Faculty Bibliography

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.

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.

BACKGROUND:Carcinosarcoma (CS) or malignant mixed Müllerian tumor (MMMT), is a rare malignant biphasic tumor, which contains both a malignant epithelial and mesenchymal component. That being said, they have an aggressive clinical course. Given that immune checkpoint inhibitors have mustered significant excitement in the oncology world - immunotherapy could offer significant promise to this poor prognostic cancer subtype. A total of 75 carcinosarcoma cases were identified in our institutional database from 2010 to 2019 and immunohistochemistry for PD-L1, PD-1 and IDO-1 was performed. Out of the 75 patients, 65(87 %) demonstrated >1 % PD-1 expression and 50(67 %) expressed >1 % PD-L1 in either the tumoral and immune stromal components. 29 (39 %) cases demonstrated >20 % PD-1 expression and 14 (19 %) cases expressed >20 % PD-L1. 41(55 %) cases demonstrating co-expression of PD-1 and PD-L1. For IDO-1 64 (85 %) patients showed at least >5 %, while 34 (45 %) showed staining above 20 %. 45 patients (60 %) showed co-expression of IDO-1 and PD-L1, while 59 (79 %) patients had co-expression of IDO and PD-1 above 5 and 1 % respectively. Regarding clinicopathologcial features; older patients (> 65) were more likely to express PD-L1 (>1 %) and IDO-1 (>20 %). For tumor size, IDO-1 expression (>5 %), along with PD-1/IDO-1 Co-expression (>1/5 %), was associated with larger tumor size (>5cm). For myometrial invasion, CSs with >50 % invasion were more likely to express IDO-1 (>20 %) and PD-1/IDO-1 (>1/5 %). Ultimately, the effect of IDO-1, PD-1 and PD-L1 on the clinical profile may be less important than its potential use as a immunotherapeutic, where safe and effective corresponding drugs could be used to treat particular patient populations. Future clinical trials are needed to decipher the association between immune check point inhibitor expression and therapeutic response. This is the only way to definitively prove immune checkpoint immunohistochemistry as predictive biomarkers in this cancer subtype.

Gastrointestinal neuroendocrine tumors, or GI-NETs are a highly diverse group of tumors derived from neuroendocrine cells of the GI tract. In GI-NET, a spectrum of histological and molecular parameters exists to predict prognosis and survival. Immunohistochemistry for Ki67, a nuclear antigen that is present in all but the G0 phase of the cell cycle with specificity for proliferating cells, can be used to determine a tumors proliferation index. With this in mind, grading of gastrointestinal neuroendocrine tumors is critical for prognosis and can impact clinical decision making. Recently, digital image analysis (DIA) has been shown in studies to be a superior and less time-consuming alternative to the manual scoring of Ki-67 in breast cancer, secondary to its theoretical diagnostic reproducibility. In DIA, the correct identification of tumor cells and non-tumor is paramount to avoid over or under calculation of biomarker expression. Additionally, DIA requires a pathologist to manually outline a tumor in large tissue areas of hematoxylin and eosin (H&E) sections, which is impractical. The findings in our study showed that ventana virtuoso software computer analyzed Ki-67 only correlated well with Neuroendocrine carcinomas while manual analysis of mitotic index and Ki67 were found to be gold standard. The performance of DIA in our study was plagued by software issues. In future, the advent of new digital imaging technologies such as virtual dual staining will hopefully improve diagnostic accuracy and reproducibility across different DIA platforms. Ultimately, determination of therapeutic strategies should be guided by an amalgamation of clinicopathologic characteristics not limited to mitotic index and Ki-67. As well, A visual check of the results should always be performed and correlated with other findings.