Arnulf H. Hölscher

The Number of Lymph Nodes Removed Predicts Survival in Esophageal Cancer: An International Study on the Impact of Extent of Surgical Resection

Objective:Surveillance, Epidemiology and End Results (SEER) data indicate that number of lymph nodes removed impacts survival in gastric cancer. Our aim was to study this relationship in esophageal cancer. Methods:The study population included 2303 esophageal cancer patients (1381 adenocarcinoma, 922 squamous) from 9 international centers that had R0 esophagectomy prior to 2002 and were followed at regular intervals for 5 years or until death. Patients treated with neoadjuvant or adjuvant therapy were excluded. Results:Operations consisted of esophagectomy with (1700) and without (603) thoracotomy. Median number of nodes removed was 17 (IQR10-29). There were 508 patients with stage I, 853 stage II, and 942 stage III. Five-year survival was 40%. Cox regression analysis showed that the number of lymph nodes removed was an independent predictor of survival (P < 0.0001). The optimal threshold predicted by Cox regression for this survival benefit was removal of a minimum of 23 nodes. Other independent predictors of survival were the number of involved nodes, depth of invasion, presence of nodal metastasis, and cell type. Conclusions:The number of lymph nodes removed is an independent predictor of survival after esophagectomy for cancer. To maximize this survival benefit a minimum of 23 regional lymph nodes must be removed.

Predicting Systemic Disease in Patients With Esophageal Cancer After Esophagectomy: A Multinational Study on the Significance of the Number of Involved Lymph Nodes

Objective:The aim of this study was to determine whether the risk of systemic disease after esophagectomy can be predicted by the number of involved lymph nodes. Summary Background Data:Primary esophagectomy is curative in some but not all patients with esophageal cancer. Identification of patients at high risk for systemic disease would allow selective use of additional systemic therapy. This study is a multinational, retrospective review of patients treated with resection alone to assess the impact of the number of involved lymph nodes on the probability of systemic disease. Methods:The study population included 1053 patients with esophageal cancer (700 adenocarcinoma, 353 squamous carcinoma) who underwent R0 esophagectomy with ≥15 lymph nodes resected at 9 international centers: Asia (1), Europe (5), and United States (3). To ensure a minimum potential follow-up of 5 years, only patients who had esophagectomy before October 2002 were included. Patients treated with neoadjuvant or adjuvant therapy were excluded. The impact of the number of involved lymph nodes on the risk of systemic disease recurrence was assessed using univariate and multivariate analyses. Results:Systemic disease occurred in 40%. The number of involved lymph nodes ranged from 0 to 26 with 55% of patients having at least 1 involved lymph node. The frequency of systemic disease after esophagectomy was 16% for those without nodal involvement and progressively increased to 93% in patients with 8 or more involved lymph nodes. Conclusions:This study shows that the number of involved lymph nodes can be used to predict the likelihood of systemic disease in patients with esophageal cancer. The probability of systemic disease exceeds 50% when 3 or more nodes are involved and approaches 100% when the number of involved nodes is 8 or more. Additional therapy is warranted in these patients with a high probability of systemic disease.

Prognostic factors of resected adenocarcinoma of the esophagus

BACKGROUND The main purpose of this study was to determine prognostic factors in patients with surgical treatment of adenocarcinoma of the esophagus. METHODS Within a 12.5-year period, esophageal adenocarcinoma was resected in 165 patients by radical transhiatal esophagectomy (n = 134) or transthoracic en bloc esophagectomy (n = 31). Tumors were analyzed according to the 1992 UICC classification with respect to pTNM stage, residual tumor (R) status, grading, and ratio of infiltrated to resected lymph nodes (lymph node ratio); both univariate and multivariate analysis of prognostic factors were performed. RESULTS The 30-day mortality rate was 6.1%. A complete removal of the tumor was achieved in 83% of the patients. Lymph node metastases were not detected in mucosal cancer (pT1a) but were detected in 18% of submucosal cancer (pT1b), 77% of pT2, 83% of pT3, and 96% of pT4. The overall 5-year survival rate was 34%; for patients without postoperative residual tumor (R0) it was 41%, and for those without lymph node metastases (pN0, R0) 63%. The 5-year survival rate for patients (pN1) with less than 30% invaded lymph nodes was 45%, compared with 0% for more than 30% invaded nodes. Independent prognostic factors for R0 resected patients excluding postoperative fatal outcome were pT and lymph node ratio. CONCLUSIONS Long-term survival after resection of esophageal adenocarcinoma is mainly associated with complete tumor removal, limited esophageal wall penetration, and ratio of infiltrated to removed lymph nodes of less than 0.3.

Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett's esophagus at two high-volume centers.

