Ninth Version of the AJCC and UICC Nasopharyngeal Cancer TNM Staging Classification.

Importance: Accurate staging is a fundamental step in treating patients with nasopharyngeal carcinoma (NPC) worldwide; this is crucial not only for prognostication, but also for guiding treatment decisions. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) system is the global language for clinicians, researchers, and cancer registries. Continual improvement that aligns with contemporary pattern of care is essential. Objective: To improve the prognostic accuracy and clinical applicability of the eighth edition (TNM-8) for NPC. Design, Setting, and Participants: This multicenter study analyzed patients with NPC with detailed tumor features during January 2014 and December 2015 and was reviewed by experienced radiologists. The data analysis was completed in December 2023. The findings were further confirmed with internal and external validation. Statistical analyses and clinical considerations were reviewed by the AJCC/UICC multidisciplinary head and neck panels and attained consensus. The recommendations were evaluated by the AJCC Evidence-Based Medicine Committee before final endorsement as the ninth version (TNM-9). Main Outcomes and Measures: The primary end point was overall survival. Adjusted hazard ratios of different subgroups were then assessed for confirmation of optimal stage grouping. Results: Of the 4914 patients analyzed, 1264 (25.7%) were female and 3650 (74.3%) were male; the median (SD) age was 48.1 (12.0) years. Advanced radiological extranodal extension (with involvement of adjacent muscles, skin, and/or neurovascular bundles) was identified as an independent adverse factor for all end points: this was added as a criterion for N3. Patients with nonmetastatic disease were regrouped into stages I to III instead of TNM-8 stages I to IVA. Significant hazard discrimination was achieved by grouping T1-2N0-1 as stage I, T3/N2 as stage II, and T4/N3 as stage III. Although the T1-2N0-1 subgroups had comparable 5-year overall survival, subdivisions into IA (T1-T2N0) and IB (T1-T2N1) were recommended due to the distinction in adjusted hazard ratios following adjustment for chemotherapy use. Metastatic disease was exclusively classified as stage IV, and prognostication was further refined by subdivision into IVA (M1a, ≤3 lesions) and IVB (M1b, >3 lesions). TNM-9 demonstrated superiority compared with TNM-8 in major statistical aspects. Conclusion and Relevance: The results of this diagnostic study suggest that the ninth version of TNM staging for NPC, based on robust analyses and a comprehensive review by the AJCC/UICC staging committees, provides an improved staging system for global application and a framework for future incorporation of nonanatomical factors. This will be launched for global application in January 2025.

Parsing the thyroid cytopathology suspicious for malignancy diagnosis through molecular-derived risk of malignancy and other related parameters: Insights into nodule characteristics and practice patterns.

INTRODUCTION: Thyroid cytopathology cases with suspicious for malignancy (SFM) diagnosis often result in resection. However, molecular testing offers details that may provide additional insights. In this study, the molecular profiles of SFM cases from two institutions that routinely used ThyroSeq v3 (TSV3) were examined. MATERIALS AND METHODS: Following institutional review board approval, SFM thyroid cytopathology cases with TSV3 results were retrieved from the databases of two institutions. Molecular information including molecular-derived risk of malignancy (MDROM), cytologic-histologic correlation data, and other related parameters were calculated. Statistical comparisons were made with a p <.05 considered significant. RESULTS: The core data set comprised 114 SFM cases that passed TSV3 quality assurance. All TSV3 results were reported as positive or negative for genomic alterations and all except five cases provided a probability of malignancy estimate. The overall combined baseline MDROM of 75.7% (95% CI, 70.0-81.4) was comparable to the risk of malignancy (74%) published in the Bethesda System. There was a statistically significant difference between the combined MDROMs of resected and unresected cohorts (79.0% vs 58.6%; p = .0153). Interestingly, the MDROMs of the resected cohorts from the two institutions were statistically different (75.0% vs 85.3%; p = .020). Cytologic-histologic correlation revealed malignant outcome in 88.5% of resected cases. CONCLUSIONS: Molecular analyses of SFM cases demonstrated higher risk genomic alterations that were associated with histologically overt neoplasms, resulting in increased malignancy outcome compared to baseline. MDROM analysis revealed differences in the cytopathologic practice patterns regarding follicular-patterned neoplasms at the two institutions.

