopharynx) patients with prior (chemo) radiation were evaluated on H&E stains for the following parameters: viable tumor cells, necrosis, swirled keratin debris, foamy histiocytes, bleeding residues, fibrosis, elastosis, pyknotic cells, calcification, cholesterol crystals, multinucleated giant cells, perineural, and vascular invasion. Histological features were correlated with survival outcomes., Results: Only the presence / amount (area) of viable tumor cells correlated with a worse clinical outcome (local and regional recurrence-free survival, (LRRFS), distant metastasis-free survival, disease-specific survival, and overall survival, p < 0.05) in both the univariable and multivariable analyses., Conclusion: We could confirm the presence of viable tumor cells as a relevant negative prognostic factor after (chemo) radiation. The amount (area) of viable tumor cells further substratified patients with worse LRRFS. None of the other parameters correlated with a distinctive worse outcome. Importantly, the presence of (swirled) keratin debris alone should not be considered viable tumor cells (ypN0)., (© 2023. The Author(s).)

Purpose: To develop and evaluate a lymph node invasion (LNI) prediction model for men staged with [ 68 Ga]Ga-PSMA-11 PET., Methods: A consecutive sample of intermediate to high-risk prostate cancer (PCa) patients undergoing [ 68 Ga]Ga-PSMA-11 PET, extended pelvic lymph node dissection (ePLND), and radical prostatectomy (RP) at two tertiary referral centers were retrospectively identified. The training cohort comprised 173 patients (treated between 2013 and 2017), the validation cohort 90 patients (treated between 2016 and 2019). Three models for LNI prediction were developed and evaluated using cross-validation. Optimal risk-threshold was determined during model development. The best performing model was evaluated and compared to available conventional and multiparametric magnetic resonance imaging (mpMRI)-based prediction models using area under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA)., Results: A combined model including prostate-specific antigen, biopsy Gleason grade group, [ 68 Ga]Ga Ga-PSMA-11 positive volume of the primary tumor, and the assessment of the [ 68 Ga]Ga-PSMA-11 report N-status yielded an AUC of 0.923 (95% CI 0.863-0.984) in the external validation. Using a cutoff of  ≥ 17%, 44 (50%) ePLNDs would be spared and LNI missed in one patient (4.8%). Compared to conventional and MRI-based models, the proposed model showed similar calibration, higher AUC (0.923 (95% CI 0.863-0.984) vs. 0.700 (95% CI 0.548-0.852)-0.824 (95% CI 0.710-0.938)) and higher net benefit at DCA., Conclusions: Our results indicate that information from [ 68 Ga]Ga-PSMA-11 may improve LNI prediction in intermediate to high-risk PCa patients undergoing primary staging especially when combined with clinical parameters. For better LNI prediction, future research should investigate the combination of information from both PSMA PET and mpMRI for LNI prediction in PCa patients before RP., (© 2023. The Author(s).)

Purpose: Immunotherapy using immune checkpoint inhibitors (ICI) has revolutionized cancer treatment in recent years, particularly in melanoma. While response to immunotherapy is associated with high tumor mutational burden (TMB), PD-L1 expression, and microsatellite instability in several cancers, tumors lacking these biomarkers can still respond to this treatment. Especially, mucosal melanoma, commonly exhibiting low TMB compared to cutaneous melanoma, may respond to immunotherapy with immune checkpoint inhibitors. Therefore, the aim of our study was to investigate novel biomarkers in mucosal melanoma that predict response to combined ipilimumab and nivolumab., Methods: We investigated 10 tumor samples from 10 patients (three responders, seven non-responders) before treatment and six tumor samples from five patients after progression using a targeted Next Generation Sequencing (NGS) gene expression panel. The findings were corroborated with an independent method (i.e., immunohistochemical staining) on the same 10 tumor samples before treatment and, to increase the cohort, in addition on three tumor samples before treatment of more recent patients (one responder, two non-responders)., Results: With the targeted gene expression panel, we found the three tumor testis antigens CTAG1B (NY-ESO-1), MAGE-A3, and MAGE-A4 to be predominantly expressed in responding tumors. This marker panel was either not or not completely expressed in non-responders (p < 0.01). Using immunohistochemistry for all three markers, we could confirm the elevated expression in tumors responding to the ipilimumab/nivolumab combination therapy., Conclusion: In conclusion, these three biomarkers await validation in a larger patient cohort and could be easily used in future routine diagnostics to predict the outcome of ipilimumab/nivolumab combination therapy in mucosal melanoma patients., (© 2022. The Author(s).)

