Faculty Bibliography

Lung transplant is increasingly performed for the treatment of end-stage lung disease. As the number of lung transplants and transplant centers continues to rise, radiologists will more frequently participate in the care of patients undergoing lung transplant, both before and after transplant. Potential donors and recipients undergo chest radiography and CT as part of their pretransplant assessment to evaluate for contraindications to transplant and to aid in surgical planning. After transplant, recipients undergo imaging during the postoperative hospitalization and also in the long-term outpatient setting. Radiologists encounter a wide variety of conditions leading to end-stage lung disease and a myriad of posttransplant complications, some of which are unique to lung transplantation. Familiarity with these pathologic conditions, including their imaging findings and their temporal relationship to the transplant, is crucial to accurate radiologic interpretation. Knowledge of the surgical techniques and expected postoperative appearance prevents confusing normal posttransplant imaging findings with complications. A basic understanding of the indications, contraindications, and surgical considerations of lung transplant aids in imaging interpretation and protocoling and also facilitates communication between radiologists and transplant physicians. Despite medical and surgical advances over the past several decades, lung transplant recipients currently have an average posttransplant life expectancy of only 6.7 years. As members of the transplant team, radiologists can help maximize patient survival and hopefully increase posttransplant life expectancy and quality of life in the coming decades. ^©RSNA, 2021 An invited commentary by Bierhals is available online. Online supplemental material is available for this article.

OBJECTIVES/OBJECTIVE:To describe the histologic features that are helpful in the diagnosis of the rare bronchiolar adenomas/ciliated muconodular papillary tumors (BAs/CMPTs) during intraoperative consultation. METHODS:Multi-institutional retrospective review of frozen sections of 18 BAs/CMPTs. RESULTS:In 14 of 18 cases, BA/CMPT was the primary reason for sublobar lung resection, and in 4 cases, BA/CMPT was an incidental finding intraoperatively for resections performed for carcinoma in other lobes. There were 11 proximal-type/classic BAs/CMPTs and 7 distal-type/nonclassic BAs/CMPTs. Only 3 (16.7%) of 18 were correctly diagnosed at the time of frozen section, all of which were proximal type/classic. The remainder were diagnosed as adenocarcinoma (n = 7); invasive mucinous adenocarcinoma (n = 1); non-small cell lung carcinoma (n = 1); cystic mucinous neoplasm, favor adenocarcinoma (either mucinous or colloid type) (n = 1); favor adenocarcinoma, cannot exclude CMPT (n = 1); atypical proliferation (n = 2); mucinous epithelial proliferation (n = 1); and mucous gland adenoma (n = 1). CONCLUSIONS:BA/CMPT can potentially be misdiagnosed as carcinoma during intraoperative consultation. On retrospective review of the frozen sections, the presence of the following may help to avoid misdiagnosis: a mixture of bland ciliated columnar cells, mucinous cells, and, most important, a basal cell layer, as well as a lack of necrosis, significant atypia, and mitoses.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