Characterisation of Kürsteiner canals of parathyroid: imparting relevance to a one-and-a-quarter-century-old concept.

AIMS: Kürsteiner canals (KC) were described at least 125 years ago as pharyngeal pouch embryological remnants of parathyroid and thymic development. While considered precursors for a subset of parathyroid cysts and salivary heterotopias (SH), they remain enigmatic. We now define a comprehensive phenotype of KC remnants and investigate their role in a spectrum of parathyroid lesions. METHODS AND RESULTS: `Sixty-two cystic and 22 non-cystic parathyroid lesions (73 patients) were retrieved from our institutional archive (2011-23) and evaluated for the presence of KC and prevalence of KC phenotype in parathyroid hormone (PTH)-positive and PTH-negative cysts. KC phenotype was defined as: cysts and tubules with surrounding sclerosis; bland, unilayered lining with frequent nuclear indentation of lumina; vesicular chromatin relative to chief cells; attenuated eosinophilic to 'hyper-cleared' cytoplasm; and staining pattern PTH-negative, SOX-10-positive, CK7-positive, GATA-3-positive and PAX-9 dim, a subset with oestrogen/progesterone receptor (ER/PR) positivity. Thirty PTH-negative cysts were identified in the neck/mediastinum; 14 of this group also showed SH. Thirty-two PTH-positive cysts included: 11 cystic parathyroid adenomas, 17 hyperplastic parathyroids, and four carcinomas. KC showed two distinct subtypes and were often found near PTH-negative cysts. PTH-negative cysts were associated with inferior parathyroids, SOX-10 positivity, fibrosclerosis, vesicular nuclei indenting cyst lumina and hyper-cleared or attenuated eosinophilic cytoplasm. CONCLUSIONS: KC are common in parathyroids and show a distinct histological and immunohistochemical profile, with an inferior predilection favouring branchial cleft III distribution. Diagnostically, the high prevalence of this phenotype in PTH-negative cysts and salivary heterotopia supports derivation of non-functioning cysts from KC. Conversely, PTH-positive cysts are more compatible with cystic change within hyperfunctioning glands.

DOTATATE PET Imaging in Olfactory Neuroblastoma and Association with SSTR Expression.

Introduction Olfactory neuroblastoma (ONB), or esthesioneuroblastoma, is a rare neuroectodermal tumor of the nasal cavity and paranasal sinuses. Most of these tumors express somatostatin receptors (SSTRs), providing a potential target for radionuclide imaging with Ga-68 DOTATATE. However, this imaging modality has not been extensively studied in ONB. Methods We conducted a retrospective chart review of 96 endoscopic endonasal skull base surgery cases for ONB performed at our institution between 2000 and 2021. Histo (H) scores were assigned to each tumor and normalized DOTATATE standardized uptake values (nSUVs) were measured as well. Results Nine patients (5 males and 4 females) with ONB were ultimately included in the study. The average age of the patients was 50 years. All ONBs had a positive SSTR2 expression (H-score > 105; mean: 180). All ONBs showed DOTATATE avidity (mean nSUV for ONB: 6.7). However, there was no correlation between H-score and nSUV, with an r 2 of 0.24 ( p = 0.18). Conclusion Our study shows that SSTR2 expression is found in all ONBs with associated DOTATATE avidity, which may serve as a valuable imaging modality to monitor for recurrent and metastatic disease in ONB.

Performance Characteristics of Incisional and Core Needle Biopsies for Diagnosis in Parotid Gland: Single-Institutional Experience and Assessment of the Value of a Milan System for Reporting Salivary Gland Cytopathology-Like Risk Stratification Model.

