Faculty Bibliography

Background: PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.
Method(s): The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).
Result(s): 344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.
Conclusion(s): There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally. Keywords: global survey, NSCLC, PD-L1 immunohistochemistry
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Sarcomatoid carcinoma is rarely found in pleural or pericardial fluid, with very few cases published to date. Here, we describe a 59-year-old female who presented with cough persisting for 5 months. Chest CT scan revealed a 6.0 cm cavitary mass in the left lung base with bulky mediastinal and hilar lymphadenopathy. An additional 1.2 cm right adrenal mass was seen and was suspicious for metastatic disease. The patient developed dyspnea, tachycardia, pleuritic chest pain and generalized weakness and was admitted to the hospital. She was found to have pleural and pericardial effusions, which were drained and sent to cytology. The fluid revealed enlarged highly pleomorphic malignant cells, some displaying multinucleation with irregular nuclear borders, coarse chromatin and prominent nucleoli. Tumor cells were positive for CK7 and Vimentin and negative for MOC-31, Ber-EP4, B72.3, Sox10, Melan-A, TTF-1, Napsin-A and CK20. A concurrent surgical biopsy of the tumor mass displayed immunopositivity for AE1/AE3 and CAM5.2. The tumor was negative for p40, TTF-1, calretinin, D2-40 and STAT6. A diagnosis of sarcomatoid carcinoma with giant cells and spindle cells was rendered. Sarcomatoid carcinomas of the lung are very uncommon consisting of 1% of non-small-cell lung carcinomas and are even more unusual in cytology specimens. Despite its rarity, it is important to keep this entity in mind in the differential diagnosis of a fluid specimen with bizarre nuclear atypia and the above staining pattern.

Background: Banking of human biospecimens linked to prospective, well-annotated clinical information is critical for advancing biomedical research. However, the establishment of an efficient biobank encompasses many issues including adherence to federal regulations, institutional policies and governance of the relationship between the biobank, investigators and funding agents. Here we report on the efforts of the Center for Biospecimen Research and Development (CBRD) at NYULH to establish a state-of-the-art biobank. Method(s): In 2015, we identified the need to establish a centralized infrastructure to facilitate research collaborations and support clinical trial studies. The four main considerations were: 1) creating a centralized mechanism to consent, collect and bank human biospecimens 2) Organizing, de-identifying, and annotating subjects' samples linked to their clinical data 3) Establishing multidisciplinary involvement of pathology departments 4) Enhancing quality control measures to achieve CAP and NYS DOH accreditation. To address these considerations, we created a Universal Consent (UC) form; developed a Laboratory Information Management System that assists in specimen organization and links subject samples to clinical data in their electronic medical record and fostered a partnership between the pathology department, individual researchers and the CBRD to develop best practices in biobanking. Result(s): Since June 2016, using the UC, 18,906 of 27,355 (70%) subjects agreed to use their specimens and data for research. 9,054 patients had specimens collected using the UC and additional specific consent if needed. We collected 4,178 unique samples (tissue, blood and fluids)-13,969 aliquots by the UC method and 7,713 samples from fresh and archival collections for specific research studies or clinical trials. The CBRD supported 93 research projects and 251 clinical trials. Conclusion(s): Establishment of the CBRD permitted the increase in absolute number of patients approached for research; enhancement of specimen quality and organization and introduction of the electronic crosslink to minimize the time and overhead needed for clinical data retrieval. Building on this success, we are upgrading our IT infrastructure to expand upon the data collected, digitalizing tissue slides to improve quality control and building an automated molecular genotyping database using existing NGS data to increase the number of trans-lational research projects

With an escalating number of predictive biomarkers emerging in non-small cell lung carcinoma (NSCLC), immunohistochemistry (IHC) is being used as a rapid and cost-effective tool for the screening and detection of many of these markers. In particular, robust IHC assays performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue are widely used as surrogate markers for ALK and ROS1 rearrangements and for detecting programmed death ligand 1 (PD-L1) expression in patients with advanced NSCLC; in addition, they have become essential for treatment decisions. Cytology samples represent the only source of tumor in a significant proportion of patients with inoperable NSCLC, and there is increasing demand for predictive biomarker testing on them. However, the wide variation in the types of cytology samples and their preparatory methods, the use of alcohol-based fixatives that interfere with immunochemistry results, the difficulty in procurement of cytology-specific controls, and the uncertainty regarding test validity have resulted in underutilization of cytology material for predictive immunocytochemistry (ICC), and most cytopathologists limit such testing to FFPE cell blocks (CBs). The purpose of this review is to: 1) analyze various preanalytical, analytical, and postanalytical factors influencing ICC results; 2) discuss measures for validation of ICC protocols; and 3) summarize published data on predictive ICC for ALK, ROS1, EGFR gene alterations and PD-L1 expression on lung cancer cytology. Based on our experience and from a review of the literature, we conclude that cytology specimens are in principal suitable for predictive ICC, but proper optimization and rigorous quality control for high-quality staining are essential, particularly for non-CB preparations.

Ancillary techniques play an essential role in pulmonary cytopathology. Immunoperoxidase and special stains are by far the most common ancillary techniques used in cytopathology; however, the role of molecular diagnosis is growing, especially in the fields of pulmonary oncology and infectious disease. In this article, we review the uses of ancillary techniques in lung tumor diagnosis, lung tumor classification, predictive marker determination, primary versus metastasis differential diagnosis, and infectious organism detection.