Rationale:Malignant pleural mesothelioma(MPM) has a poor prognosis with median survival of 12-24 months. We are not aware of prior studies examining the immune microenvironment in tumor draining lymph nodes (TDLN) in MPM. Our aim is to compare the tumor microenvironment(TME) and the microenvironment of TDLN. We hypothesize that the TME will display an immunosuppressive phenotype reflected in the TDLN.
Method(s):We performed digital spatial profiling(DSP) using the GeoMx (NanoString) platform on stored primary tumor and nodal biopsy specimens from 3 patients from our tumor bank. Samples from both primary tumor and lymph nodes were sectioned and labeled with pancytokeratin (CK). Tissue was then classified as "tumor" or "nontumor" using semi-automated segmentation based on pan-Cytokeratin (panK) labeling. The slides were then labeled with antibodies to 58 selected markers, with each unique antibody attached to a respective oligonucleotide. The tissue was exposed to UV light separately for tumor and non-tumor regions, cleaving the oligonucleotides from the attached antibodies. The oligonucleotides from the separate tumor and non-tumor regions were quantified using nCounter (NanoString).
Result(s):The non-neoplastic regions of the primary tumor contained higher expression of proteins associated with inflammatory cells including helper T-cells, cytotoxic T-cells, B-cells, macrophages, neutrophils, natural killer cells(Table 1). Furthermore, there was greater expression of immune checkpoint proteins, PD-L1 and CTLA-4, and CD163 and CD14, proteins associated with immunosuppressive macrophages, in the non-neoplastic region compared to the neoplastic region of the tumoe(Table 1). TDLNs contained similar levels of expression of lymphocyte markers, including those delineating cytotoxic T-cells and helper T-cells, as the primary tumor(Table 1). Despite this, TME expressed higher levels of T-cell exhaustion and immunsupression markers (FOXP3, LAG3, PD-1, CTLA-4) than TDLN(Table 1).
Conclusion(s):DSP is feasible in Formalin-fixed paraffin embedded (FFPE) mesothelioma specimens, providing a method for using quantitative immunopathology to study corresponding immune microenvironments. In our study, the non-tumor region of the primary tumor contained macrophages, lymphocytes, natural killer cells, and cancer-associated fibroblasts consistent with prior descriptions of the mesothelioma TME. Increased expression of immune checkpoint molecules in the non-tumor region suggests an immunosuppressive TME. TDLNs demonstrated similar lymphocyte markers, but without corresponding immune checkpoint expression of t suggesting the immunosuppressive phenotype of the TME may not be reflected in TDLNs. This pilot study is the first to use DSP to preliminarily characterize TDLNs in mesothelioma. We plan to apply this approach to stored additional MPM and NSCLC specimens to gain an in-depth understanding of the relationship between TME and TDLN

INTRODUCTION:Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is required to determine the eligibility for pembrolizumab monotherapy in advanced NSCLC worldwide and for several other indications depending on the country. Four assays have been approved/ Communauté Européene-In vitro Diagnostic (CV-IVD)-marked, but PD-L1 IHC seems diversely implemented across regions and laboratories with the application of laboratory-developed tests (LDTs). METHOD:To assess the practice of PD-L1 IHC and identify issues and disparities, the International Association for the Study of Lung Cancer Pathology Committee conducted a global survey for pathologists from January to May 2019, comprising multiple questions on preanalytical, analytical, and postanalytical conditions. RESULT:A total of 344 pathologists from 64 countries participated with 41% from Europe, 24% from North America, and 18% from Asia. Besides biopsies and resections, cellblocks were used by 75% of the participants and smears by 11%. The clone 22C3 was most often used (69%) followed by SP263 (51%). They were applied as an LDT by 40% and 30% of the users, respectively, and 76% of the participants developed at least one LDT. Half of the participants reported a turnaround time of less than or equal to 2 days, whereas 13% reported that of greater than or equal to 5 days. In addition, quality assurance (QA), formal training for scoring, and standardized reporting were not implemented by 18%, 16%, and 14% of the participants, respectively. CONCLUSIONS:Heterogeneity in PD-L1 testing is marked across regions and laboratories in terms of antibody clones, IHC assays, samples, turnaround times, and QA measures. The lack of QA, formal training, and standardized reporting stated by a considerable minority identifies a need for additional QA measures and training opportunities.