CONTEXT.­: Unlike parotid fine-needle aspiration biopsy, standardized reporting for core needle biopsy (CNB) and incisional biopsy (IB) is not established. OBJECTIVE.­: To examine the value of risk stratification by a Milan System for Reporting Salivary Gland Cytopathology (MSRSGC)-like classifier for parotid CNB/IB. DESIGN.­: Five hundred ninety-two parotid biopsy records (CNB = 356, IB = 236) were retrieved (1994-2022) along with clinicopathologic data. Diagnoses were transformed to an MSRSGC-like classifier and compared with end points including risk of malignancy. RESULTS.­: Over time, CNB was progressively more used compared with IB. Overall malignancy call rate was 223 of 592 (37.7%). Common specific diagnoses included Warthin tumor, lymphoma subtypes, and metastatic squamous cell carcinoma for CNB and IB, in addition to pleomorphic adenoma for CNB. Descriptive diagnoses were still frequent. Nondiagnostic rates were higher in CNB (26 of 356; 7.30%) than IB (5 of 236; 2.12%; P <.001). Tissue volumes significantly influenced CNB adequacy, with minimum and optimal volumes of 4.76 mm³ (J index, receiver operating characteristic curve) and 12.92 mm³ (95th percentile of distribution), respectively. One hundred forty-four patients (112 CNBs) had follow-up resections; diagnoses were concordant for 66 of 73 adequate CNBs (90.41%). Our restructured risk grouping of MSRSGC categories performed robustly in terms of risk of malignancy (sensitivity = 85.5%, specificity = 100%, accuracy = 92.3%, area under the curve = 0.9677). CONCLUSIONS.­: Although CNB and IB are amenable to a risk stratification system, there are some differences as compared with fine-needle aspiration biopsy, particularly given the high baseline prevalence of malignancy. Specific diagnoses are often feasible and concordant with resection. CNB tissue volume can inform optimal and minimal sampling recommendations for adequacy.

Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

A Novel Scoring System for MYB RNA In Situ Hybridization Displays High Sensitivity and Specificity for Adenoid Cystic Carcinoma in a Clinical Setting.

BACKGROUND: MYB RNA in situ hybridization (ISH) has emerged as a reliable and accessible marker to support adenoid cystic carcinoma (ACC) diagnosis, though still not well studied. Here, we report our results in a validation and prospective cohort to improve MYB RNA ISH diagnostic accuracy. METHODS: 79 cases (23 retrospective and 56 prospective) underwent MYB RNA ISH testing (44 ACC and 35 non-ACC). MYB RNA ISH results were initially interpreted based on previously established (original) scoring criteria. Weighted "i-scores", percent positive tumor cells, percent tumor cells with large signals (% LS), and staining pattern (abluminal, diffuse, focal non-patterned, or negative) were inputs for logistic regression models. Final model performance characteristics were compared with original scoring criteria and MYB::NFIB FISH results. RESULTS: An abluminal pattern was characteristic and exclusive to ACC. All i-scores, % LS, and percent positive were significantly higher in ACC. Original scoring criteria yielded a 95.5% sensitivity (Sn), 68.6% specificity (Sp), and 83.5% accuracy. MYB::NFIB FISH yielded a 42.9% sensitivity, 100% specificity, and 60% accuracy. Optimizing for performance, simplicity, and minimal collinearity, our final model was defined as: abluminal pattern and/or % LS > 16.5%, which resulted in a 93.2% Sn, 97.1% Sp, and 94.9% accuracy for ACC diagnosis. False negatives included an ACC with striking tubular eosinophilia and a MYBL1::NFIB translocated ACC. One false positive exclusive to the final model was a nasopharyngeal carcinoma with MYB amplification. CONCLUSIONS: MYB RNA ISH has a higher Sn than MYB::NFIB FISH while retaining high Sp. Our model provides improvements to specificity compared to original scoring criteria and highlight the importance of abluminal staining pattern and % LS. Nonetheless, alternate fusions remain key false negatives while rare non-ACC with other mechanisms of MYB activation may present as false positives.

Seven years of Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Rate of Acceptance and Variation of Diagnostic Approaches Across Different Continents.

