Faculty Bibliography

OBJECTIVES/OBJECTIVE:Recent investigations have shown strong correlations between cytology and surgical non-small cell lung carcinoma (NSCLC) specimens in programmed death-ligand 1 (PD-L1) immunohistochemical (IHC) evaluations. Our study aims to evaluate the reproducibility of PD-L1 IHC scoring in NSCLC cytology cell blocks (CBs) and to assess the impact of CB cellularity, method of sample collection, and observer subspecialty on scoring agreement. METHODS:PD-L1 IHC was performed on 54 NSCLC cytology CBs and was scored independently by seven cytopathologists (three of seven with expertise in pulmonary pathology). Three-tier scoring of negative (<1%), low positive (1%-49%), and high positive (≥50%) and interrater agreement were assessed. RESULTS:Total and majority agreement among cytopathologists was achieved in 48% and 98% of cases, respectively, with κ = 0.608 (substantial agreement; 95% confidence interval, 0.50-0.72). Cytopathologists with pulmonary pathology expertise agreed in 67% of cases (κ = 0.633, substantial agreement), whereas the remaining cytopathologists agreed in 56% of cases (κ = 0.62, substantial agreement). CB cellularity (P = .36) and sample collection type (P = .59) had no statistically significant difference between raters. CONCLUSIONS:There is substantial agreement in PD-L1 IHC scoring in cytology CB specimens among cytopathologists. Additional expertise in pulmonary pathology, sample collection type, and CB cellularity have no statistically significant impact on interobserver agreement.

Immune checkpoint inhibitor therapies have revolutionized the management of patients with non-small cell lung carcinoma (NSCLC) and have led to unprecedented improvements in response rates and survival in a subset of a patients with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to significant immune-related adverse events. Therefore, patient selection must be optimized through use of relevant biomarkers. PD-L1 protein expression by immunohistochemistry is widely used today for selection of PD-1 inhibitor therapy in NSCLC patients, however this approach lacks both robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to immune checkpoint inhibitors. In theory, a higher TMB increases the probability of tumor neoantigen production and, therefore, likelihood of immune recognition and tumor cell killing. While TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses employing both tumor and blood-based sequencing tools have examined the performance of TMB as a predictive biomarker and in many cases show a correlation between high TMB and immune checkpoint inhibitor response rates and progression-free survival. Many challenges remain prior to implementation of TMB as a biomarker in clinical practice. These include: identification of therapies whose response is best informed by TMB status; robust definition of a predictive TMB cutpoint; acceptable sequencing panel size and design; need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to immune checkpoint inhibitor therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges to use of TMB in routine practice.

PURPOSE/OBJECTIVE:To compare the pathology results of CT-guided and blind bone marrow aspirations and biopsies. METHODS:Ninety-eight consecutive CT-guided biopsies and 98 age- and gender-matched blind (non-CT-guided) posterior iliac crest bone marrow aspirations and biopsies performed in 2017 were reviewed for adequacy of core biopsies and aspirate smears. CT procedure images and CT abdomen/pelvis images were reviewed to evaluate anatomic features of the posterior ilium and soft tissues. Statistical analysis was performed using a T test, Fisher exact test, and Kruskal-Wallis test. RESULTS:There was no significant difference in the age and gender of the two groups (p > 0.05). However, the CT-guided group had a higher BMI (p = 0.0049) and posterior soft tissue thickness (p = 0.0016). More CT-guided biopsy samples (CT 93 (95%); blind 77 (79%); p = 0.0006) and aspirate smears (CT 90 (92%); blind 78 (80%); p = 0.042) were categorized as adequate. The CT-guided group had longer core lengths (CT 1.4 ± 0.6 (range 0.3-3.5) cm; blind 1.0 ± 0.60 (range 0-2.6) cm; p = 0.0001). Overall, 131/164 (80%) of the cases had at least one of the described features (slanted posterior ilium (angle > 30°), 30%; rounded posterior ilium, 20%; thick posterior ilium cortex, 13%; focal lesion in posterior ilium, 12%; prior procedure in posterior ilium, 5%; posterior soft tissue thickness > 3 cm, 40%). CONCLUSION/CONCLUSIONS:CT-guided bone marrow procedures were more likely to result in both adequate aspirate smears and biopsy samples and longer core lengths when compared with blind procedures.

In the 21st century, there has been a dramatic shift in the management of advanced-stage lung carcinoma, and this has coincided with an increasing use of minimally invasive tissue acquisition methods. Both have had significant downstream effects on cytology and small biopsy specimens. Current treatments require morphologic, immunohistochemical, and/or genotypical subtyping of non-small cell lung carcinoma. To meet these objectives, standardized classification of cytology and small specimen diagnoses, immunohistochemical algorithms, and predictive biomarker testing guidelines have been developed. This review provides an overview of current classification, biomarker testing, methods of small specimen acquisition and triage, clinical management strategies, and emerging technologies.

The outbreak of the novel coronavirus disease 2019 (COVID-19) and consequent social distancing practices have disrupted essential clinical research functions worldwide. Ironically, this coincides with an immediate need for research to comprehend the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathology of COVID-19. As the global crisis has already led to over 15,000 deaths out of 175,000 confirmed cases in New York City and Nassau County, NY alone, it is increasingly urgent to collect patient biospecimens linked to active clinical follow up. However, building a COVID-19 biorepository amidst the active pandemic is a complex and delicate task. To help facilitate rapid, robust, and regulated research on this novel virus, we report on the successful model implemented by New York University Langone Health (NYULH) within days of outbreak in the most challenging hot spot of infection globally. Using an amended institutional biobanking protocol, these efforts led to accrual of 11,120 patients presenting for SARS-CoV-2 testing, 4267 (38.4%) of whom tested positive for COVID-19. The recently reported genomic characterization of SARS-CoV-2 in the New York City Region, which is a crucial development in tracing sources of infection and asymptomatic spread of the novel virus, is the first outcome of this effort. While this growing resource actively supports studies of the New York outbreak in real time, a worldwide effort is necessary to build a collective arsenal of research tools to deal with the global crisis now, and to exploit the virus's biology for translational innovation that outlasts humanity's current dilemma.

Currently there is no established guidance on how to process and evaluate resected lung cancer specimens following neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response (MPR) or complete pathologic response (CPR). In other cancers such as osteosarcoma, colorectal, breast and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas following induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response including MPR and CPR following neoadjuvant therapy. A standardized approach is recommended to assess the percentages of: 1) viable tumor, 2) necrosis and 3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies including chemotherapy, chemoradiation, molecular targeted therapy, immunotherapy or any future novel therapies yet to be discovered whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer (IASLC) has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

The recent development of immune checkpoint inhibitors (ICI) has led to promising advances in the treatment of non-small cell and small cell lung cancer patients with advanced or metastatic disease. Most of ICI target the PD-1/PD-L1 axis with the aim of restoring anti-tumor immunity. Multiple clinical trials for ICI have examined a predictive value of PD-L1 protein expression in tumor cells and/or tumor-infiltrating immune cells by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms and many laboratories have set up in-house or laboratory developed tests, which are more affordable than generally expensive clinical trial-validated assays. Although PD-L1 IHC test is now deployed in the most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging due to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. As many articles have been published since the issue of the IASLC Atlas of PD-L1 immunohistochemistry testing in lung cancer, this review by the IASLC pathology committee provides updates on the indications of ICI for lung cancer in 2019, and discusses important considerations on pre-analytical, analytical and post-analytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance and training.