Faculty Bibliography

INTRODUCTION/BACKGROUND:Papillary thyroid cancer (PTC) often follows an indolent course with a favorable prognosis. This has led to evolving guideline-based, low-intensity treatment options for low-risk patients. Recently, the purported benefit of total thyroidectomy (TT) over unilateral lobectomy for PTC with clinical lateral neck nodal metastasis (cN1b) has come into question. MATERIALS AND METHODS/METHODS:A retrospective analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results database was performed to study patients with PTC with ipsilateral cN1b disease from 1975 to 2020. Kaplan-Meier curves and log-rank tests were used to compare disease-specific survival (DSS) difference between lobectomy and TT at 10 y. Multivariable Cox proportional hazards analysis was performed to determine the independent association of lobectomy versus TT with DSS, correcting for age and lymph node ratio, defined as the ratio of pathologically positive lymph nodes to total number examined. RESULTS:Among 2943 patients (median [interquartile range] age, 45 [26] y), 42 underwent lobectomy and 2901 underwent TT. Unadjusted DSS at 10 y in the lobectomy and TT groups were 51.0% (95% confidence interval, 31.4%-82.8%) and 86.8% (95% confidence interval, 84.8%-88.9%), respectively. On multivariable analysis of all patients, older age (hazard ratio [HR], 1.08; P < 0.001) and male gender (HR, 1.74; P < 0.001) were associated with lower adjusted DSS, whereas treatment with TT (HR, 0.387; P = 0.005) and receipt of radioactive iodine (RAI) (HR, 0.604; P < 0.001) were associated with improved adjusted DSS. In addition, we observed that the magnitude of survival benefit conferred by RAI and TT were reduced with decreasing age (P < 0.001). CONCLUSIONS:This longitudinal cohort study suggests that, while TT is associated with a DSS benefit in most patients with PTC and ipsilateral cN1b disease, this association may not exist in a smaller cohort of younger patients. These findings raise the possibility that unilateral surgical clearance without RAI could offer adequate oncologic outcomes in selected younger individuals; however, further investigation is warranted to confirm these observations and inform clinical decision-making.

INTRODUCTION/UNASSIGNED:Outcomes for NSCLC remain suboptimal. Recent data suggest that cryoablation can generate antitumor immune effects. In this first-in-human phase I clinical trial, we investigated the safety and feasibility of bronchoscopic cryoimmunotherapy (BCI) delivered during standard-of-care bronchoscopy and explored associated systemic immune responses. METHODS/UNASSIGNED:Subjects with known or suspected advanced-stage NSCLC were recruited. BCI was delivered in dose-escalated freeze-thaw cycles to determine maximum dose tolerance. Feasibility assessment was determined with a pre-set goal of achieving successful BCI in more than or equal to 80% of subjects. Safety was assessed by review of BCI-related complications, including grades 2 to 3 bleeding, pneumothorax requiring intervention, and National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 to 5 adverse events. Pre- and post-BCI blood samples were collected to explore changes in the systemic immune profile. RESULTS/UNASSIGNED:Subjects with predominantly clinical TNM stage 3 or 4 adenocarcinoma or squamous cell carcinoma were enrolled. We reached the maximum dose of 30 seconds with 100% feasibility and no BCI-related adverse events. In peripheral blood analysis, we observed a significant decrease in derived neutrophil-to-lymphocyte ratio in the high-dose BCI group in comparison to the low-dose BCI cohort. We also observed increases in inflammatory cytokines-GM-CSF, IFN-γ, IL-1β, IL-17A, and IL-2-and effector memory T cells post-BCI. CONCLUSION/UNASSIGNED:BCI is safe and feasible. In addition, we provide preliminary evidence that at higher dose levels there is a systemic immune response consistent with a cytotoxic profile. Further immune analyses will determine the potential of BCI as an adjunctive therapy in combination with immune checkpoint inhibition in NSCLC treatment.

Pulmonary high attenuation may be caused by calcification or ossification, both of which are common phenomena with distinct pathogeneses, histologies, and radiologic appearances. Pulmonary calcification is divided into metastatic pulmonary calcification (MPC), caused by systemic hypercalcemia, and dystrophic pulmonary calcification (DPC), caused by local lung injury. MPC often demonstrates diffuse calcified nodules, which can be subtle and amorphous on CT images, with associated sandlike, fine ground-glass, or consolidative opacities. Conversely, DPC often appears nodular and is localized to areas of lung injury and thus is associated with other signs of lung damage, such as prior infection, fibrosis, or scarring. In contrast to calcification, pulmonary ossification is not a consequence of a localized or systemic metabolic abnormality but instead is found in the setting of chronic lung disease, which induces fibroblast-to-osteoblast transformation and bone deposition. Pulmonary ossification can be divided into nodular (NPO) and dendriform (DPO) patterns. NPO often appears as multiple small well-defined round nodules that are uniform in size and appearance. NPO classically is seen with chronic venous congestion in a subpleural predominant distribution and increasingly is recognized in pathologic findings in the setting of fibrosing interstitial lung disease (ILD). DPO appears more commonly as peripheral irregular branching opacities and can be seen with ILD. Additionally, pulmonary calcification or ossification can occur in association with protein deposition disease, including pulmonary amyloidosis, or in benign neoplasms or metastatic malignancies. Pulmonary alveolar microlithiasis is a distinct entity relating to phosphate metabolism. Pulmonary calcification and ossification can provide insight into patients' underlying disease processes and clinical context for radiologic study interpretation. ^©RSNA, 2025 Supplemental material is available for this article.

There is a body-wide network of interstitial spaces that includes three components: a large-scale fascial network made up of fluid-filled spaces containing collagens and other extracellular matrix components like hyaluronic acid (HA), the peri-vascular/capillary interstitium, and intercellular interstitial spaces. Staining for HA within the colon, skin, and liver has demonstrated spatial continuity of the fascial interstitium across tissue layers and between organs, while continuity of HA staining between perineurial and adventitial sheathes beyond organ boundaries confirmed that they also participate in this body-wide network. We asked whether the pulmonary interstitium comprises a continuous organ-wide network that also connects to the body-wide interstitium via routes along nerves and the vasculature. We studied archival lung lobectomy specimens containing normal tissues inclusive of all lung anatomical units from six females and three males (mean age 53+/- 16.5 years). For comparison, we also studied normal mouse lung. Multiplex immunohistochemical cocktails were used to identify: (1) HA, CD34, and vimentin - highlighting interstitium; (2) HA, CD34, and podoplanin (D2-40) - highlighting relationships between the interstitium, vasculature, and lymphatics. Sizes of extracellular APP were measured. Tissues from nine patients (six females, three males, mean age 53+/- 16.5 years) were studied. HA staining was continuous throughout the five major anatomic compartments of the lung: alveolar walls, subpleural connective tissue, centrilobular peribronchovascular compartment, interlobular septal compartment, and axial peribronchovascular of the hilum, with similar findings in murine lung tissue. Continuity with interstitial spaces of the perineurium and adventitia was confirmed. The distribution of APP corresponded to known routes of lymphatic drainage, superficial and deep. APP within perineurium and perivascular adventitia further demonstrated continuity between intra- and extrapulmonary interstitium. To conclude, all segments of the lung interstitium are connected and are linked along nerves and the vascular tree to a body-wide communication network. These findings have significant implications for understanding lung physiology and pathobiology, suggesting routes of passage for inflammatory cells and mediators, malignant cells, and infectious agents. Interstitial spaces may be important in microbiome signaling within and beyond the lung and may be a component of the lung-brain axis.

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.

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.

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.