Clinical predictors of negative/equivocal SPECT imaging outcomes in primary hyperparathyroidism: Factors calling for 18F-choline-PET.

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 18F-choline-PET. The aim of our study was to identify predictors for inconclusive SPECT imaging and subsequently determine in which cases 18F-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 18F-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 18F-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 18F-choline-PET imaging. Our study reinforces the clinical significance of 18F-choline-PET, especially in complex cases with disconcordant results by conventional parathyroid imaging methods.

MRI-based radiomics for predicting histology in malignant salivary gland tumors: methodology and "proof of principle".

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.

MRI-based monitoring of prostate cancer after HIFU: Inter-reader agreement and diagnostic performance of the PI-FAB score.

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.

Molecular analysis using SalvGlandDx improves risk of malignancy estimation and diagnosis of salivary gland cytopathology: An exploratory multicenter study.

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.

Molecular testing in salivary gland cytopathology: A practical overview in conjunction with the Milan system.

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.

Updates in head and neck cytopathology: Insights from European Congress of Pathology Short Course.

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.

Focal therapy with high-intensity focused ultrasound for prostate cancer: 3-year outcomes from a prospective trial.

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.

Risk factors for prostate cancer in men with false-negative mpMRI: A retrospective single center cohort study of image quality scores and clinical parameters.

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.

Genomic alterations and diagnosis of renal cancer.

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.

Proteomic-based stratification of intermediate-risk prostate cancer patients.

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.

Nasal and sinonasal tumors formed by atypical adenomatous lesions arising in respiratory epithelial adenomatoid hamartoma/seromucinous hamartoma.

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).

Sinonasal mucosal melanoma treatment response assessment to immune checkpoint inhibitors using hybrid positron emission tomography imaging.

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.

Challenging Tumor Heterogeneity with HER2, p16 and Somatostatin Receptor 2 Expression in a Case of EBV-Associated Lymphoepithelial Carcinoma of the Salivary Gland.

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.

Development and external validation of a multivariable [68Ga]Ga-PSMA-11 PET-based prediction model for lymph node involvement in men with intermediate or high-risk prostate cancer.

PURPOSE: To develop and evaluate a lymph node invasion (LNI) prediction model for men staged with [68Ga]Ga-PSMA-11 PET. METHODS: A consecutive sample of intermediate to high-risk prostate cancer (PCa) patients undergoing [68Ga]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, [68Ga]Ga Ga-PSMA-11 positive volume of the primary tumor, and the assessment of the [68Ga]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 [68Ga]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.

Histopathological Analysis of Nodal Disease After Chemoradiation Reveals Viable Tumor Cells as the most Important Prognostic Factor in Head and Neck Squamous Cell Carcinoma.

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).

The Milan system for reporting salivary gland cytopathology-A single-center study of 2156 cases.

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.

Differentiated Papillary NUT Carcinoma: An Unexpected, Deceptively Bland Presentation of a Sinonasal Carcinoma.

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.

Adenoid Cystic Carcinoma With Striking Tubular Hypereosinophilia: A Unique Pattern Associated With Nonparotid Location and Both Canonical and Novel EWSR1::MYB and FUS::MYB Fusions.

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.