Faculty Bibliography

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.

BACKGROUND:Colorectal carcinomas are one of the most commonly diagnosed malignancies. There are many prognostic factors relating to clinical course and disease progression, including tumor stage, metastasis, and tumor budding. In 2016, the International Tumor Budding Consensus Conference (ITBCC) created a system to uniformly assess tumor budding. This system includes a 3-tier system for the grading of tumor budding. In the past, there lacked uniform consensus, however the general grading practice was based on a 2-tiered system. Given that tumor budding is considered to have prognostic value, the accuracy and reproducibility of its assessment is vital. Our study aims to look at interobserver agreement in the scoring of tumor budding. DESIGN/METHODS:A total of 233 cases of colorectal carcinoma diagnosed in our health system were retrospectively analyzed and routine H&E stained slides of these cases were collected. A representative slide for tumor budding was selected per case. Four investigators with different levels of experience and expertise evaluated the selected slide of each case for tumor budding. Scoring was based on the ITBCC protocol. Clinico-pathological data was collected for each case and analyzed with tumor budding scores. Tumor budding scores per individual investigator and consensus tumor budding score were compared to patient and tumor characteristics including patient survival, tumor grade, tumor stage, and lymph node status. RESULTS:) and associated 95% confidence intervals was used to compare the ratings made by 4 pathologists. Overall, there was variation among pathologists in tumor budding score (Gwet's agreement coefficient = 0.25 and 0.326 for 3-tier and 2-tier grading system, respectively). Results show higher reliability with the 2-tier system compared to the 3-tier system. Tumor stage was significantly associated with budding score for all individual investigators and the consensus value (p value < 0.001). CONCLUSION/CONCLUSIONS:There is low inter-observer agreement in the assessment of tumor budding in colorectal carcinoma. This suggests that it is difficult to uniformly grade tumor budding and that our classification system needs improvement. We found that the older 2-tier system (Hase et al.) results in slightly higher inter-observer agreement than the recently proposed 3-tier grading system (ITBCC, 2016), though both systems lead to suboptimal agreement. Worth noting is that observers with subspecialty GI training and more work experience had higher inter-observer agreement. Our results showed that subspecialty training tends to increase agreement more than overall work experience. In addition, our exploratory results showed that there is an association of tumor budding score to tumor stage. While increasing refinement in classification, the 3-tiered system resulted in decreased agreement in tumor budding assessment. Clearly, there is more work to be done in the identification and quantification of tumor buds.