Faculty Bibliography

Colorectal cancer (CRC) is the third most common cause of cancer related death in the United States (Jasperson et al. in Gastroenterology 138:2044-2058, https://doi.org/10.1053/j.gastro.2010.01.054 , 2010). Many studies have explored prognostic factors in CRC. Today, much focus has been placed on the tumor microenvironment, including different immune cells and the extracellular matrix (ECM). The present study aims to evaluate the role of V-domain immunoglobulin suppressor of T cell activation (VISTA). We utilized QuPath for whole slides image analysis, performing superpixel image segmentation (SIS) on a 226 patient-cohort. High VISTA expression correlated with better disease-free survival (DFS), high tumor infiltrative lymphocyte, microsatellite instability, BRAF mutational status as well as lower tumor stage. High VISTA expression was also associated with mature stromal differentiation (SD). When cohorts were separated based on SD and MMR, only patients with immature SD and microsatellite stability were found to correlate VISTA expression with DFS. Considering raised VISTA expression is associated with improved survival, TILs, mature SD, and MMR in CRC; careful, well-designed clinical trials should be pursued which incorporate the underlying tumoral microenvironment.

Spindle cell lesions of the breast comprise a diverse set of tumors; harboring significant histological and immunohistochemical (IHC) overlap. Accurate diagnosis and classification of spindle cell lesions in the breast remains challenging, especially in core biopsies. In the current study, we evaluated a spectrum of spindle cell lesion of the breast with a panel of IHC antibodies in an effort to differentiate metaplastic spindle cell carcinoma from its benign and malignant mimickers. Our study included 92 patients who underwent breast core biopsies or breast resections at Northwell Health who were diagnosed with benign and malignant tumor/tumor-like spindle cell lesions. Tumors subtypes in this the study included: angiosarcoma, nodular fasciitis, fibromatosis, myofibroblastoma, phyllodes tumors (benign, borderline and malignant), primary sarcomas and metaplastic spindle cell carcinoma. Our biomarker panel included high molecular weight keratin (HMWK), CAM5.2, AE1/AE3, p63, CD34 and GATA3. GATA3 expression was significantly higher in metaplastic carcinomas (88.9 % vs 4.1 %, p < 0.001), when compared to other spindle cell lesions. The sensitivity and specificity for detecting metaplastic carcinomas reached 84.2 % and 97.3 %, respectively. Regarding cytokeratin panels, none of the three individual markers were as sensitive or specific for metaplastic breast carcinoma. GATA3 is the most specific and sensitive marker forfor the identification of metaplastic spindle cell carcinoma of the breast.

Cancer comprises epithelial tumor cells and associated stroma, often times referred to as the "tumoral microenvironment". Cancer-associated fibroblasts (CAFs) are the most notable components of the tumor mesenchyme. CAFs promote the initiation of cancer through angiogenesis, invasion and metastasis. Histologically, the differentiation of stroma has been reported to correlate with prognostic outcomes in patients with colorectal cancer. This review summarizes our current understanding of the extracellular matrix (ECM) in colorectal carcinoma (CRC), showcasing the functions of CAFs and its role in stromal differentiation (SD). We also review current state-of-the-art biology, histopathology, computation, and genomics in the setting of the stroma. SD is distinctive morphologically, and is easily recognized by a surgical pathologist; we offer a lexicon and guide for discovering the essence of stroma, as well as an incipient vision of the future for computation and molecular genomics. We propose that the mesenchymal phenotype, which encompasses a cancer migratory/metastatic capacity, could occur through the process of SD. Looking forward, pathologists will need to invest time and energy into SD, embracing the concept and propagating its use. For patients with colorectal cancer, stroma is a brave new frontier, one not only rich in biologic diversity, but also potentially critical for therapeutic decision making.

Artificial intelligence (AI) is a new frontier and often enigmatic for medical professionals. Cloud computing could open up the field of computer vision to a wider medical audience and deep learning on the cloud allows one to design, develop, train and deploy applications with ease. In the field of histopathology, the implementation of various applications in AI has been successful for whole slide images rich in biological diversity. However, the analysis of other tissue medias, including electron microscopy, is yet to be explored. The present study aims to evaluate deep learning for the classification of medical kidney disease on electron microscopy images: amyloidosis, diabetic glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), and thin basement membrane disease (TBMD). We found good overall classification with the MedKidneyEM-v1 Classifier and when looking at normal and diseased kidneys, the average area under the curve for precision and recall was 0.841. The average area under the curve for precision and recall on the disease only cohort was 0.909. Digital pathology will shape a new era for medical kidney disease and the present study demonstrates the feasibility of deep learning for electron microscopy. Future approaches could be used by renal pathologists to improve diagnostic concordance, determine therapeutic strategies, and optimize patient outcomes in a true clinical environment.

