A Model Based on Pathologic Features of Superficial Esophageal Adenocarcinoma Complements Clinical Node Staging in Determining Risk of Metastasis to Lymph Nodes.

BACKGROUND & AIMS: It is important to identify superficial (T1) gastroesophageal adenocarcinomas (EAC) that are most or least likely to metastasize to lymph nodes, to select appropriate therapy. We aimed to develop a risk stratification model for metastasis of superficial EAC to lymph nodes using pathologic features of the primary tumor. METHODS: We collected pathology data from 210 patients with T1 EAC who underwent esophagectomy from 1996 through 2012 on factors associated with metastasis to lymph nodes (tumor size, grade, angiolymphatic invasion, and submucosal invasion). Using these variables, we developed a multivariable logistic model to generate 4 categories for estimated risk of metastasis (<5% risk, 5%-10% risk, 15%-20% risk, or >20% risk). The model was validated in a separate cohort of 39 patients who underwent endoscopic resection of superficial EAC and subsequent esophagectomy, with node stage analysis. RESULTS: We developed a model based on 4 pathologic factors that determined risk of metastasis to range from 2.9% to 60% for patients in the first cohort. In the endoscopic resection validation cohort, higher risk scores were associated with increased detection of lymph node metastases at esophagectomy (P = .021). Among patients in the first cohort who did not have lymph node metastases detected before surgery (cN0), those with high risk scores (>20% risk) had 11-fold greater odds for having lymph node metastases at esophagectomy compared with patients with low risk scores (95% confidence interval, 2.3-52 fold). Increasing risk scores were associated with reduced patient survival time (P < .001) and shorter time to tumor recurrence (P < .001). Patients without lymph node metastases (pT1N0) but high risk scores had reduced times of survival (P < .001) and time to tumor recurrence (P = .001) after esophagectomy than patients with pT1N0 tumors and lower risk scores. CONCLUSIONS: Pathologic features of primary superficial EACs can be used, along with the conventional node staging system, to identify patients at low risk for metastasis, who can undergo endoscopic resection, or at high risk, who may benefit from induction or adjuvant therapy.

Tumor budding is associated with an increased risk of lymph node metastasis and poor prognosis in superficial esophageal adenocarcinoma.

The treatment approach for superficial (stage T1) esophageal adenocarcinoma critically depends on the pre-operative assessment of metastatic risk. Part of that assessment involves evaluation of the primary tumor for pathologic characteristics known to predict nodal metastasis: depth of invasion (intramucosal vs submucosal), angiolymphatic invasion, tumor grade, and tumor size. Tumor budding is a histologic pattern that is associated with poor prognosis in early-stage colorectal adenocarcinoma and a predictor of nodal metastasis in T1 colorectal adenocarcinoma. In a retrospective study, we used a semi-quantitative histologic scoring system to categorize 210 surgically resected, superficial (stage T1) esophageal adenocarcinomas according to the extent of tumor budding (none, focal, and extensive) and also evaluated other known risk factors for nodal metastasis, including depth of invasion, angiolymphatic invasion, tumor grade, and tumor size. We assessed the risk of nodal metastasis associated with tumor budding in univariate analyses and controlled for other risk factors in a multivariate logistic regression model. In all, 41% (24 out of 59) of tumors with extensive tumor budding (tumor budding in ≥3 20X microscopic fields) were metastatic to regional lymph nodes, compared with 10% (12 out of 117) of tumors with no tumor budding, and 15% (5 out of 34) of tumors with focal tumor budding (P<0.001). When controlling for all pathologic risk factors in a multivariate analysis, extensive tumor budding remains an independent risk factor for lymph node metastasis in superficial esophageal adenocarcinoma associated with a 2.5-fold increase (95% CI=1.1-6.3, P=0.039) in the risk of nodal metastasis. Extensive tumor budding is also a poor prognostic factor with respect to overall survival and time to recurrence in univariate and multivariate analyses. As an independent risk factor for nodal metastasis and poor prognosis after esophagectomy, tumor budding should be evaluated in superficial (T1) esophageal adenocarcinoma as a part of a comprehensive pathologic risk assessment.

Undifferentiated carcinoma of the esophagus: a clinicopathological study of 16 cases.

Undifferentiated carcinoma of the esophagus is a rare histologic variant of esophageal carcinoma. Using criteria based on studies of undifferentiated carcinomas arising at other sites, we have collected 16 cases of resected esophageal undifferentiated carcinomas. Patients ranged in age from 39 to 84 years (mean, 65.5 years) and were predominantly male (94%). The tumors were characterized by an expansile growth pattern of neoplastic cells organized in solid sheets and without significant glandular, squamous, or neuroendocrine differentiation. The neoplastic cells had a syncytial-like appearance, little intervening stroma, and patchy tumor necrosis. In a subset of cases, the tumor cells adopted a sarcomatoid (n = 2), rhabdoid (n = 1), or minor component (<5%) of glandular morphology (n = 3). In 1 case, reactive osteoclast-like giant cells were found interspersed among the neoplastic cells. Lymphovascular invasion, perineural invasion, and lymph node metastases were identified in 88%, 56%, and 81% of cases, respectively. In 12 (75%) specimens, the background esophageal mucosa was notable for Barrett esophagus. Consistent with the epithelial nature of these neoplasms, cytokeratin positivity was identified in all cases. In addition, SALL4 expression was present in 8 (67%) of 12 cases. Follow-up information was available for 15 (94%) of 16 patients, all of whom were deceased. Survival after surgery ranged from 1 to 50 months (mean, 11.9 months). Before death, 67% patients had documented locoregional recurrence and/or distant organ metastases. In summary, esophageal undifferentiated carcinomas are aggressive neoplasms and associated with a high incidence of recurrence and/or metastases and a dismal prognosis.

