Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study.

BACKGROUND: Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. METHODS: A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. RESULTS: 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %-36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02-1.14, for every increase of 500 µm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95-4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10-1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75-0.86). CONCLUSIONS: A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice.

Lymphovascular invasion quantification could improve risk prediction of lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma.

AIM: To quantify lymphovascular invasion (LVI) and to assess the prognostic value in patients with pT1b esophageal adenocarcinoma. METHODS: In this nationwide, retrospective cohort study, patients were included if they were treated with surgery or endoscopic resection for pT1b esophageal adenocarcinoma. Primary endpoint was the presence of metastases, lymph node metastases, or distant metastases, in surgical resection specimens or during follow-up. A prediction model to identify risk factors for metastases was developed and internally validated. RESULTS: 248 patients were included. LVI was distributed as follows: no LVI (n = 196; 79.0%), 1 LVI focus (n = 16; 6.5%), 2-3 LVI foci (n = 21; 8.5%) and ≥4 LVI foci (n = 15; 6.0%). Seventy-eight patients had metastases. The risk of metastases was increased for tumors with 2-3 LVI foci [subdistribution hazard ratio (SHR) 3.39, 95% confidence interval (CI) 2.10-5.47] and ≥4 LVI foci (SHR 3.81, 95% CI 2.37-6.10). The prediction model demonstrated a good discriminative ability (c-statistic 0.81). CONCLUSION: The risk of metastases is higher when more LVI foci are present. Quantification of LVI could be useful for a more precise risk estimation of metastases. This model needs to be externally validated before implementation into clinical practice.

Olfactomedin 4 (OLFM4) expression is associated with nodal metastases in esophageal adenocarcinoma.

To date no informative biomarkers exist to accurately predict presence of lymph node metastases (LNM) in esophageal adenocarcinoma (EAC). We studied the discriminative value of Olfactomedin 4 (OLFM4), an intestinal stem cell marker, in EAC. Patients who had undergone esophagectomy as single treatment modality for both advanced (pT2-4) and early (pT1b) adenocarcinoma of the esophagus or gastro-esophageal junction were selected for this study from an institutional database (Erasmus MC University Medical Center, Rotterdam, The Netherlands). Surgical resection specimens of 196 advanced and 44 early EAC were examined. OLFM4 expression was studied by immunohistochemistry and categorized as low (<30%) or high (> = 30%) expression. Low OLFM4 was associated with poor differentiation grade in both advanced (60% vs. 34.8%, p = 0.001) and early EAC (39.1% vs. 9.5%, p = 0.023). LNM were present in 161 (82.1%) of advanced and 9 (20.5%) of early EAC respectively. Low OLFM4 was independently associated with the presence of LNM in advanced EAC in multivariable analysis (OR 2.7; 95% CI, 1.16-6.41; p = 0.022), but not in early EAC (OR 2.1; 95% CI, 0.46-9.84; p = 0.338). However, the difference in association with LNM between advanced (OR 2.7; 95% CI, 1.18-6.34; p = 0.019) and early (OR 2.3; 95% CI, 0.47-11.13; p = 0.302) EAC was non-significant (p = 0.844), suggesting that the lack of significance in early EAC is due to the small number of patients in this group. OLFM4 was not of significance for the disease free and overall survival. Overall, low expression of intestinal stem cell marker OLFM4 was associated with the presence of LNM. Our study suggests that OLFM4 could be an informative marker with the potential to improve preoperative assessment in patients with EAC. Further studies are needed to confirm the value of OLFM4 as a biomarker for LNM.

Improved Progression Prediction in Barrett's Esophagus With Low-grade Dysplasia Using Specific Histologic Criteria.

Risk stratification of patients with Barrett's esophagus (BE) is based on diagnosis of low-grade dysplasia (LGD). LGD has a poor interobserver agreement and a limited value for prediction of progression to high-grade dysplasia or esophageal adenocarcinoma. Specific reproducible histologic criteria may improve the predictive value of LGD. Four gastrointestinal pathologists examined 12 histologic criteria associated with LGD in 84 BE patients with LGD (15 progressors and 69 nonprogressors). The criteria with at least a moderate (kappa, 0.4 to 0.6) interobserver agreement were validated in an independent cohort of 98 BE patients with LGD (30 progressors and 68 nonprogressors). Hazard ratios (HR) were calculated by Cox proportional hazard regression analysis using time-dependent covariates correcting for multiple endoscopies during follow-up. Agreement was moderate or good for 4 criteria, that is, loss of maturation, mucin depletion, nuclear enlargement, and increase of mitosis. Combination of the criteria differentiated high-risk and low-risk group amongst patients with LGD diagnosis (P<0.001). When ≥2 criteria were present, a significantly higher progression rate to high-grade dysplasia or esophageal adenocarcinoma was observed (discovery set: HR, 5.47; 95% confidence interval [CI], 1.81-17; P=0.002; validation set: HR, 3.52; 95% CI, 1.56-7.97; P=0.003). Implementation of p53 immunohistochemistry and histologic criteria optimized the prediction of progression (area under the curve, 0.768; 95% CI, 0.656-0.881). We identified and validated a clinically applicable panel of 4 histologic criteria, segregating BE patients with LGD diagnosis into defined prognostic groups. This histologic panel can be used to improve clinical decision making, although additional studies are warranted.

Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma.

INTRODUCTION: TP53 mutations are considered to be the driving factor in the initiation of esophageal adenocarcinoma (EAC). However, the impact of this gene and its encoded protein as a prognostic marker has not been definitely established yet. METHODS: In total, 204 chemoradiotherapy (CRT)-naive patients with EAC were included for p53 protein expression evaluation by immunohistochemistry (IHC) on the resection specimens, categorized as overexpression, heterogeneous or loss of expression, and correlated with disease free survival (DFS) and overall survival (OS) using multivariable Cox regression analysis. In a subset representing all three IHC subgroups mutational status of selected candidate genes (n=33) and high throughput methylation profiling (n=16) was assessed. RESULTS: Compared to heterogeneous p53 expression, loss and overexpression were both independently predictive for adverse DFS and OS. TP53 mutational status significantly correlated with the IHC categories (p=0.035). Most of the EAC with loss- or overexpression harbored TP53 mutations (18/20, representing nonsense and missense mutations respectively). In contrast, 6/13 EAC with heterogeneous expression were TP53 wild type, of which two demonstrated MDM4 or MDM2 amplification. Combined genomic hypomethylation and high frequency of intra-chromosomal breaks was found in a selection of EAC without p53 overexpression. CONCLUSION: P53 expression pattern is prognostic for DFS and OS in this historical cohort of CRT-naive EAC. P53 IHC is an informative readout for TP53 mutational status in EAC with either loss- or overexpression, but not in case of a heterogeneous p53 pattern. Different EAC pathogenesis might exist, related to p53 and other candidate gene status, DNA hypomethylation and intrachromosomal breaks.

Value of cyclin A immunohistochemistry for cancer risk stratification in Barrett esophagus surveillance: A multicenter case-control study.

The value of endoscopic Barrett esophagus (BE) surveillance based on histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value of cyclin A expression and to combine these results with our previously reported immunohistochemical p53, AMACR, and SOX2 data, to identify a panel of biomarkers predicting neoplastic progression in BE.We conducted a case-control study within a prospective cohort of 720 BE patients. BE patients who progressed to high-grade dysplasia (HGD, n = 37) or esophageal adenocarcinoma (EAC, n = 13), defined as neoplastic progression, were classified as cases and patients without neoplastic progression were classified as controls (n = 575). Cyclin A expression was determined by immunohistochemistry in all 625 patients; these results were combined with the histological diagnosis and our previous p53, AMACR, and SOX2 data in loglinear regression models. Differences in discriminatory ability were quantified as changes in area under the ROC curve (AUC) for predicting neoplastic progression.Cyclin A surface positivity significantly increased throughout the metaplasia-dysplasia-carcinoma sequences and was seen in 10% (107/1050) of biopsy series without dysplasia, 33% (109/335) in LGD, and 69% (34/50) in HGD/EAC. Positive cyclin A expression was associated with an increased risk of neoplastic progression (adjusted relative risk (RR) 2.4; 95% CI: 1.7-3.4). Increases in AUC were substantial for P53 (+0.05), smaller for SOX2 (+0.014), minor for cyclin A (+0.003), and none for AMARC (0.00).Cyclin A immunopositivity was associated with an increased progression risk in BE patients. However, compared to p53 and SOX2, the incremental value of cyclin A was limited. The use of biomarkers has the potential to significantly improve risk stratification in BE.

Optimizing prostate cancer detection: 8 versus 12-core biopsy protocol.

PURPOSE: We compared prostate cancer detection rates achieved using an 8 and 12-core biopsy protocol in a clinical population to determine the significance of additional transition zone sampling on repeat biopsy. MATERIALS AND METHODS: Between September 2004 and September 2007, 269 eligible patients with a clinical suspicion of prostate cancer referred to our department were randomized to an 8-core lateral (group 1) or a 12-core lateral and parasagittal (group 2) transrectal ultrasound guided prostate biopsy protocol. Study inclusion criteria were age dependent increased serum prostate specific antigen (1.25 ng/ml or greater at ages less than 50 years, 1.75 or greater at ages 50 to less than 60 years, 2.25 or greater at ages 60 to less than 70 years and 3.25 or greater at ages 70 years or greater), positive digital rectal examination and/or suspicious transrectal ultrasound. After negative first round biopsy patients underwent 12-core biopsy, including 4 transition zone cores. RESULTS: Nine patients were excluded from analysis because of protocol violation or they did not complete the whole biopsy procedure due to discomfort. The cancer detection rate in groups 1 and 2 did not differ significantly (34.1% or 45 of 132 patients and 38.3% or 49 of 128, respectively, p = 0.48). Detected cancer median Gleason scores were similar in the groups. Of 109 patients who underwent repeat biopsy prostate cancer was detected in 20 (14.4%), of whom 9 had positive cores from the transition zone and 6 had positive biopsies only from the transition zone. CONCLUSIONS: There are no statistically significant differences in the prostate cancer detection rate between 8 and 12-core prostate biopsy protocols. Transition zone biopsies contribute to prostate cancer detection in a repeat biopsy protocol.