Background: Fine-needle aspiration cytology (FNAC) represents an important diagnostic tool for the workup of salivary gland (SG) lesions. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a six-tiered system for standardizing diagnoses and improvement of communication between pathologists and clinicians, providing risk of malignancy (ROM) rates for every category. The aims of the present study were (i) to validate the use of MSRSGC in a large series of SG FNAC in a tertiary center in Switzerland, (ii) to determine ROM for each category and compare them with data from MSRSGC and similar studies, and (iii) to investigate whether there were relevant differences of non-diagnostic results between fine-needle aspirations (FNA) performed by cytopathologists compared to non-cytopathologists., Methods: The files of the department of Pathology in the University Hospital Zurich (UHZ) were searched for SG FNAC between 2010 and 2019. The MSRSGC guidelines were applied retrospectively. Furthermore, ROM, risk of neoplasia (RON), sensitivity, and specificity were calculated based on the cases with histopathological follow-up., Results: A total of 2156 SG FNAC including 753 cases with histopathological follow-up were evaluated. Generally, ROM was within the range of values provided by MSRSGC, with some minor deviations. Sensitivity was 94.6%, and specificity was 99.3%., Conclusions: Our study confirms the usefulness of MSRSGC. In addition, it provides a detailed insight into the wide spectrum of SG FNAC. Finally, we showed that the rate of non-diagnostic FNA was significantly lower in FNAs performed by cytopathologists compared to non-cytopathologists., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The added value of hybrid positron emission tomography is increasingly recognised in head and neck cancer. However, its potential role in salivary gland carcinomas has been scarcely investigated., Methods: A consecutive cohort of 45 salivary gland carcinoma patients who underwent pre-therapeutic hybrid positron emission tomography and surgical resection was reviewed. This study investigated whether maximum standardised uptake value correlated with tumour phenotype., Results: Tumours of high-grade disease on histology (salivary duct carcinoma, carcinoma ex pleomorphic adenoma) had higher maximum standardised uptake value (Kruskal-Wallis test, p = 0.011) than low-grade tumours (adenoid cystic carcinoma and acinic cell carcinoma). Patients with pathologically confirmed node-positive disease had significantly higher maximum standardised uptake value of the primary tumour than patients with pathologically confirmed node-negative disease (Kruskal-Wallis test, p = 0.012)., Conclusion: Maximum standardised uptake value of the primary tumour may guide clinical decision-making in patients with salivary gland carcinomas, as a high maximum standardised uptake value is associated with high-grade tumour histology and the presence of lymph node metastases. Clinicians may consider more aggressive surgery for these patients.