Smad4 loss in esophageal adenocarcinoma is associated with an increased propensity for disease recurrence and poor survival.

Previously regarded as a rare neoplasm, the incidence of esophageal adenocarcinoma has risen rapidly in recent decades. It is often discovered late in the disease process and has a dismal prognosis. Current prognostic markers including clinical, radiographic, and histopathologic findings have limited utility and do not consider the biology of this deadly disease. Genome-wide analyses have identified SMAD4 inactivation in a subset of tumors. Although Smad4 has been extensively studied in other gastrointestinal malignancies, its role in esophageal adenocarcinoma remains to be defined. Herein, we show, in a large cohort of esophageal adenocarcinomas, Smad4 loss by immunohistochemistry in 21 of 205 (10%) tumors and that Smad4 loss correlated with increased postoperative recurrence (P=0.040). Further, patients whose tumors lacked Smad4 had shorter time to recurrence (TTR) (P=0.007) and poor overall survival (OS) (P=0.011). The median TTR and OS of patients with Smad4-negative tumors was 13 and 16 months, respectively, as compared with 23 and 22 months, respectively, among patients with Smad4-positive tumors. In multivariate analyses, Smad4 loss was a prognostic factor for both TTR and OS, independent of histologic grade, lymphovascular invasion, perineural invasion, tumor stage, and lymph node status. Considering Smad4 loss correlated with postoperative locoregional and/or distant metastases, Smad4 was also assessed in a separate cohort of 5 locoregional recurrences and 43 metastatic esophageal adenocarcinomas. In contrast to primary tumors, a higher prevalence of Smad4 loss was observed in metastatic disease (44% vs. 10%). In summary, loss of Smad4 protein expression is an independent prognostic factor for TTR and OS that correlates with increased propensity for disease recurrence and poor survival in patients with esophageal adenocarcinoma after surgical resection.

MUC2 expression is an adverse prognostic factor in superficial gastroesophageal adenocarcinomas.

Mucin core proteins (MUCs) are expressed in tissue-specific patterns in the gastrointestinal tract and expression is deregulated in Barrett's metaplasia. Based on differential expression, MUCs have been used to classify adenocarcinomas into distinct phenotypes (eg, intestinal, gastric, pancreaticobiliary, etc). Because MUC expression patterns carry prognostic significance in other tumors, we evaluated MUC expression in superficial adenocarcinomas of the gastroesophageal junction and esophagus (EAC) to determine whether there are differences in outcome associated with MUC subtype in this potentially curable subset of EAC. We classified 142 resected, superficial (T1) EAC based on their pattern of expression of MUC2, MUC5AC, MUC6 and MUC1. The association between survival and MUC expression pattern was determined in univariate and multivariate analyses. The MUC2 positive "intestinal" phenotype was associated with significantly worse prognosis in submucosal EAC (hazard ratio 2.2, 95% confidence interval 1.2-4.2), independent of node stage and other prognostic factors. MUC2 expression in submucosal EAC also showed significantly accelerated time to recurrence (hazard ratio 2.8, 95% confidence interval 1.2-6.8) after adjusting for node stage. The classification of superficial EAC by MUC protein expression has prognostic significance. MUC2 expression is an adverse prognostic indicator in submucosal EAC, independent of node stage and other prognostic factors.

Transoral endoscopic inner layer esophagectomy: management of high-grade dysplasia and superficial cancer with organ preservation.

INTRODUCTION: Limitations of endoscopic therapies for Barrett's esophagus and superficial cancer include a compromised histological assessment, the need for surveillance, subsequent procedures, and stricture formation. Circumferential en bloc resection of the mucosa-submucosa complex followed by deployment of a biologic scaffold onto the remaining muscularis propria may address these concerns. The objective of this study was to determine technical feasibility of transoral resection of the esophageal lining. MATERIALS AND METHODS: Transoral endoscopic inner layer esophagectomy was performed in ten swine. Endpoints included procedure duration, hemorrhage, number of perforations, and adequacy of resection length and depth. RESULTS: Procedures were successfully completed in all animals without perioperative mortality. Procedure times averaged 179 min (range 125-320). No perforations were found, and a mean of 1.7 (0-4) interventions for hemorrhage was required. Complete longitudinal resection was achieved in nine of ten animals. Resection depth included all mucosal layers in 100% of tissue sections, the submucosal layers, SM1 in 100%, and SM2 in 96%. A portion of SM3 was adherent to the muscularis propria in 70%. CONCLUSION: Transoral endoscopic resection of the inner esophageal layers was feasible and reproducible. This technique may facilitate a single-step definitive treatment and staging tool for early neoplastic lesions, obviating the need for esophagectomy.