Faculty Bibliography

Cystic degeneration of thymoma can occur, although rarely to the extent that the lesion appears entirely cystic. We present a case of a 26-year-old man with a large anterior mediastinal cyst that was resected with histopathologic examination revealing a cystic thymoma.

Ca2+ signaling via the store operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 (Stim1/2K14Cre(+)) in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD.

Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T_reg) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T_reg cells depend on store-operated Ca²⁺ entry (SOCE), which is mediated by ORAI1 Ca²⁺ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3⁺ T_reg cell-specific deletion of Stim1 and Stim2 develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (T_H1) and interferon (IFN) signaling. CD4⁺ T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ-dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4⁺ T cell-induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4⁺ T cells from patients with SjD, which indicate enhanced T_H1 but reduced memory T_reg cell function. Together, our study provides evidence for a critical role of dysfunctional T_reg cells and IFN-γ-producing T_H1 cells in the pathogenesis of SjD.

CONTEXT.—/UNASSIGNED:Adenocarcinomas are the most common histologic subtype of lung cancer, and exist within a widely divergent clinical, radiologic, molecular, and histologic spectrum. There is a strong association between histologic patterns and prognosis that served as the basis for a recently described grading system. As the study of molecular pathology rapidly evolves, all targetable mutations so far have been found in adenocarcinomas, thus requiring accurate diagnosis and classification for triage of molecular alterations and adequate therapy. OBJECTIVE.—/UNASSIGNED:To discuss the rationale for adenocarcinoma classifications within the 2021 5th edition of the World Health Organization, with a focus on nonmucinous tumors, including tumor grading and biopsy/cytology diagnosis. DATA SOURCES.—/UNASSIGNED:PubMed search. CONCLUSIONS.—/UNASSIGNED:A grading system for adenocarcinoma has improved prognostic impact of the classification of pulmonary adenocarcinoma. An accurate diagnosis of adenocarcinoma in small biopsy material is important for tissue triage for molecular studies and ultimately for patient management and treatment.

Tumors of the major and minor salivary glands histologically encompass a diverse and partly overlapping spectrum of frequent diagnostically challenging neoplasms. Despite recent advances in molecular testing and the identification of tumor-specific mutations or gene fusions, there is an unmet need to identify additional diagnostic biomarkers for entities lacking specific alterations. In this study, we collected a comprehensive cohort of 363 cases encompassing 20 different salivary gland tumor entities and explored the potential of DNA methylation to classify these tumors. We were able to show that most entities show specific epigenetic signatures and present a machine learning algorithm that achieved a mean balanced accuracy of 0.991. Of note, we showed that cribriform adenocarcinoma is epigenetically distinct from classical polymorphous adenocarcinoma, which could support risk stratification of these tumors. Myoepithelioma and pleomorphic adenoma form a uniform epigenetic class, supporting the theory of a single entity with a broad but continuous morphologic spectrum. Furthermore, we identified a histomorphologically heterogeneous but epigenetically distinct class that could represent a novel tumor entity. In conclusion, our study provides a comprehensive resource of the DNA methylation landscape of salivary gland tumors. Our data provide novel insight into disputed entities and show the potential of DNA methylation to identify new tumor classes. Furthermore, in future, our machine learning classifier could support the histopathologic diagnosis of salivary gland tumors.

OBJECTIVES/OBJECTIVE:Fine needle aspiration (FNA) plays a crucial role in their initial assessment of salivary gland neoplasms. In the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC), the category of Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP) categorizes lesions with ambiguous features. This study aims to investigate the risk of neoplasm (RON) and risk of malignancy (ROM) within different subgroups of SUMP lesions using data from three large academic institutions. METHODS:We analyzed salivary gland (FNA) cases from three academic institutions post-MSRSGC implementation. Salivary gland FNA cases categorized as Milan IVB (SUMP) with subsequent surgical pathology follow-up were analyzed. Cases were divided into basaloid, oncocytic, and clear cell SUMP subtypes, with RON and ROM assessed and compared. RESULTS:Out of 1377 MSRSGC cases, 231 were SUMP (16.8%), with 101 subjected to surgical pathology follow-up. The overall ROM for SUMP was 20.8%, with variations of 10% to 29.5% observed amongst institutions, but no significant difference was observed among three institutions (p = 0.15). Basaloid and oncocytic SUMP displayed 17.1% and 20.5% ROM, respectively, without significant disparity. However, all clear cell SUMP cases were malignant on surgical resection. CONCLUSIONS:This study highlights the variability in ROM for SUMP lesions and the significantly higher ROM in SUMP cases with clear cell features. These findings emphasize the importance of accurately subcategorizing SUMP lesions, particularly those with clear cell features, for appropriate clinical management.

TOPIC IMPORTANCE/UNASSIGNED:Chest CT imaging holds a major role in the diagnosis of lung diseases, many of which affect the peribronchovascular region. Identification and categorization of peribronchovascular abnormalities on CT imaging can assist in formulating a differential diagnosis and directing further diagnostic evaluation. REVIEW FINDINGS/RESULTS:The peribronchovascular region of the lung encompasses the pulmonary arteries, airways, and lung interstitium. Understanding disease processes associated with structures of the peribronchovascular region and their appearances on CT imaging aids in prompt diagnosis. This article reviews current knowledge in anatomic and pathologic features of the lung interstitium composed of intercommunicating prelymphatic spaces, lymphatics, collagen bundles, lymph nodes, and bronchial arteries; diffuse lung diseases that present in a peribronchovascular distribution; and an approach to classifying diseases according to patterns of imaging presentations. Lung peribronchovascular diseases can appear on CT imaging as diffuse thickening, fibrosis, masses or masslike consolidation, ground-glass or air space consolidation, and cysts, acknowledging that some diseases may have multiple presentations. SUMMARY/CONCLUSIONS:A category approach to peribronchovascular diseases on CT imaging can be integrated with clinical features as part of a multidisciplinary approach for disease diagnosis.

Marantic endocarditis is defined as a sterile endocarditis that is rarely encountered in clinical practice. This case series illustrates five cases of marantic endocarditis. All cases were diagnosed on trans thoracic echocardiography and verified on transesophageal echocardiography. The first three cases occur in the setting of antiphospholipid syndrome; the last two occur in the setting of advanced malignancy. Two cases were treated successfully with anticoagulation, while two others required valvular surgery. One case resulted in mortality. The treatment course of these five patients mirrors certain patterns described in the literature.

Lung adenocarcinoma staging and grading were recently updated to reflect the link between histologic growth patterns and outcomes. The lepidic growth pattern is regarded as "in-situ," whereas all other patterns are regarded as invasive, though with stratification. Solid, micropapillary, and complex glandular patterns are associated with worse prognosis than papillary and acinar patterns. These recent changes have improved prognostic stratification. However, multiple pitfalls exist in measuring invasive size and in classifying lung adenocarcinoma growth patterns. Awareness of these limitations and recommended practices will help the pathology community achieve consistent prognostic performance and potentially contribute to improved patient management.