The classification of salivary gland tumors is ever-evolving with new variants of tumors being described every year. Next-generation sequencing panels have helped to prove and disprove prior assumptions about tumors' relationships to one another, and have helped refine this classification. Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs at all major and minor salivary gland and seromucous gland sites. Most AdCC are predominantly myoepithelial and basaloid with variable cribriform, tubular, and solid growth. The luminal tubular elements are often less conspicuous. AdCC has largely been characterized by canonical MYB fusions, with MYB::NFIB and rarer MYBL1::NFIB. Anecdotal cases of AdCC, mostly in nonmajor salivary gland sites, have been noted to have unusual patterns, including squamous differentiation and macrocystic growth. Recently, this has led to the recognition of a subtype termed "metatypical adenoid cystic carcinoma." Another unusual histology that we have seen with a wide range of architecture, is striking tubular hypereosinophilia. The hypereosinophilia and luminal cell prominence is in stark contrast to the vast majority of AdCC that are basaloid and myoepithelial predominant. A total of 16 cases with tubular hypereosinophilia were collected, forming morular, solid, micropapillary, and glomeruloid growth, and occasionally having rhabdoid or Paneth-like cells. They were subjected to molecular profiling demonstrating canonical MYB::NFIB (5 cases) and MYBL1::NFIB (2 cases), as well as noncanonical EWSR1::MYB (2 cases) and FUS::MYB (1 case). The remaining 6 cases had either no fusion (3 cases) or failed sequencing (3 cases). All cases were present in nonmajor salivary gland sites, with seromucous glands being the most common. These include sinonasal tract (7 cases), laryngotracheal (2 cases), external auditory canal (2 cases), nasopharynx (1 case), base of tongue (2 cases), palate (1 case), and floor of mouth (1 case). A tissue microarray of 102 conventional AdCC, including many in major salivary gland sites was examined for EWSR1 and FUS by fluorescence in situ hybridization and showed that these novel fusions were isolated to this histology and nonmajor salivary gland location. In summary, complex and striking tubular hypereosinophilia and diverse architectures are present within the spectrum of AdCC, particularly in seromucous gland sites, and may show variant EWSR1/FUS::MYB fusions., 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 © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To evaluate different image quality scoring systems in the assessment of factors limiting diagnostic accuracy of prostate MRI., Methods: This retrospective IRB-approved study included 281 patients undergoing prostate MRI prior to biopsy. Four readers (2 experienced, 2 novice) independently reviewed all MRI examinations (n = 295) and assigned scores for subjective image quality (1-5; 1:poor, 5:excellent), the PI-QUAL and the PSHS scoring system. The original PI-RADS scores were extracted from the report and transperineal template saturation biopsy served as histopathological reference., Results: Inter-reader agreement was found to be good, with PSHS showing highest agreement (kappa: 0.65). The PSHS scoring system performed well assessing the influence of image quality on sensitivity of MR for clinically-significant cancer for the experienced readers using a PI-RADS score cut-off ≥ 3/≥4, as did the PI-QUAL scoring system with a PI-RADS cut-off ≥ 4. For the less experienced radiologist, this was true for PSHS (clinically-significant and all cancers) and PI-QUAL scores (clinically-significant cancers) for a PI-RADS score ≥ 3. PSHS scores were positively associated with the detection of clinically-significant cancer based on a PI-RADS cut-off ≥ 4, OR 1.86 (95 % CI 1.22-2.82), and had the highest Somers' D., Conclusions: The PSHS scoring system performed well in assessing the effect of image quality on detection rates, as did the PI-QUAL system. Since both systems focus on different aspects of image quality, their incorporation into prostate MRI reports could further enhance standardization and allow for a reliable assessment of image quality as a potential confounder in prostate MRI., 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 © 2023 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to investigate the value of metabolic tumor imaging using hybrid PET for the preoperative detection of extranodal extension (ENE) in lymph node metastases of oropharyngeal squamous cell carcinoma (OPSCC)., Methods: We performed a retrospective analysis of a consecutive cohort of patients with OPSCC treated with primary surgery with or without adjuvant (chemo-) radiotherapy at the Kantonsspital Sankt-Gallen and the University Hospital Zurich, Switzerland, from 2010 until 2019. Hybrid PET was compared to conventional cross-sectional imaging with MRI and CT. Histopathological presence of ENE of neck dissection specimen served as gold standard., Results: A total number of 234 patients were included in the study, 95 (40.6%) of which had pathological ENE (pENE). CT has a good specificity with 93.7%; meanwhile, MRI was the most sensitive diagnostic method (72.0%). The nodal metabolic tumor parameters (SUV max , TLG, MTV) were significantly higher in patients with positive ENE (p < 0.001 for all three parameters) than in patients with negative ENE (p < 0.001, for all three parameters)., Conclusions: CT achieved the best specificity, while MRI had the best sensitivity to detect ENE. Nodal metabolic tumor parameters differed significantly between ENE-positive/negative and p16-positive/negative patients. Hence, quantitative data obtained by metabolic imaging might predict presence of ENE and, therefore, could be helpful in customizing therapy management., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The landscape of salivary gland carcinomas is ever-changing, with a growing list of new tumors and newly elucidated variants of well-known tumor entities. The routine use of next-generation sequencing has been instrumental in identifying novel fusions and tumor entities, which has helped bring the classification to a more objective and evidenced-based model. However, morphology remains critical in assessing the validity of these novel molecular findings, and most importantly, in assessing which of these findings will have an impact on the prognosis and treatment decisions for patients. The recognition of microsecretory adenocarcinoma (MSA) as a distinct low-grade malignancy of salivary glands, underpinned by MEF2C::SS18 , and a single possibly related case of SS18::ZBTB7A , recently expanded this growing list of distinctive tumors. It was not until now, however, that the morphology of the latter case was known to be unique and reproducible. The authors have now seen 4 of these distinctive tumors that show a combination of distinctive oncocytic cells forming compact glandular growth as well as amphophilic cells forming tubular growth, and suggest the appellation "microcribriform adenocarcinoma" (MCA). So far, these tumors appear to preferentially occur in nonoral sites (2 parotid, 1 submandibular gland, and 1 bronchial seromucous glands). By immunohistochemistry, they express S100 and SOX-10 with focal outer myoepithelial cells marked by circumferential p63, p40, and smooth muscle actin staining around some of the nests and tubules. The tumors show infiltrative growth within a hyalinized and myxoid stroma. Cytologically, they appear generally low grade, similar to MSA. The morphologic and molecular uniformity of these 4 microcribriform adenocarcinoma cases warrants their recognition, and while related to MSA, they are sufficiently different to be classified as a distinct tumor. So far, in limited follow-up, these tumors appear to be relatively indolent., 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 © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The 8th edition of the TNM Cancer Staging Manual incorporates depth of invasion (DOI) into the pathologic tumor classification for oral squamous cell carcinoma (OSSC). While deep invading tumors with small tumor diameters (TD) have been categorized as early stage tumors in the 7th edition, they are now upstaged, potentially influencing the decision to initiate adjuvant radiotherapy (RT)., Methods: OSCC patients surgically treated with curative intent between 2010 and 2019 were consecutively included. Tumors were staged based on TD only (according to the 7th edition TNM Cancer Staging Manual), then restaged based solely on DOI., Results: Of the 133 included patients, 58 patients (43.6%) had a different pT-stage when using DOI instead of TD for staging (upstaging in 23.3%). Overall survival (OS) was significantly worse in patients who were upstaged with DOI. In addition, stratification by adjuvant RT showed significant worse OS in upstaged patients without receiving adjuvant RT., Conclusions: DOI seems to be an import indicator for adjuvant RT in OSCC-patients., (© 2022. The Author(s).)

