Faculty Bibliography

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.

Carcinosarcoma (CS) is a rare, aggressive malignancy of the Mullerian system often termed mixed malignant Mullerian tumor (MMMT). It is biphasic in nature, differentiating into epithelial and sarcomatous components. Tumor-node-metastasis (TNM) staging and mismatch repair (MMR) status is the basis for both prognostication and therapeutic decision making. However, stromal differentiation (SD) is a new frontier in the field of histopathology and many studies have demonstrated its prognostic significance. The present study is the first study to evaluate the role of SD in carcinosarcoma. Here we found immature SD to be a significant prognostic signature (p = 0.04). It outperformed age, nodal metastasis, and lymphovascular invasion for predicting cancer-free survival. Immature SD also corelated with both myometrial invasion (p = 0.01) and tumor stage (p = 0.02). Carcinosarcoma has been previously thought to have universally poor outcomes; however, mature SD was found to be protective in this cancer subtype. Our findings support the integration of SD into the synoptic reporting for carcinosarcoma; however, this will require pathologists to shoulder the adoption of SD into clinical practice.

Whole slide imaging (WSI) has recently received FDA approval for sign out in surgical pathology and some anticipate this to mature into the gold standard. During this transition, it will be important to validate WSI for its intended use. And many studies have validated whole slide imaging by comparing diagnostic accuracy with that of conventual light microscopy (CLM); however, the assessment of histopathologic markers is prone to much more discrepancy. One of the best examples being tumor-bud scoring in colorectal carcinoma. Other signatures, including stromal differentiation or desmoplastic reaction; could better represent the epithelial-mesenchymal transition. The findings in our study suggest stromal differentiation on both digital and glass slides to be much more reproducible (0.3585-0.9368) when compared to tumor budding (0.0968-0.7871). When comparing interobserver variation between glass and digital slides for three observers; stromal differentiation was more reliable on glass slides (0.4492), when compared to its digital counterpart (0.3016). On the other hand, interobserver variation for tumor bud scoring was more reliable on digital (0.1661), than glass slides (0.1026). Overall, there is significant variation between different observers and reproducibility issues present on conventual light microscopy transfer to digital slides. Although it is possible that too much emphasis is being placed on the concordance of WSI with CLM. In future, applications in artificial intelligence may be key to diagnostic precision and improved patient outcomes.

As of now, therapeutic strategies for the novel coronavirus (SARS-CoV-2) are limited and much focus has been placed on social distancing techniques to "flatten the curve". Initial treatment efforts including ventilation and hydroxychloroquine garnered significant controversy and today, SARS-CoV-2 outbreaks are still occurring throughout the world. Needless to say, new therapeutic strategies are needed to combat this unprecedented pandemic. Nature Reviews Immunology recently published an article hypothesizing the pathogenesis of TAM (Tyro3, Axl, and Mer) receptor signaling in COVID-19. In it they expressed that hypercoagulation and immune hyper-reaction could occur secondary to decreased Protein S (PROS1). And hypoxia has been recently discovered to significantly decrease expression of PROS1. Regarding the cause of hypoxia in COVID-19; NIH funded research utilizing state-of-the-art topologies has recently demonstrated significant metabolomic, proteomic, and lipidomic structural aberrations in hemoglobin (Hb) secondary to infection with SARS-CoV-2. In this setting, Hb may be incapacitated and unable to respond to environmental variations, compromising RBCs and oxygen delivery to tissues. The use of red blood cell exchange would target hypoxia at its source; representing a Gemini of therapeutic opportunities.

The outbreak of the novel coronavirus (2019-nCoV) began in Wuhan, China and spread rapidly throughout the world. As of now, there have been numerous reports demonstrating clinical, radiological and pathological findings in adults. In children, the disease has essentially been seen as mild and self-limiting. However, more recently, children have been presenting with findings reminiscent of Kawasaki's disease. And secondary to this, the benign nature of COVID-19 disease in children is beginning to be challenged. This phenomenon is now referred to as multisystem inflammatory syndrome in children (MIS-C). Further understanding the clinical course in MIS-C and its temporal association with coronavirus disease 2019 will be paramount for treatment and public health decision making. This correspondence describes a case of MIS-C with gastrointestinal manifestations mimicking acute appendicitis in a child presenting from a COVID-19 endemic area.