Objectives/UNASSIGNED:To evaluate whether non-small cell lung carcinoma (NSCLC) cytology specimens are reliable for programmed death-ligand 1 (PD-L1) immunohistochemical (IHC) testing. Methods/UNASSIGNED:Fifty-two cell blocks (CBs) with corresponding surgical pathology PD-L1 IHC testing were stained with a Dako PD-L1 pharmDX antibody (clone-22C3). Tumor cellularity was recorded as <100 or ≥100 cells. PD-L1 IHC was scored by percentage of tumor cells staining (<1%, ≥1%-49%, ≥50%) and compared between matched cases. Results/UNASSIGNED:Substantial agreement (κ = 0.63; 95% CI, 0.53-0.73) was reached between matched CB and surgical cases in CBs with ≥100 tumor cells compared to CBs with <100 tumor cells (slight agreement, κ = 0.19; 95% CI, 0.04-0.35). Overall, there was 67% agreement among paired cases (35/52 cases, κ = 0.51; 95% CI, 0.42-0.60). Conclusions/UNASSIGNED:CBs can be utilized for PD-L1 IHC testing, as illustrated by the 67% agreement between CB and surgical cases in our study. Disagreement is attributable to intratumoral heterogeneity and CB cellularity.

We assessed a priori aggressive features using quantitative diffusion-weighted imaging metrics to preclude an active surveillance management approach in patients with papillary thyroid cancer (PTC) with tumor size 1-2 cm. This prospective study enrolled 24 patients with PTC who underwent pretreatment multi-b-value diffusion-weighted imaging on a GE 3 T magnetic resonance imaging scanner. The apparent diffusion coefficient (ADC) metric was calculated from monoexponential model, and the perfusion fraction (f), diffusion coefficient (D), pseudo-diffusion coefficient (D*), and diffusion kurtosis coefficient (K) metrics were estimated using the non-Gaussian intravoxel incoherent motion model. Neck ultrasonography examination data were used to calculate tumor size. The receiver operating characteristic curve assessed the discriminative specificity, sensitivity, and accuracy between PTCs with and without features of tumor aggressiveness. Multivariate logistic regression analysis was performed on metrics using a leave-1-out cross-validation method. Tumor aggressiveness was defined by surgical histopathology. Tumors with aggressive features had significantly lower ADC and D values than tumors without tumor-aggressive features (P < .05). The absolute relative change was 46% in K metric value between the 2 tumor types. In total, 14 patients were in the critical size range (1-2 cm) measured by ultrasonography, and the ADC and D were significantly different and able to differentiate between the 2 tumor types (P < .05). ADC and D can distinguish tumors with aggressive histological features to preclude an active surveillance management approach in patients with PTC with tumors measuring 1-2 cm.

Since the 2015 WHO classification was introduced into clinical practice, the importance of immunohistochemistry (IHC) has figured prominently in lung cancer diagnosis. In addition to distinction of small versus non-small cell carcinoma (NSCC), patients' treatment of choice is directly linked to histological subtypes of NSCC, which pertains to IHC results, particularly for poorly-differentiated tumors. The use of IHC has improved diagnostic accuracy in the lung carcinoma classification, but the interpretation remains challenging in some instances. Also, pathologists must be aware of many interpretation pitfalls, and the use of IHC should be efficient to spare the tissue for molecular testing. The IASLC Pathology Committee received questions on practical application and interpretation of IHC in lung cancer diagnosis. After discussions in several IASLC Pathology Committee meetings, the issues and caveats were summarized as eleven key questions, which cover common and important diagnostic situations in a daily clinical practice with some relevant challenging queries. The questions included best IHC markers for distinguishing NSCLC subtypes, differences in TTF1 clones, utility of IHC in diagnosing uncommon subtypes of lung cancer and distinguishing primary from metastatic tumors." This article provides answers and explanations for the key questions about the use of IHC in lung carcinoma diagnosis representing viewpoints of experts in thoracic pathology that should assist the community in the appropriate use of IHC in diagnostic pathology.

Fine needle aspiration cytology (FNAC) of mediastinal masses allows for rapid on-site evaluation and the triaging of material for ancillary studies. However, surgical pathology is often considered to be the gold standard for diagnosis. This study examines the sensitivity and specificity of FNAC compared to a concurrent or subsequent surgical pathology specimen in 77 mediastinal lesions. The overall sensitivity for mediastinal mass FNAC was 78% and the overall specificity was 98%. For individual categories the sensitivity and specificity of FNAC was respectively as follows: inflammatory/infectious (33%, 99%), metastatic carcinoma (93%, 100%), lymphoma (84%, 97%), cysts (25%, 100%), soft tissue tumors (100%, 100%), paraganglioma (50%, 100%), germ cell tumor (100%, 99%), thymoma (87%, 94%), thymic carcinoma (60%, 100%), benign thymus (0%, 100%), and indeterminate (100%, 90%). For different locations within the mediastinum the sensitivity and specificity of FNAC was respectively as follows: anterosuperior mediastinum (80%, 98%), posterior mediastinum (33%, 95%), middle mediastinum (100%, 100%), and mediastinum, NOS (79%, 99%). Thus, mediastinal FNAC is fairly sensitive, very specific, and is a valuable technique in the diagnosis of mediastinal masses.