Background: Endolymphatic sac tumors are rare neoplasia characterized by slow growth. However, their clinical impact should not be underestimated, considering their potential for local aggressive behavior and strong association with von Hippel-Lindau syndrome. Therefore, early detection with emerging theragnostic examinations such as 68 Ga-DOTATATE-PET/CT might improve patient management and reduce morbidity., Methods: We report the clinicopathological features of seven endolymphatic sac tumors. In this cohort, we performed immunohistochemical analysis of somatostatin receptor 2A (SSTR2A) and prostate specific membrane antigen (PSMA) protein expression patterns; two targets providing rationale for novel imaging modalities such as PSMA- or SSTR-targeted PET., Results: The tumor cells of all cases were negative for prostate specific membrane antigen and somatostatin receptor 2A, however immunolabeling was consistently detected in intratumoral endothelial cells of endolymphatic sac tumors for PSMA (7/7 cases, 100%), and for SSTR2A (5/7 cases, 71%)., Conclusions: Our results show a high rate of PSMA and SSTR2A expression in the tumor vasculature of endolymphatic sac tumors. PSMA and SSTR2A can be targeted with appropriate radioligands for diagnostic and therapeutic purposes. This finding provides a rationale for prospective clinical studies to test this approach as a sensitive screening tool for patients with suspected endolymphatic sac tumors including an improved management of von Hippel-Lindau syndrome., (© 2022. The Author(s).)

., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC., (© 2022. The Author(s).)

Purpose: Recently, a significant association was shown between novel growth patterns on histopathology of prostate cancer (PCa) and prostate-specific membrane antigen (PSMA) uptake on [ 68 Ga]PSMA-PET. It is the aim of this study to evaluate the association between these growth patterns and ADC (mm 2 /1000 s) values in comparison to [ 68 Ga]PSMA uptake on PET/MRI., Methods: We retrospectively evaluated patients who underwent [ 68 Ga]PSMA PET/MRI for staging or biopsy guidance, followed by radical prostatectomy at our institution between 07/2016 and 01/2020. The dominant lesion per patient was selected based on histopathology and correlated to PET/MRI in a multidisciplinary meeting, and quantified using SUV max for PSMA uptake and ADC mean for diffusion restriction. PCa growth pattern was classified as expansive (EXP) or infiltrative (INF) according to its properties of forming a tumoral mass or infiltrating diffusely between benign glands by two independent pathologists. Furthermore, the corresponding WHO2016 ISUP tumor grade was evaluated. The t test was used to compare means, Pearson's test for categorical correlation, Cohen's kappa test for interrater agreement, and ROC curve to determine the best cutoff., Results: Sixty-two patients were included (mean PSA 11.7 ± 12.5). The interrater agreement between both pathologists was almost perfect with κ = 0.81. While 25 lesions had an EXP-growth with an ADC mean of 0.777 ± 0.109, 37 showed an INF-growth with a significantly higher ADC mean of 1.079 ± 0.262 (p < 0.001). We also observed a significant difference regarding PSMA SUV max for the EXP-growth (19.2 ± 10.9) versus the INF-growth (9.4 ± 6.2, p < 0.001). Within the lesions encompassing the EXP- or the INF-growth, no significant correlation between the ISUP groups and ADC mean could be observed (p = 0.982 and p = 0.861, respectively)., Conclusion: PCa with INF-growth showed significantly lower SUV max and higher ADC mean values compared to PCa with EXP-growth. Within the growth groups, ADC mean values were independent from ISUP grading., (© 2022. The Author(s).)