CONTEXT: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a new entity replacing the diagnosis of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC). Significant variability in the incidence of NIFTP diagnosed in different world regions has been reported. OBJECTIVE: To investigate the rate of adoption of NIFTP, change in practice patterns, and uniformity in applying diagnostic criteria among pathologists practicing in different regions. METHODS: Two surveys distributed to pathologists of the International Endocrine Pathology Discussion Group with multiple-choice questions on NIFTP adoption into pathology practice and whole slide images of 5 tumors to collect information on nuclear score and diagnosis. Forty-eight endocrine pathologists, including 24 from North America, 8 from Europe, and 16 from Asia/Oceania completed the first survey and 38 the second survey. RESULTS: A 94% adoption rate of NIFTP by the pathologists was found. Yet, the frequency of rendering NIFTP diagnosis was significantly higher in North America than in other regions (P = .009). While the highest concordance was found in diagnosing lesions with mildly or well-developed PTC-like nuclei, there was significant variability in nuclear scoring and diagnosing NIFTP for tumors with moderate nuclear changes (nuclear score 2) (case 2, P < .05). Pathologists practicing in North America and Europe showed a tendency for lower thresholds for PTC-like nuclei and NIFTP than those practicing in Asia/Oceania. CONCLUSION: Despite a high adoption rate of NIFTP across geographic regions, NIFTP is diagnosed more often by pathologists in North America. Significant differences remain in diagnosing intermediate PTC-like nuclei and respectively NIFTP, with more conservative nuclear scoring in Asia/Oceania, which may explain the geographic differences in NIFTP incidence.

Acinic cell Carcinoma with high-grade Squamoglandular and Chondrosarcomatous Transformation Mimicking 'Carcinosarcoma ex-pleomorphic Adenoma': A Wrinkle in the Proposed Nomenclature Revision for Sarcomatoid Salivary Gland Neoplasms.

While acinic cell carcinoma (AciCC) can undergo high-grade transformation (HGT) to high-grade adenocarcinoma or poorly differentiated carcinoma, other morphologies such as spindle cell/sarcomatoid carcinoma are rare and not well-characterized. We herein report a novel case of AciCC with squamoglandular and chondrosarcomatous HGT mimicking a so-called 'carcinosarcoma ex-pleomorphic adenoma'. The patient is an 81-year-old male with a two-month history of neck swelling and referred otalgia who presented with a left parapharyngeal space mass extending into retropharyngeal space and pterygoid muscles. On resection, the tumor showed considerable morphologic diversity with high-grade serous and mucous acinar components as well as cribriform to solid apocrine-like components with comedonecrosis and squamous differentiation, all of which were embedded in a chondromyxoid background ranging from paucicellular and bland to a high-grade chondrosarcoma/pleomorphic sarcoma-like appearance. Only a minor conventional AciCC component was noted. Immunostains were negative for AR and only focally positive for GCDFP-15 arguing against a true apocrine phenotype, while PLAG1 and HMGA2 were negative arguing against an antecedent pleomorphic adenoma. On the other hand, SOX-10, DOG-1 and PAS after diastase highlighted serous acinar differentiation, and mucicarmine, and NKX3.1 highlighted mucous acinar differentiation. NR4A3 immunohistochemical staining and NR4A3 fluorescence in situ hybridization were positive in the carcinomatous and sarcomatoid components while sequencing analysis of both components revealed identical alterations involving TP53, PIK3CB, ARID1A, and STK11. This unique case warrants caution in designating all salivary sarcomatoid carcinomas with heterologous elements as part of the 'carcinoma ex-pleomorphic adenoma' family.

High-Grade Transformation and Carcinosarcoma.

CONTEXT.­: High-grade transformation, previously known as dedifferentiation, in salivary gland carcinoma and carcinosarcoma ex pleomorphic adenoma is a rare phenomenon. It is, however, clinically relevant and affects treatment and prognosis. OBJECTIVE.­: To review the existing literature, describe the histologic and immunophenotypic features, and highlight the diagnostic criteria of high-grade transformation in various salivary gland carcinomas and carcinosarcoma; to review its effect on clinical presentation and prognosis; and to review relevant molecular characteristics and recent concepts and advances. DATA SOURCES.­: Literature search in PubMed using key words such as "high-grade transformation," "dedifferentiation," and "carcinosarcoma" in salivary gland. Relevant articles were reviewed, and additional articles were curated from the references of these articles. CONCLUSIONS.­: High-grade transformation occurs rarely but has a significant impact on prognosis and management. By microscopy, the high-grade area is usually a distinct nodule and shows solid and nested architecture, cellular atypia, high mitotic count, and necrosis. The molecular features are not well established. Carcinosarcoma almost always arises in a pleomorphic adenoma and likely follows an adenoma-carcinoma-sarcoma pathway.