Background: Growing evidence suggests the prognostic significance of SATS in patients with early-stage lung adenocarcinoma, in particular, those with sublobar resection. However, published studies used various definitions for STAS; the diagnosis of STAS may be subject to interobserver variability that, in turn, may result in the difference in prevalence and prognostic significance of STAS across institutions.
Design(s): The study cohort consisted of stage 1 lung adenocarcinomas resected at two institutions (cohort A: n=283; cohort B: n=198) during similar time periods with similarly decent follow-up. Both institutions had applied similar grossing/processing protocols. The prevalence of STAS and its association with clinicopathologic variables, recurrence free survival (RFS), and overall survival (OS) were compared between the cohorts. The variables included type of operation, AJCC 8th stage, histologic grade, as well as the presence of lepidic, micropapillary (mPAP), or solid (SOL) patterns (5% cut-off for presence).
Result(s): The prevalence of STAS was 7% in cohort A and 39% in cohort B (p<0.0001). The tumor histologic grade (high grade: 21% in A vs. 37% in B, p=0.0001) and AJCC stage (Stage 1B: 19% in A vs. 13% in B, p=0.048) also differed between the cohorts, while no difference was seen in the other variables. STAS was associated with high grade histology, the absence of lepidic and the presence of mPAP and SOL patterns (p<0.01 for all) in both cohorts, while it was also associated with stage 1B in cohort A (p=0.016). In multivariate analysis, STAS was associated with high grade histology (p<0.0001) and marginally with the presence of mPAP (p=0.065) in cohort A, and lobectomy (p=0.016), the presence of mPAP (p<0.0001) and SOL (p=0.027) in cohort B. Regarding survival, STAS was associated with shorter RFS (p=0.030) and OS (p=0.048) in cohort B and with shorter OS (p=0.040) and marginally with shorter RFS (p=0.060) in the sublobar resection subset of cohort B by univariate analysis, while STAS had no bearing on survival in the lobectomy subset or cohort A. Of note, no difference in RFS and OS was seen as a whole between the cohorts.
Conclusion(s): The prevalence and prognostic significance of STAS differ between the two institutional cohorts. While this may be explained in part by the difference in patient populations, subjectivity to the diagnosis of STAS may potentially contribute. Additional multi-institutional studies to better define and improve reproducibility of STAS are warranted

Patients with severe coronavirus disease 2019 from infection with severe acute respiratory syndrome coronavirus 2 mount a profound inflammatory response and are predisposed to thrombotic complications. Pulmonary vein thrombosis is a rare disease process resulting in pulmonary congestion, infarction, and potential mortality. This report describes a patient with coronavirus disease 2019 requiring venovenous extracorporeal membrane oxygenation for hypoxic respiratory failure who developed hemorrhagic infarction of the right lower lobe. During emergency exploration the patient was found to have a right inferior vein thrombosis and marked lobar hemorrhage mandating lobectomy.

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in group IIIB-IV TNM stage lung cancer and is associated with poor prognosis, as shown by decreased survival among subjects with early stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with IIIB-IV stage disease. In addition, this lower airway microbiota signature was associated with upregulation of IL-17, PI3K, MAPK and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL-17 inflammatory phenotype and activation of checkpoint inhibitor markers.

Many state-wide, city-wide, and hospital-wide changes have been implemented due to the ongoing COVID-19 crisis. We describe lessons learned in an anatomic pathology division at a tertiary care center during the peak of the COVID-19 pandemic in the hopes that knowledge of our experiences can benefit other pathology departments as they encounter this pandemic. Five categories that are critical in strategic planning for the COVID-19 pandemic are discussed: workload, departmental policy revisions, impact on faculty, workforce staffing, and impact on educational programs, including residency and fellowship training. Although the volume of COVID-19 testing had grown placing increased demands on the clinical pathology laboratory, the volume of anatomic pathology cases had declined during the COVID-19 peak. Lessons learned were widespread including changes in the anatomic pathology workflow due to declining surgical and cytologic case volumes and increases in autopsy requests. Modifications were required in gross room policies, levels of personal protective equipment, and workforce. Travel and meeting policies were impacted. Adaptations to residency and fellowship programs were vast and included innovations in didactic and interactive education. We must learn from our experiences thus far in order to move forward, and we hope that our experiences in an anatomic pathology department in the epicenter of the COVID-19 pandemic can help other pathology departments across the country.