Background: Magnetic resonance imaging (MRI) is recommended by the European Urology Association guidelines as the standard modality for imaging-guided biopsy. Recently positron emission tomography with prostate-specific membrane antigen (PSMA PET) has shown promising results as a tool for this purpose. The aim of this study was to compare the accuracy of positron emission tomography with prostate-specific membrane antigen/magnetic resonance imaging (PET/MRI) using the gallium-labeled prostate-specific membrane antigen ( 68 Ga-PSMA-11) and multiparametric MRI (mpMRI) for pre-biopsy tumour localization and interreader agreement for visual and semiquantitative analysis. Semiquantitative parameters included apparent diffusion coefficient (ADC) and maximum lesion diameter for mpMRI and standardized uptake value (SUV max ) and PSMA-positive volume (PSMA vol ) for PSMA PET/MRI., Results: Sensitivity and specificity were 61.4% and 92.9% for mpMRI and 66.7% and 92.9% for PSMA PET/MRI for reader one, respectively. RPE was available in 23 patients and 41 of 47 quadrants with discrepant findings. Based on RPE results, the specificity for both imaging modalities increased to 98% and 99%, and the sensitivity improved to 63.9% and 72.1% for mpMRI and PSMA PET/MRI, respectively. Both modalities yielded a substantial interreader agreement for primary tumour localization (mpMRI kappa = 0.65 (0.52-0.79), PSMA PET/MRI kappa = 0.73 (0.61-0.84)). ICC for SUV max , PSMA vol and lesion diameter were almost perfect (≥ 0.90) while for ADC it was only moderate (ICC = 0.54 (0.04-0.78)). ADC and lesion diameter did not correlate significantly with Gleason score (ρ = 0.26 and ρ = 0.16) while SUV max and PSMA vol did (ρ =  - 0.474 and ρ =  - 0.468)., Conclusions: PSMA PET/MRI has similar accuracy and reliability to mpMRI regarding primary prostate cancer (PCa) localization. In our cohort, semiquantitative parameters from PSMA PET/MRI correlated with tumour grade and were more reliable than the ones from mpMRI., (© 2022. The Author(s).)

Aims: Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a recently described renal tumour entity with frequent cytokeratin (CK)20 positivity, commonly harbouring TSC mutations. In contrast, frequency of CK20 expression and presence of TSC mutations are unclear in TFEB-amplified RCC and TFEB-translocated RCC, which frequently express Melan A. Herein, we provide a comparative analysis of six ESC RCC with four TFEB-amplified/translocated RCC., Methods and Results: We assessed the frequency of CK20 and Melan A expression by immunohistochemistry and of TSC mutations by next-generation sequencing. TFEB alterations were confirmed by fluorescence in-situ hybridisation (FISH). All tumours showed voluminous eosinophilic cells with granular cytoplasm, prominent nucleoli, and most showed admixture of solid and cystic areas. CK20 expression was found in all six ESC RCC and in all RCCs with TFEB alterations. Melan A positivity was identified in five of six ESC RCC and four of four RCC with TFEB alterations. We found TSC mutations in two ESC RCCs, including in one case also harbouring a CIC fusion, and identified a TSC mutation in one TFEB-amplified RCC., Conclusions: ESC RCC represents an emerging renal tumour entity with some histological, immunohistochemical and molecular overlap to TFEB-amplified/translocated RCC. FISH for TFEB aids in this differential diagnosis in challenging cases., (© 2022 John Wiley & Sons Ltd.)

Objectives: The natural history of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is still largely unknown. Since reports of second primary tumors (SPTs) in patients with HPV-related OPSCCs are increasing, a multifocal HPV infection, hinting a «virus-induced field effect», has been hypothesized. This study aimed to investigate the HPV-prevalence in normal appearing oropharyngeal tissue in patients with OPSCCs., Materials and Methods: 49 OPSCC patients undergoing panendoscopy were prospectively enrolled. Tumor specimens and biopsies of normal appearing oropharyngeal tissue adjacent to and distant from the index OPSCC underwent histopathological examination, p16 INK4A immunohistochemical staining, HPV DNA and mRNA-detection. Patient characteristics and follow-up data on SPTs were obtained., Results: 26 of 49 (53%) OPSCC were positive for HPV DNA and p16 INK4A . HPV mRNA was detected in 23 of 26 (88%) of these tumor samples. HPV DNA was detected in 36% adjacent mucosa and in 17% distant mucosa samples and only in patients with an HPV-related index OPSCC. HPV mRNA could not be detected in tumor-free distant and adjacent mucosa samples. No evidence of association between HPV detection in normal appearing mucosa and development of second primary tumors was found., Conclusions: HPV was detectable but not transcriptionally active in adjacent/distant tumor-free oropharyngeal tissue. This suggests that a multifocal HPV infection, hinting a «virus-induced fielcd cancerization», may not be pertaining to HPV-related OPSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guarda, Schroeder, Pawlita, Ikenberg, Rupp, Jochum, Stoeckli, Holzinger and Broglie.)

Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. This study aims to identify prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated microenvironment by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1.6 million cells from 58 men with localized prostate cancer. We perform this task, using a high-dimensional clustering pipeline named Franken to describe subpopulations of immune, stromal, and prostate cells, including changes occurring in tumor tissues and high-grade disease that provide insights into the coordinated progression of prostate cancer. Our results further indicate that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease., Competing Interests: P.J.W. has received consulting fees and honoraria (institutional/personal) for lectures by Bayer, Janssen-Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol-Myers Squibb, Thermo Fisher Scientific, Molecular Health, Sophia Genetics, Qiagen, and Astra Zeneca. L.D.V.R. is an employee at Monte Rosa Therapeutics. All other authors have declared no competing interests., (© 2022 The Author(s).)

PCa screening is based on the measurements of the serum prostate specific antigen (PSA) to select men with higher risks for tumors and, thus, eligible for prostate biopsy. However, PSA testing has a low specificity, leading to unnecessary biopsies in 50-75% of cases. Therefore, more specific screening opportunities are needed to reduce the number of biopsies performed on healthy men and patients with indolent tumors. Urine samples from 45 patients with elevated PSA were collected prior to prostate biopsy, a mass spectrometry (MS) screening was performed to identify novel biomarkers and the best candidates were validated by ELISA. The urine quantification of PEDF, HPX, CD99, CANX, FCER2, HRNR, and KRT13 showed superior performance compared to PSA. Additionally, the combination of two biomarkers and patient age resulted in an AUC of 0.8196 (PSA = 0.6020) and 0.7801 (PSA = 0.5690) in detecting healthy men and high-grade PCa, respectively. In this study, we identified and validated novel urine biomarkers for the screening of PCa, showing that an upfront urine test, based on quantitative biomarkers and patient age, is a feasible method to reduce the number of unnecessary prostate biopsies and detect both healthy men and clinically significant PCa.

Objectives: To investigate whether dynamic contrast-enhanced (DCE)-MR bone perfusion could serve as surrogate for morphologic ultra-short echo time (UTE) bone images and to correlate perfusion with morphologic hallmarks in histologically proven foci of medication-related osteonecrosis of the jaw (MRONJ)., Methods: Retrospective study including 20 patients with established diagnosis of MRONJ. Qualitative consensus assessment of predefined jaw regions by two radiologists was used as reference standard using Likert scale (0-3) for standard imaging hallmarks in MRONJ (osteolysis, sclerosis, periosteal thickening). DCE-MRI measurements performed in corresponding regions of the mandible were then correlated with qualitative scores. Regions were grouped into "non-affected" and "pathologic" based on binarized Likert scores of different imaging hallmarks (0-1 vs 2-3). DCE-MRI measurements among hallmarks were compared using Mann-Whitney- U -testing. ROC (receiver-operating-characteristic) analysis was performed for each of the perfusion parameters to assess diagnostic performance for identification of MRONJ using morphologic ratings as reference standard., Results: Median perfusion measurements of "pathologic" regions in wash-in, peak enhancement intensity and integrated area under the curve are significantly higher than those of "non-affected" regions, irrespective of reference imaging hallmark ( p < 0.05). No significant perfusion differences were found between "pathologic" regions with and without osteolysis ( p = 0.180). ROC analysis showed fair diagnostic performance of DCE-MRI parameters for identification of MRONJ (AUC 0.626-0.727)., Conclusions: DCE bone perfusion parameters are significantly increased in MRONJ compared to non-affected regions, irrespective of osteolysis. Due to certain overlap DCE-MRI bone perfusion cannot serve as full surrogate for UTE bone imaging but may enhance reader confidence.