The Journey to Improve the College of American Pathologists Cancer Biomarker Reporting Protocols.

CONTEXT.­: Biomarker reporting has increasingly become a key component of pathology reporting, providing diagnostic, prognostic, and actionable therapeutic data for patient care. OBJECTIVE.­: To expand and improve the College of American Pathologists (CAP) biomarker protocols. DESIGN.­: We surveyed CAP members to better understand the limitations they experienced when reporting cancer biomarker results. A Biomarker Workgroup reviewed the survey results and developed a strategy to improve and standardize biomarker reporting. Drafts of new and revised biomarker protocols were reviewed in both print and electronic template formats during interactive webinars presented to the CAP House of Delegates. Feedback was collected, and appropriate revisions were made to finalize the protocols. RESULTS.­: The first phase of the CAP Biomarker Workgroup saw the development of (1) a new stand-alone general Immunohistochemistry Biomarker Protocol that includes reporting for ER (estrogen receptor), PR (progesterone receptor), Ki-67, HER2 (human epidermal growth factor receptor 2), PD-L1 (programmed death ligand-1), and mismatch repair; (2) a new Head and Neck Biomarker Protocol that updates the prior 2017 paper-only version into an electronic template, adding new diagnostic and theranostic markers; (3) a major revision to the Lung Biomarker Protocol to streamline it and add in pan-cancer markers; and (4) a revision to the Colon and Rectum Biomarker Protocol to add HER2 reporting. CONCLUSIONS.­: We have taken a multipronged approach to improving biomarker reporting in the CAP cancer protocols. We continue to review current biomarker reporting protocols to reduce and eliminate unnecessary methodologic details and update with new markers as needed. The biomarker templates will serve as standardized modular units that can be inserted into cancer-reporting protocols.

Molecular-derived risk of malignancy and the related positive call rate of indeterminate thyroid cytology diagnoses as quality metrics for individual cytopathologists.

BACKGROUND: Indeterminate thyroid cytopathology diagnoses represent differing degrees of risk that are corroborated by follow-up studies. However, traditional cytologic-histologic correlation may overestimate the risk of malignancy (ROM) because only a subset of cases undergo resection. Alternatively, some molecular tests provide probability of malignancy data to calculate the molecular-derived risk of malignancy (MDROM) and the positive call rate (PCR). The authors investigated MDROMs and PCRs of indeterminate diagnoses for individual cytopathologists as quality metrics. METHODS: This study was approved by the Department of Pathology Quality Improvement Program. Thyroid cytopathology diagnoses and ThyroSeq v3 results were retrieved for each cytopathologist for a 2-year period with at least 3 years of follow-up for the atypia of undetermined significance (AUS), follicular neoplasia (FN), and follicular neoplasia, oncocytic-type (ONC) cytopathologic diagnoses. MDROMs and PCRs were compared with reference ROMs and cytologic-histologic correlation outcomes. RESULTS: The overall MDROMs (and ranges for cytopathologists) for the AUS, FN, and ONC categories were 13.4% (range, 5.8%-20.8%), 28.1% (range, 22.1%-36.7%), and 27.0% (range, 19.5%-41.5%), respectively, and most individual cytopathologists' MDROMs were within reference ROM ranges. However, PCRs more effectively parsed the differences in cytopathologists' ROM performance. Although the overall PCRs were not significantly different across cytopathologists (p = .06), the AUS PCRs were quite different (p = .002). By cytologic-histologic correlation, six of 55 resected cases (10.9%) were falsely negative, and there were no false-positive cases. CONCLUSIONS: MDROMs and PCRs evaluate concordance with reference ROMs and with one another and provide individual feedback, which potentially facilitates quality improvement.

Biphenotypic Sinonasal Sarcoma With High-Grade Features: A Diagnostic Challenge.

