PD-L1 expression in vulvar cancer: a systematic review and meta-analysis.

Programmed cell death ligand-1 (PD-L1) expression in cancer may predict clinical response to immunotherapeutic treatment with PD-1/PD-L1 inhibitors. Within the vulvar cancer field, PD-L1 expression has only been assessed by a few studies. We conducted a meta-analysis to examine the prevalence of PD-L1 positivity in vulvar cancer. PubMed, Embase, and Cochrane were searched for articles reporting on PD-L1 expression in vulvar cancer. Study selection and data extraction were performed independently by two authors. We extracted data on PD-L1 prevalence in vulvar cancer according to combined positive score (CPS) and tumour proportion score (TPS). Cutoff values for positivity were ≥1 or ≥10 for CPS and ≥1% and ≥5% for TPS. Random-effects models were used to estimate pooled PD-L1 prevalence, with 95% confidence intervals (CIs). Tests of between-study heterogeneity were evaluated by the I2 statistics. Sources of heterogeneity were explored by subgroup analyses and meta-regression. In total, 19 studies were included. Pooled PD-L1 prevalence in vulvar cancer was 83.4% (95% CI: 70.8-91.3; I2 = 80.0) and 53.9% (95% CI: 37.4-69.6; I2 = 93.0) according to CPS and TPS, respectively. Based on TPS, human papillomavirus (HPV)-associated vulvar squamous cell carcinomas (SCC) showed a lower PD-L1 prevalence (39.9%; 95% CI: 13.3-74.2) compared with HPV-independent SCC (62.6%; 95% CI: 33.7-84.6), but meta-regression showed no significant variation in PD-L1 prevalence by HPV status. PD-L1 prevalence was similar in advanced (44.9%; 95% CI: 29.8-61.1) and localized vulvar cancer (56.7%; 95% CI: 18.9-76.7). In conclusion, PD-L1 expression in vulvar cancer is frequent but between-study heterogeneity was high. Based on a subgroup of heterogenous studies, we found no strong variation in PD-L1 prevalence according to HPV status and stage.

Combined endoscopic and laparoscopic surgery (CELS) for early colon cancer in high-risk patients.

BACKGROUND: Local excision of early colon cancers could be an option in selected patients with high risk of complications and no sign of lymph node metastasis (LNM). The primary aim was to assess feasibility in high-risk patients with early colon cancer treated with Combined Endoscopic and Laparoscopic Surgery (CELS). METHODS: A non-randomized prospective feasibility study including 25 patients with Performance Status score ≥ 1 and/or American Society of Anesthesiologists score ≥ 3, and clinical Union of International Cancer Control stage-1 colon cancer suitable for CELS resection. The primary outcome was failure of CELS resection, defined as either: Incomplete resection (R1/R2), local recurrence within 3 months, complication related to CELS within 30 days (Clavien-Dindo grade ≥ 3), death within 30 days or death within 90 days due to complications to surgery. RESULTS: Fifteen patients with clinical T1 (cT1) and ten with clinical T2 (cT2) colon cancer and without suspicion of metastases were included. Failure occurred in two patients due to incomplete resections. Histopathological examination classified seven patients as having pT1, nine as pT2, six as pT3 adenocarcinomas, and three as non-invasive tumors. In three patients, the surgical strategy was changed intraoperatively to conventional colectomy due to tumor location or size. Median length of stay was 1 day. Seven patients had completion colectomy performed due to histological high-risk factors. None had LNM. CONCLUSIONS: In selected patients, CELS resection was feasible, and could spare some patients large bowel resection.

Development of a Fully Automated Method to Obtain Reproducible Lymphocyte Counts in Patients With Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide. Although clinical outcome varies among patients diagnosed within the same TNM stage it is the cornerstone in treatment decisions as well as follow-up programmes. Tumor-infiltrating lymphocytes have added value when evaluating survival outcomes. The aim of this study was to develop a fully automated method for quantification of subsets of T lymphocytes in the invasive margin and central tumor in patients with CRC based on Deep Learning powered artificial intelligence. The study cohort consisted of 163 consecutive patients with a primary diagnosis of CRC followed by a surgical resection. Double-labeling immunohistochemical staining with cytokeratin in combination with CD3 or CD8, respectively, was performed on 1 representative slide from each patient. Visiopharm Quantitative Digital Pathology software was used to develop Application Protocol Packages for visualization of architectural details (background, normal epithelium, cancer epithelium, surrounding tissue), identification of central tumor and invasive margin as well as subsequent quantitative analysis of immune cells. Fully automated counts for CD3 and CD8 positive T cells were obtained in 93% and 92% of the cases, respectively. In the remaining cases, manual editing was required. In conclusion, the development of a fully automated method for counting CD3 + and CD8 + lymphocytes in a cohort of patients with CRC provided excellent results eliminating not only observer variability in lymphocyte counts but also in identifying the regions of interest for the quantitative analysis. Validation of the performance of the Application Protocol Packages including clinical correlation is needed.

Immunohistochemical Staining With Neuroendocrine Markers is Essential in the Diagnosis of Neuroendocrine Neoplasms of the Esophagogastric Junction.