Background: The aim of this study was to assess the relationship between the histopathological properties of hyperfunctioning parathyroids and parathyroid 18F-choline uptake., Patients and Methods: A total of 31 parathyroid adenomas were retrospectively analyzed in patients with primary hyperparathyroidism and preoperative 18F-choline PET/MR. PET/MR parameters of parathyroid glands (SUVmax and target-to-background ratio in early-phase [EP] and late-phase [LP]), MRI volume, preoperative parathyroid hormone (PTH) serum concentration, and postoperative histopathology (predominant cell type and growth pattern of adenoma cells, location and size of adenoma) were assessed. The relationship of PET/MR parameters, PTH, and histological parameters was determined using linear regression, Spearman correlation and Kruskal-Wallis test., Results: The median volume of parathyroid adenoma was 421.78 ± 142.46 mm3 (46.39-4412.69). Adenomas were predominantly composed of chief, water-clear, and oncocytic/oxyphilic cells in 27/31, 2/31, and 2/31 cases, respectively. The growth pattern was predominantly solid, follicular, and trabecular in 18/31, 8/31, and 5/31, respectively. The SUVmax was 6.71 ± 3.39 in EP and 6.91 ± 3.97 in LP. Follicular growth pattern had slightly higher EP SUVmax (trabecular: 4.12 ± 0.56; solid: 6.62 ± 3.19; follicular: 8.56 ± 3.96; P = 0.046). Spearman correlation showed strong positive correlation between volume and both EP and LP SUVmax (0.626; P = 0.0001 and 0.576; P = 0.0001, respectively). Linear regression analysis revealed significant correlation between PTH level and EP and LP SUVmax (both P = 0.001); in contrast, no correlation was found between PTH level and both cell type and growth pattern., Conclusions: Our findings suggest that 18F-choline uptake of parathyroid adenomas might be associated both with the histological growth pattern and adenoma volume, but not with a specific cell type., Competing Interests: Conflicts of interest and sources of funding: M.W.H. is a recipient of speaker's fees and grants from GE Healthcare. Apart from that, the other authors of this manuscript declare no relationship with any companies, whose products or services may be related to the subject matter of the article. The University Hospital Zurich holds a research agreement with GE Healthcare (unrelated to the current study). M.W.H. is a recipient of grants for translational and clinical cardiac and oncological research from the Alfred and Annemarie von Sick legacy, and grants from the Artificial Intelligence in Oncological Imaging Network by the University of Zurich. No further specific grants from funding agencies in the public, commercial, or not-for-profit sectors were received for this study., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

PLAG1 rearrangements have been described as a molecular hallmark of salivary gland pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (CEPA), and myoepithelial carcinoma (MECA). Several fusion partners have been described, however, commonly no further assignment to the aforementioned entities or a morphological prediction can be made based on the knowledge of the fusion partner alone. In contrast, TGFBR3-PLAG1 fusion has been specifically described and characterized as an oncogenic driver in MECA, and less common in MECA ex PA. Here, we describe the clinicopathological features of three TGFBR3-PLAG1 fusion-positive salivary gland neoplasms, all of which arose in the deep lobe of the parotid gland. Histopathology showed high morphological similarities, encompassing encapsulation, a polylobular growth pattern, bland basaloid and oncocytoid cells with myoepithelial differentiation, and a distinct sclerotic background. All cases showed at least limited, unusual foci of minimal invasion into adjacent salivary gland tissue, including one case with ERBB2 (Her2/neu) amplified, TP53 mutated high-grade transformation, and lymph node metastases. Of note, all cases illustrated focal ductal differentiation. Classification remains difficult, as morphological overlaps between myoepithelial-rich cellular PA, myoepithelioma, and MECA were observed. However, evidence of minimal invasion advocates classification as low-grade MECA. This case series further characterizes the spectrum of uncommon cellular myoepithelial neoplasms harboring TGFBR3-PLAG1 fusion, which show recurrent minimal invasion of the adjacent salivary gland tissue, a predilection to the deep lobe of the parotid gland, and potential high-grade transformation., (© 2021 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Background: Fibro-osseous lesions (FOL) of the jaw represent a rare, benign group of lesions that share similar clinical, radiological, and histopathological features and are characterized by progressive, variable replacement of healthy bone tissue by fibrous connective tissue., Methods: This retrospective study aimed to evaluate the incidence of fibro-osseous lesions and to reassess the efficacy of case-specific treatment management from a clinical, radiological, and histopathological perspective based on 14 years of data., Results: Forty-four patients with a radiological and/or histopathological diagnosis of benign FOLs were identified and re-evaluated. Cemento-osseous dysplasia was the most common group of FOLs present in our patient cohort (45%), followed by ossifying fibroma (39%) and fibrous dysplasia (16%). The diagnostic imaging technique of choice was CBCT (68%), followed by PAN (18%), with most patients (95 %) additionally undergoing biopsy. The mean age of the patients at the time of diagnosis was 40.54 ± 13.7 years, with most lesions being located in the mandible (86%), with females being predominantly affected (73%)., Conclusion: An interdisciplinary approach that analyzes all case-specific factors, including demographic data, medical history, intraoperative findings, and, most importantly, histopathological and radiological features, is essential for an accurate diagnosis and key to avoiding inappropriate treatment.