Biphenotypic sinonasal sarcoma (BSNS) is a rare neoplasm of the sinonasal tract. These tumors show neural and myogenic differentiation and are characterized by PAX3 translocations. The immunophenotypic features reflect their dual differentiation. They are low-grade sarcomas that show monomorphic spindle cells in sheets, fascicles, and herringbone patterns and are positive for S100 and smooth muscle actin. These tumors are common in elderly female patients and have a locally aggressive course. High-grade presentation or transformation was not documented until recently. Total 3 BSNSs have now been documented in the literature and we report a fourth tumor with high-grade transformation 8 years after the initial presentation. We identify the morphologic and immunohistochemical features of the high-grade areas and we highlight the stark differences with the low-grade areas based on literature and our specimen. We also discuss the diagnostic challenges that may come up with such a presentation.

Glomangiosarcoma-like Anaplastic Transformation in Papillary Thyroid Carcinoma: A Novel Form of Heterologous Differentiation and a Systematic Review of Heterologous Element Prevalence.

Anaplastic thyroid carcinoma (ATC) demonstrates a wide variety of morphologies and is characteristically associated with a differentiated thyroid carcinoma component. Heterologous differentiation is a rare, potentially challenging phenomenon in ATC, mostly observed as osteosarcomatous or chondrosarcomatous differentiation. We now describe a novel 'glomangiosarcoma-like' differentiation, review our archival experience from two institutions (UPMC, CC), and perform a systematic review for the prevalence of heterologous elements in ATC. The patient is a 57-year-old female who presented with 4.5 cm left thyroid, and 3.4 cm neck masses. Histologically, the thyroid demonstrated a differentiated high grade papillary thyroid carcinoma, tall cell and hobnail/micropapillary subtypes transitioning into an anaplastic component with spindled to ovoid cells with hemangiopericytoma-like vasculature showing CD34 positivity, variable muscle marker expression and pericellular lace-like type IV collagen deposition. The neck mass consisted solely of the latter morphology. Targeted next-generation sequencing was performed on high grade DTC and adjacent ATC from the thyroid as well as ATC from the neck metastasis. All three components shared BRAFV600E, TERT promoter, and PIK3CA mutations confirming a clonal origin. Archival (UPMC: n = 150, CC: n = 74) and literature review showed no prior examples. Systematic review and meta-analysis of prevalence showed a baseline pooled prevalence (generalized linear mixed model) of heterologous elements of any type to be 1.6% (95% confidence interval: 1.0-2.6%) for studies where this was specifically addressed. ATC with glomangiosarcoma-like heterologous differentiation is a rarity among an already rare morphologic category with unique diagnostic pitfalls.

True Oncocytic Acinic Cell Carcinoma: A Case Image.

A 67-year-old female with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presented with right sided otalgia and a 2-3 cm firm, tender right posterior parotid mass. Fine needle aspiration biopsy (FNAB) established a diagnosis of acinic cell carcinoma (AciCC). Further workup demonstrated lung nodules which were confirmed by FNAB to represent metastatic AciCC. A right radical parotidectomy with sacrifice of the facial nerve, segmental mandibulectomy, and selective neck dissection (levels II-IV) was performed. Microscopically, the tumor displayed an infiltrative border with a solid multinodular growth pattern and fibrosclerotic septation. The tumor was composed mainly of uniform cells with abundant eosinophilic granular cytoplasm with round nuclei with prominent nucleoli. Nuclei were fairly monomorphic, mitotic counts were 3-4 per 2mm2 and there was no necrosis despite the aggressive growth pattern. An anti-mitochondrial immunohistochemical stain showed strong reactivity in the tumor cells, with an internal positive control of adjacent striated ducts. An immunohistochemical stain for NR4A3 demonstrated strong nuclear reactivity in the tumor cells. Electron microscopy highlighted the tumor cells with numerous mitochondria and distinctive electron dense intramitochondrial inclusions. Concurrent CLL/SLL was identified on histologic examination of the lymph nodes, but they were free of AciCC. After eight weeks of follow-up, she tolerated the surgery well and is currently receiving radiation therapy to the parotid and neck. In this illustrative case, we justify the oncocytic designation of AciCC by morphology, immunohistochemistry, and electron microscopy.

New Entities and Concepts in Salivary Gland Tumor Pathology: The Role of Molecular Alterations.