Colorectal cancer is a heterogenous disease with striking biological diversity. Colorectal carcinoma (CRC) is one of the most common malignancies, accounting for over 9% of all cancers worldwide. To put it in perspective, 5% of people will develop CRC in their lifetime. Biomarkers specific to a particular cancer type can assist in the evaluation of survival probability and help clinicians assess treatment modalities, an example being programmed death ligand-1 (PD-L1). With regards to PD-L1, this is the first study to evaluate the SP-142 antibody clone in CRC. The Ventana PD-L1 (SP-142) assay for PD-L1 expression identifies patients who may benefit from treatment with atezolizumab. SP-142 was chosen as large stage 3 clinical trials are being undertaken with atezolizumab in CRC. Indoleamine 2,3-dioxygenase (IDO-1) was also chosen as there are several ongoing trials for Epacadostat, the best-in-class oral IDO-1 enzyme inhibitor, in many solid tumors. For solid tumors, IDO-1-based immune escape has the potential to inhibit monotherapeutic efficacy of PD-L1-based therapeutics. In this study, a total of 223 cases of CRC were retrospectively reviewed and clinicopathologic data were analyzed in relation to PD-L1 and IDO-1 protein expression. Moreover, tumor-infiltrating lymphocytes, mismatch repair deficiency, high mitotic index, and worse survival outcomes were found in cohorts with significant PD-L1 and IDO-1 expression. Both PD-L1 and IDO-1 are actionable biomarkers, with potential therapeutic implications in CRC. Our findings support the theoretical foundation for targeting PD-L1 and IDO-1 in CRC, which now needs verification in well-designed robust clinical trials.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2, created an unprecedented need for comprehensive laboratory testing of populations, in order to meet the needs of medical practice and to guide the management and functioning of our society. With the greater New York metropolitan area as an epicenter of this pandemic beginning in March 2020, a consortium of laboratory leaders from the assembled New York academic medical institutions was formed to help identify and solve the challenges of deploying testing. This report brings forward the experience of this consortium, based on the real-world challenges which we encountered in testing patients and in supporting the recovery effort to reestablish the health care workplace. In coordination with the Greater New York Hospital Association and with the public health laboratory of New York State, this consortium communicated with state leadership to help inform public decision-making addressing the crisis. Through the length of the pandemic, the consortium has been a critical mechanism for sharing experience and best practices in dealing with issues including the following: instrument platforms, sample sources, test performance, pre- and post-analytical issues, supply chain, institutional testing capacity, pooled testing, biospecimen science, and research. The consortium also has been a mechanism for staying abreast of state and municipal policies and initiatives, and their impact on institutional and laboratory operations. The experience of this consortium may be of value to current and future laboratory professionals and policy-makers alike, in dealing with major events that impact regional laboratory services.

Endometrial cancer (EC) is a disease with good and poor prognostic subtypes. Dedifferentiated endometrial carcinoma (DEC), undifferentiated endometrial carcinoma (UEC), and clear cell endometrial carcinoma (CEC) are rare high-grade tumors, associated with a poor prognosis and high pathologic stage. Many studies have been performed on the programmed death-ligand 1 (PD-L1) axis mainly focus on endometrioid adenocarcinomas and little research has been done on rare subtypes. The present body of work aims to evaluate the role of indoleamine-2,3-dioxygenase (IDO-1) and stromal differentiation (SD), their correlation with clinicopathologic features and overall survival. Here we found that positive IDO-1 expression in immune cells correlated with worse disease-free survival (p = 0.02), recurrence (p = 0.03), high pathologic tumor stage (p = 0.024), lymph node metastasis (p = 0.028), and myometrial invasion (p = 0.03). Our findings suggest IDO-1 to be relevant in both MMR intact and deficient tumors; however, >20% immune cell staining was restricted to MMR deficient cancers. For the stroma, immature, myxoid differentiation was found to correlate with worse disease-free survival (p = 0.04). We also found the correlation between IDO-1 expression and immature stroma. Looking forward, IDO-1 could be promising for immunotherapy and SD could be the answer to clinical heterogeneity.