Faculty Bibliography

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.

Cytology serves a fundamental role in the evaluation of the lower respiratory tract. Cytological specimens are often the first diagnostic attempt for the evaluation of radiographic alterations. The categorization of the pathological process as infectious, inflammatory or neoplastic is critical in guiding further clinical management of the affected patient. Therefore it is imperative that cytopathologists use a standardized approach to sample handling and reporting in order to establish clear communication with the treating physician. The Papanicolaou Society of cytopathology has been an active leader in this field and has proposed several guidelines for sampling, handling, and reporting of lower respiratory tract cytology. These guidelines have been updated to incorporate new emerging concepts and technologies in the field. Respiratory medicine is a fast growing area with constant new challenges, thus requiring an ever demanding adaptation from cytopathologists and cytology specific guidelines.

Cardiac amyloid A (AA) amyloidosis is rare. We present the case of a 72-year-old woman with obstructive hypertrophic cardiomyopathy (HCM) and biopsy-proven renal AA amyloidosis whose dyspnea and exercise intolerance had worsened over the previous year. Her AA amyloidosis was suspected to be secondary to chronic diverticulitis for which she had undergone hemicolectomy and sigmoidectomy 3 years prior. Echocardiographic findings were consistent with worsening left ventricular outflow tract obstruction at rest. Cardiac magnetic resonance imaging revealed patchy areas of midwall late gadolinium enhancement. Right ventricular endomyocardial biopsy did not reveal amyloid deposition, and cardiac technetium-99m pyrophosphate scintigraphy did not suggest transthyretin amyloidosis. The patient underwent septal myectomy with resection of an accessory papillary muscle. Pathological examination of the myectomy specimen was consistent with HCM. In addition, there was a thick layer of diffuse endocardial and vascular amyloid deposition that was identified as AA type by laser-microdissection with liquid chromatography-coupled tandem-mass spectrometry. This case report highlights the presence of 2 distinct disease processes occurring simultaneously and the importance of tissue diagnosis of AA amyloidosis, a condition that is not commonly associated with HCM.

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.

INTRODUCTION/BACKGROUND:Overexpression of the mesenchymal-epithelial transition (MET) receptor, a receptor tyrosine kinase, can propel the growth of cancer cells and portends poor prognoses for patients with lung cancer. Evaluation of MET by immunohistochemistry is challenging, with MET protein overexpression varying from 20% to 80% between lung cancer cohorts. Clinical trials using MET protein expression to select patients have also reported a wide range of positivity rates and outcomes. MATERIALS AND METHODS/METHODS:To overcome this variability, the Lung Cancer Mutation Consortium Pathologist Panel endeavored to standardize the evaluation of MET protein expression with "Round Robin" conferences. This panel used randomly selected Aperio-scanned formalin-fixed paraffin-embedded lung cancer specimens stained by MET immunohistochemistry for the Lung Cancer Mutation Consortium 2.0 study (N=838). Seven pathologists in separate laboratories scored images of 5 initial cases and 2 subsequent rounds of 39 cases. The pathologists' scores were compared for consistency using the intraclass correlation coefficient. Issues affecting reproducibility were discussed in Round Robin conferences between rounds, and steps were taken to improve scoring consistency, such as sharing reference materials and example images. RESULTS:The overall group intraclass correlation coefficient comparing the consistency of scoring improved from 0.50 (95% confidence interval, 0.37-0.64) for the first scoring round to 0.74 (95% confidence interval, 0.64-0.83) for the second round. DISCUSSION/CONCLUSIONS:We found that the consistency of MET immunohistochemistry scoring is improved by continuous training and communication between pathologists.

INTRODUCTION/BACKGROUND:Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma (MPM) where pathologic diagnosis has been essentially limited to three histologic subtypes. METHODS:A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists and oncologists), sponsored by EURACAN/IASLC met in 2018, to critically review the current classification. RESULTS:Recommendations include: 1) classification should be updated to include architectural patterns, and stromal and cytologic features that refine prognostication 2) subject to data accrual, malignant mesothelioma in situ could be an additional category, 3) grading of epithelioid MPMs should be routinely undertaken, 4) favorable/unfavorable histologic characteristics should be routinely reported, 5) clinically relevant molecular data (PD-L1, BAP1, CDKN2A) should be incorporated into reports, if undertaken, 6) other molecular data should be accrued as part of future trials 7) resection specimens (i.e. extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged, 8) ideally, at least 3 separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging, 9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging, 10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered, 11) all histologic subtypes should be considered potential candidates for chemotherapy, 12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first line clinical trials unless there is a compelling reason, 13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy, 14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome. CONCLUSION/CONCLUSIONS:These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.