CONTEXT.­: Salivary gland tumors are rare tumor types for which the molecular understanding has resulted in a rapid expansion and shuffling of entities. These changes are reflected in the 5th edition World Health Organization Classification of Head and Neck Tumours (WHO 5th edition), although many nuances still remain. OBJECTIVE.­: To review how molecular alterations have helped recategorize, justify, and reinstate entities into our lexicon as well as defining interrelationships between categories, new entities, and subtypes. Furthermore, newer theranostic applications to molecular phenotype will be summarized. DATA SOURCES.­: World Health Organization Classification of Head and Neck Tumours (WHO 3rd through 5th editions), literature review, personal and institutional experience. CONCLUSIONS.­: Molecular alterations have helped reclassify, retain, and create new categories by augmenting rather than replacing standard criteria. Key entities that have emerged include sclerosing polycystic adenoma, microsecretory adenocarcinoma, and mucinous adenocarcinoma. Molecular phenotypes solidify the range of morphology in established entities such as mucoepidermoid carcinoma and facilitate connectivity between entities. Molecular characteristics now allow for targeted therapeutic approaches for secretory carcinoma and adenoid cystic carcinoma.

Solitary sclerotic fibroma of the palpebral conjunctiva: a unique presentation of a rare entity.

Sclerotic fibroma (SF) is an uncommon yet benign tumor that may occasionally be associated with Cowden's disease that presents as an asymptomatic, well-circumscribed lesion. We present a rare case of a patient with a solitary SF of the palpebral conjunctiva. The patient was an 85-year-old male who presented with a right lower lid nodule that was initially treated as a chalazion. Excision yielded a dense mass that was sent to pathology for evaluation. Histologically, the lesion showed a bland storiform spindle cell proliferation embedded in a sclerotic stroma with prominent clefting.

Odontogenic Carcinosarcoma: Clinicopathologic and Molecular Features of Three Cases, a Literature Review and Nomenclature Proposal.

BACKGROUND: Odontogenic carcinosarcoma (OCS) is a rare odontogenic malignancy with limited characterization and unexplored molecular features. We report clinicopathologic and molecular findings in 3 additional OCS and review the literature. METHODS: 3 OCS (5.1%) were identified among 59 malignant odontogenic tumors (in our archives from 1992 to 2022). Clinical, radiologic, histopathologic, immunophenotypic, and molecular findings were reviewed. Data from prior case reports and systematic or non-systematic reviews were extracted for analysis. RESULTS: Three mandibular OCS (age range: 66 to 72 years; 1 male, 2 females) were identified. Case 1 had novel clear-cell morphology, multiple recurrences, and a lethal outcome 28 months after resection. EWSR1 rearrangements were negative, but the tumor showed focal nuclear ß-catenin and strong LEF-1 immunoreactivity. Case 2 demonstrated ameloblastic and sclerosing features and encased the inferior alveolar nerve; the patient was disease-free 22 months after resection with adjuvant chemoradiation therapy. LEF-1 was again strongly positive, and next-generation sequencing demonstrated 9p region-(CDKN2A, CDKN2B) copy number loss, and 12q region-(MDM2, CDK4) copy number gain. Case 3 showed clear-cell and markedly sclerosing features; no follow-up information was available. Literature review along with the current cases yielded 20 cases. OCS showed a male predilection (1.5:1), mandibular predominance (80%, typically posterior), and a bimodal age distribution (modes: 27.7 years, 62.7 years). OCS presented as masses (100%), often with pain (55%), and paresthesia (45%). Tumors were typically radiolucent (88.9%), with bone destruction (61.1%), and/or tooth effacement (27.8%). Preoperative biopsy was sensitive for malignancy (85.7%). At least 45% show evidence for a precursor lesion. 3-year DSS and DFS were 58% and 35%, respectively. Regional and distant (usually lung) metastatic rates were 25% and 31.3%, respectively. Increased mitotic rates and presence of tumor necrosis trended toward worse DSS and DFS. CONCLUSION: OCS is a rare but aggressive malignancy, often arising from precursor tumors and may represent a terminal phenotype rather than a distinct entity. We describe novel clear-cell and sclerosing morphologies. Wnt pathway alterations appear important. Mitotic rates and necrosis may be adverse prognosticators. In keeping with nomenclature trends in other sites, OCS may be more appropriately designated as "biphasic sarcomatoid odontogenic carcinomas."