Background: Dutasteride has been shown to increase expression of the prostate-specific membrane antigen (PSMA) in prostate cancer cells in previous in vitro studies. This 5-alpha-reductase inhibitor is commonly used for the treatment of symptomatic benign prostatic enlargement. The modulation of PSMA expression might affect PSMA-based prostate cancer imaging and therapy., Aim: The purpose of this work was to further analyze concentration-dependent effects of Dutasteride on PSMA expression in a mouse xenograft model., Methods and Results: Four groups of mice bearing LNCaP xenografts were treated for 14 days with daily intraperitoneal injections of either vehicle control or different concentrations of Dutasteride (0.1, 1, 10 mg/kg). Total expression of PSMA, androgen receptor (AR), and caspase-3 protein was analyzed using immunoblotting (WES). In addition, PSMA, cleaved caspase-3 and Ki-67 expression was assessed and quantified by immunohistochemistry. Tumor size was measured by caliper on day 7 and 14, tumor weight was assessed following tissue harvesting. The mean PSMA protein expression in mice increased significantly after treatment with 1 mg/kg (10-fold) or 10 mg/kg (sixfold) of Dutasteride compared to vehicle control. The mean fluorescence intensity significantly increased by daily injections of 0.1 mg/kg Dutasteride (1.6-fold) as well as 1 and 10 mg/kg Dutasteride (twofold). While the reduction in tumor volume following treatment with high concentrations of 10 mg/kg Dutasteride was nonsignificant, no changes in AR, caspase-3, cleaved caspase-3, and Ki-67 expression were observed., Conclusion: Short-term Dutasteride treatments with concentrations of 1 and 10 mg/kg significantly increase the total PSMA protein expression in a mouse LNCaP xenograft model. PSMA fluorescence intensity increases significantly even using lower daily concentrations of 0.1 mg/kg Dutasteride. Further investigations are needed to elucidate the impact of Dutasteride treatment on PSMA expression in patients., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

The ability to combine multiple immunohistochemical (IHC) markers within a single tissue section facilitates the evaluation and detection of co-expressions, while saving tissue. A newly developed 5x multiplex (MPX) IHC staining of five different IHC markers (Basal cell cocktail (34βE12 + p63), p504s (SP116), ERG (EPR3864), Ki-67 (30-9), PSMA (EP192)) was applied on whole sections of n = 37 radical prostatectomies (RPE) including normal and cancerous tissue. Four different colors including brown, magenta, yellow and teal coded for different stainings, whereas magenta was used twice for nuclear Ki-67 and cytosolic / membranous PSMA. The staining of multiplex IHC was compared to single stains of ERG, PSMA and p504s. The proper staining of the basal cell cocktail and Ki-67 could be assessed by internal positive controls in the multiplex staining. The proportion of PSMA and p504s expression revealed a significant correlation between multiplex and single stains (p < 0.01) as well as a concordant staining pattern for ERG (n = 14 prostate cancers were identified ERG positive with both methods). Our proof of concept study demonstrates a robust staining pattern of all five different antibodies with this newly developed 5x MPX IHC. This approach facilitates the recognition of prostate cancer, in particular by adding PSMA in cases with low p504s expression., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Purpose: Prostate-specific membrane antigen (PSMA-) PET has become a promising tool in staging and restaging of prostate carcinoma (PCa). However, specific primary tumour features might impact accuracy of PSMA-PET for PCa detection. We investigated histopathological parameters and immunohistochemical PSMA expression patterns on radical prostatectomy (RPE) specimens and correlated them to the corresponding 68 Ga-PSMA-11-PET examinations., Methods: RPE specimens of 62 patients with preoperative 68 Ga-PSMA-11-PET between 2016 and 2018 were analysed. WHO/ISUP grade groups, growth pattern (expansive vs. infiltrative), tumour area and diameter as well as immunohistochemical PSMA heterogeneity, intensity and negative tumour area (PSMA %neg ) were correlated with spatially corresponding SUV max on 68 Ga-PSMA-11-PET in a multidisciplinary analysis., Results: All tumours showed medium to strong membranous (2-3 +) and weak to strong cytoplasmic (1-3 +) PSMA expression. Heterogeneously expressed PSMA was found in 38 cases (61%). Twenty-five cases (40%) showed at least 5% and up to 80% PSMA %neg . PSMA %neg , infiltrative growth pattern, smaller tumour area and diameter and WHO/ISUP grade group 2 significantly correlated with lower SUV max values. A ROC curve analysis revealed 20% PSMA %neg as an optimal cutoff with the highest sensitivity and specificity (89% and 86%, AUC 0.923) for a negative PSMA-PET scan. A multiple logistic regression model revealed tumoural PSMA %neg (p < 0.01, OR = 9.629) and growth pattern (p = 0.0497, OR = 306.537) as significant predictors for a negative PSMA-PET scan., Conclusions: We describe PSMA %neg , infiltrative growth pattern, smaller tumour size and WHO/ISUP grade group 2 as parameters associated with a lower 68 Ga-PSMA-11 uptake in prostate cancer. These findings can serve as fundament for future biopsy-based biomarker development to enable an individualized, tumour-adapted imaging approach., (© 2021. The Author(s).)