BACKGROUND:Colorectal carcinomas (CC) are one of the most commonly diagnosed malignancies. Tumor budding (the histologic process of dissociation that occurs at the invasive margin of colorectal cancer), has significant prognostic implications, in that higher tumor budding is associated with adverse histopathologic and clinical outcomes. Because of this prognostic significance, more research is needed to further understand the pathologic and immunohistochemical (IHC) associations pertaining to this important prognostic variable. In this study, we will further evaluate selective clinopathologic and IHC variables with possible association to tumor budding. DESIGN/METHODS:A total of 234 cases of CC diagnosed in our health system were retrospectively reviewed and routine hematoxylin and eosin-stained slides of these cases were collected. A representative slide for tumor budding was selected per case and selective IHC staining was performed. Clinicopathologic data were collected for each case and analyzed in relation to tumor budding scores. In exploratory analyses, tumor budding scores per individual investigator and consensus tumor budding scores were compared with selected IHC stains (MLH1, PMS2, and PHH3) as well as numerous clinicopathologic variables. RESULTS:We found a paradoxical association between tumor budding and mitosis score using PHH3 immunostaining in univariate and multivariable analysis. Furthermore, patients with intact nuclear expression for MLH1 and/or PMS2 are more likely to have higher tumor budding compared with patients with lost expression. For multivariable analysis, the following covariates were significantly associated with higher tumor budding: the presence of lymphovascular invasion, higher pathologic tumor stage, and finally infiltrating border was more likely to be associated with higher tumor budding compared with cases with a pushing border. Regarding nonmucinous versus mucinous CC, nonmucinous adenocarcinoma (MCA) was more likely to be associated with higher tumor budding compared with MCA. CONCLUSION/CONCLUSIONS:Numerous clinicopathologic variables were found to be associated with tumor budding including lymphovascular invasion, tumor stage, infiltrating tumor border, non-MCA was more likely to be associated with higher tumor budding compared with MCA, possibly related to MUC-2 and MSI. Furthermore, regarding the paradoxical association between tumor budding and mitosis score using a PHH3 immunostaining (high tumor budding having lower mitosis), this is possibly related to the tumoral stomal microenvironment and cancer associated fibroblasts. An idea for a future study would be to look at the maturity of cancer-associated fibroblasts (immature vs. mature) and the tumoral stroma microenvironment, with regards to markers of tumor aggressiveness such as mitosis. In addition, we found that patients with intact nuclear expression for MLH1 and/or PMS2 were more likely to have higher tumor budding compared with patients with lost expression, possibly related to mismatch repair CC's not being as reliant on tumor budding. Future research will hopefully concede further insight into the variables that affect tumor budding, especially regarding the tumoral microenvironment and variations between different patient populations, inclusive of patients lacking activity of the mismatch repair. Ultimately, this will allow for better prognostic information, and more precise treatment modalities.

Many pathological characteristics have utility for predicting prognosis in colorectal carcinoma (CRC). Some of the most important include tumor stage (TS), lymph node status (LNS) and tumor budding (TB). Tumor budding is a phenomenon originally described in 1949 as sprouting. TB assessment is not always reliable however, as it is subject to high inter-observer variation. This finding persists despite the current trends for sub-specialty training in surgical pathology. In light of this, new and reproducible histological prognostic markers could change the way we diagnose and manage patients with colorectal carcinoma. Studies have shown that desmoplastic reaction (DR) categorization can actually outperform other conventional prognostic factors, including tumor budding and tumor stage in predicting disease-free survival (DFS). Our study aimed to evaluate and assess the prognostic value of desmoplastic reaction in an American cohort with colorectal cancer using 3 different stromal classification scoring systems. In all three stromal grading systems, immature stroma was the most significant independent prognostic factor in CRC. Currently, none of the reporting protocols for the College of American Pathologists, the Royal College of Pathologists of the United Kingdom, and the Japanese Society for Cancer report on the presence of immature stroma. Importantly, regarding the ability to predict survival outcomes, our novel classification system has the potential to outperform other scoring methodologies.

Merkel cell carcinoma (MCC) is a rare entity that most commonly arises from the skin. Angiosarcoma (AS) is a rare malignancy with a predilection for elderly males, has endothelial differentiation and a notoriously poor prognosis despite aggressive therapy. Herein, we report an angiosarcoma colliding with a MCC, in a patient with a past medical history of squamous cell carcinoma, status-post radiation therapy. More specifically, our case represents a collision tumor, a rare entity composed of two histologically distinct neoplasms which coincide together at the same location. This case represents the first documented report of such a presentation. With that being said, its clinical course, prognosis, pathogenesis, and molecular profile, currently remains unclear. Importantly, neoplasms are increasingly being found to be associated with radiation therapy, of which our patient had received. Ultimately, however, with the lack of c-MYC immunohistochemical staining, and a short duration between radiation exposure and presentation, the AS in our case was likely coincidental.