Neuroendocrine neoplasms (NENs) of the esophagogastric junction (EGJ) are uncommon and the classification of these tumors has been revised several times. Since 2016, at the Department of Pathology, Rigshospitalet, Denmark, all adenocarcinomas and poorly differentiated carcinomas of the EGJ have been stained routinely with the neuroendocrine markers, synaptophysin and chromogranin A, to detect a possible neuroendocrine component. This study aimed to determine if routine immunohistochemical staining is necessary to detect neuroendocrine differentiation of the EGJ tumors by evaluating how often a neuroendocrine component of the tumors was correctly identified or missed on routine hematoxylin and eosin-stained slides, and by evaluating the interobserver agreement among several pathologists. Of 262 cases a NEN was identified in 24 (9.2%). Up to 22.7% of all EGJ NENs would have been missed without routinely performed neuroendocrine staining in all EGJ tumors. The interobserver agreement between 3 pathologists was slight to moderate. In conclusion, immunohistochemical staining with neuroendocrine markers is essential for the diagnosis of NENs, and to detect all NENs, we recommend to perform this routinely on all resected tumors of the EGJ.

Impact of isolated tumor cells in regional lymph nodes in adeno-and squamous cell carcinoma of the esophagus and the esophagogastric junction-A systematic review.

BACKGROUND/INTRODUCTION: Isolated tumor cells (ITC) are tumor cells identified in the regional lymph nodes of patients with adeno- or squamous cell carcinoma of the esophagogastric junction (EGJ) or the esophagus. The current staging guidelines for these cancers do not assign any prognostic relevance to ITC, but their role remains debatable. We evaluated current literature to provide an overview of the prognostic relevance of ITC in regional lymph nodes of patients diagnosed with node negative cancer of the esophagus and EGJ. METHODS: A systematic search of several databases according to PRISMA guidelines. Three main criteria for inclusion were selected: 1. The studies had to include a group of patients with histopathologically identified ITC as defined by the Union for International Cancer Control Tumor, Node, Metastasis-classification 8th edition. 2. The studies had to include a group of patients classified as pN0. 3. The studies had to present the survival rate of patients with pN0, ITC. RESULTS: A total of five studies met the inclusion criteria. Combined, the studies included 434 pN0-patients of which 88 patients had ITC when evaluating the lymph nodes more extensively. The rate of ITC varied from 8% to 56% between studies. Significant differences in surgical techniques, neoadjuvant treatment and histological subtypes were observed. Three studies found a significant prognostic impact of ITC while one did not, and one had conflicting results. The largest difference in 5-year-survival was 33% for patients with ITC compared with 60% without ITC. CONCLUSION: Although, the results were conflicting, ITC appeared to be a negative prognostic factor in esophageal and EGJ cancer. However, heterogeneity between the studies did not allow for a definitive conclusion.

Microscopic colitis in Denmark and Sweden: incidence, putative risk factors, histological assessment and endoscopic activity.

OBJECTIVE: The significantly higher incidence rates of microscopic colitis (MC) in Denmark compared to Sweden remains unexplained. METHODS: Consecutive patients with newly diagnosed MC in the neighbouring regions of Skåne in 2011-2015 and Zealand in 2010-2016 were prospectively identified. Data on large bowel endoscopies and biopsies rates were retrieved. Information on putative factors were obtained from registers and literature. Interobserver agreement between pathologists from both regions on 40 blinded hematoxylin and eosin (H&E)-stained colon biopsies (collagenous colitis (CC), lymphocytic colitis (LC), non-specific inflammation and normal) was evaluated using kappa statistics. RESULTS: The mean annual incidence per 105 inhabitants in Skåne and Zealand 2010-2015 was 5.9 (95% CI 4.6-7.3) versus 16.4 (95% confidence intervals (95% CI) 13.6-19.2) for CC and 2.7 (95% CI 1.0-4.3) versus 11.1 (95% CI 8.8-13.4) for LC, respectively. Number of endoscopies with biopsy per 1000 and the rate of MC per endoscopy with biopsy was higher in Zealand (34-52/1000) than in Skåne (12-21/1000). The kappa value for overall agreement between pathologists was good (0.72; 95% CI 0.64-0.79). Prescription of proton pump inhibitors and selective serotonin reuptake inhibitors was higher in Skåne in the relevant age groups and prescription of non-steroidal anti-inflammatory drugs and smoking rate higher in Zealand. Alcohol consumption was higher in Denmark than in Sweden. CONCLUSION: The incidence of MC and number of cases per colonic biopsy was higher in Zealand and could not be readily explained by endoscopy or biopsy rates, differences in histological assessment or putative risk factors.

MiR-21 expression in the tumor stroma of oral squamous cell carcinoma: an independent biomarker of disease free survival.

Oral squamous cell carcinoma (OSCC) patients have a high mortality rate; thus, new clinical biomarkers and therapeutic options are needed. MicroRNAs (miRNAs) are short noncoding RNAs that regulate posttranscriptional gene expression and are commonly deregulated in OSCC and other cancers. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several types of cancer, and it might be a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in OSCC, paraffin-embedded tumor tissue samples from 86 patients with primary OSCC were analyzed by in situ hybridization. We found that miR-21 was primarily expressed in the tumor stroma and in some tumor-associated blood vessels with no expression in the adjacent normal epithelia or stroma. Using image analysis, we quantitatively estimated miR-21 expression levels specifically in the stroma of a cohort of OSCC samples. These miR-21 levels significantly correlated with disease free survival with the highest levels being located in the stroma. Stromal miR-21 expression was independently associated with a poorer prognosis, even after adjusting for clinical parameters (perineural invasion and N-stage) in a multivariate analysis. In summary, we have shown that miR-21 is located in the carcinoma cells, stroma and blood vessels of tumors, and its expression specifically in the stromal compartment has a negative prognostic value in OSCC.