Background and Objective:Esophagectomy has previously been the gold standard for patients with mucosal adenocarcinoma in Barretts esophagus (Barretts carcinoma, BC). Because of the minimal invasiveness and excellent results obtained with endoscopic resection (ER), the latter has become an accepted alternative. However, few data have so far been published comparing the 2 treatment methods. Methods:A total of 114 patients with mucosal BC who were treated surgically or endoscopically in 2 high-volume centers were included in this study. Between 1996 and 2009, 38 patients with mucosal BC received transthoracic esophageal resection with 2-field lymphadenectomy (median 29 lymph nodes removed; all pN0) in the Department of Surgery at the University of Cologne. Seventy-six patients with BC treated with ER followed by argon-plasma-coagulation of the remaining non-dysplastic Barretts esophagus in the Department of Gastroenterology in Wiesbaden were matched according to the following criteria: age, gender, infiltration depth (pT1m1–3), differentiation grade (G1/2 vs. 3) and follow-up period. Results:There were no significant differences between the 2 groups with regard to epidemiologic and tumor criteria. Complete remission (CR) was achieved in all patients in the surgery group and all but 1 patient in the ER group (98.7%; the patient died of other causes before CR was achieved). Major complications after surgery occurred in 32% of the patients, significantly more often than in the ER group (0% major complications, P < 0.001). The 90-day mortality rates were 0% in the ER group and 2.6% in the surgical group (1 of 38; P = 0.333). The median follow-up periods were 4.1 years in the ER group and 3.7 years in the surgical group. During this period, 1 patient in the ER group had a local recurrence and 4 had metachronous neoplasia (overall recurrence rate 6.6%). However, repeat endoscopic treatment was possible in all of the patients, and the long-term CR rates in the surgical and ER groups were 100% and 98.7%, respectively. No tumor-related mortality was observed in either group. Conclusions:For patients with mucosal BC, both surgery and ER are effective treatment modalities. Surgery is associated with a higher morbidity rate and shows a risk for procedure-related mortality. However, the recurrence rate is higher in patients treated with ER, so that thorough follow-up procedures are mandatory.

Laparoscopic Ischemic Conditioning of the Stomach for Esophageal Replacement

Objectives:A considerable percentage of morbidity and mortality after esophagectomy and gastric pull-up is due to leakage of the esophagogastrostomy, which is mainly caused by ischemia of the gastric fundus. Previous clinical studies demonstrated that impaired microcirculation of the gastric conduit almost recovers within the first 5 postoperative days. Therefore, this study was designed to improve gastric perfusion by laparoscopic ischemic conditioning of the stomach. Methods:The study group consisted of 83 patients with 44 esophageal adenocarcinomas and 39 squamous cell carcinomas. A total of 51% received neoadjuvant radiochemotherapy. First, all patients underwent laparoscopic mobilization of the stomach including the cardia and preparation of the gastric conduit. After a mean delay of 4.3 days (range, 3–7 days), a conventional right-sided transthoracic en bloc esophagectomy was performed. Reconstruction was done by gastric pull-up and high intrathoracic esophagogastrostomy. Results:Three conversions (3.6%) to open surgery were necessary during laparoscopic mobilization of the stomach. The reoperation rate was 2.4% (one relaparoscopy for control of a bleeding of the stapler line, one rethoracotomy for chylothorax). Two patients showed circumscribed necroses of the upper part of the fundus after gastric pull-up into the chest. These necroses were resected for reconstruction by esophagogastrostomy. Five patients (6.0%) developed small anastomotic leakages with minor clinical symptoms; however, the gastric conduits were well vascularized. All leakages healed after endoscopic stenting. Major postoperative complications were observed in 13.3% of the patients and the 90-day mortality was 0%. Conclusion:Laparoscopic ischemic conditioning of the gastric conduit is feasible and safe and may contribute to the reduction of postoperative morbidity and mortality after esophagectomy and gastric pull-up.

Prognosis of early esophageal cancer. Comparison between adeno‐and squamous cell carcinoma

Background. The purpose of this study was to compare the prognosis of patients with T1 squamous cell carcinoma (SCC) with those with Tl adenocarcinoma of the esophagus and to explain prognostic differences by an analysis of clinicopathologic characteristics.

Lymph Node Size and Metastatic Infiltration in Colon Cancer

Background: Detection of metastatic lymph nodes in colon cancer is essential for determining stage and adjuvant treatment modalities. Lymph node size has been used as one possible criterion for nodal metastasis. Although enlarged regional lymph nodes are generally interpreted as metastases, few data are available that correlate lymph node size with metastatic infiltration in colon cancer.Methods: In a prospective morphometric study, the regional lymph nodes from 30 colon specimens from consecutive patients with primary colon cancer were analyzed. The lymph nodes were counted and the largest diameter of each lymph node was measured and analyzed for metastatic involvement by histological examination.Results: A total of 698 lymph nodes were present in the 30 specimens examined for this study. A mean number of 23 (range, 19–39) lymph nodes was found in each specimen. Of these nodes, 566 (81%) were tumor-free and 132 (19%) contained metastases. The mean diameter of the lymph nodes free of metastases was 3.9 mm, whereas those infiltrated by metastases averaged 5.9 mm in diameter (P< 0.0001). Of the tumor-free lymph nodes, 528 (93%) measured < 5 mm in diameter, whereas 70 (53%) lymph nodes containing metastases measured < 5 mm in diameter.Conclusions: Lymph node size is not a reliable indicator for lymph node metastasis in colon cancer. A careful histological search for small lymph node metastasis in the specimen should be undertaken to avoid false-negative node staging.

International consensus on standardization of data collection for complications associated with esophagectomy: Esophagectomy Complications Consensus Group (ECCG)

INTRODUCTION Perioperative complications influence long- and short-term outcomes after esophagectomy. The absence of a standardized system for defining and recording complications and quality measures after esophageal resection has meant that there is wide variation in evaluating their impact on these outcomes. METHODS The Esophageal Complications Consensus Group comprised 21 high-volume esophageal surgeons from 14 countries, supported by all the major thoracic and upper gastrointestinal professional societies. Delphi surveys and group meetings were used to achieve a consensus on standardized methods for defining complications and quality measures that could be collected in institutional databases and national audits. RESULTS A standardized list of complications was created to provide a template for recording individual complications associated with esophagectomy. Where possible, these were linked to preexisting international definitions. A Delphi survey facilitated production of specific definitions for anastomotic leak, conduit necrosis, chyle leak, and recurrent nerve palsy. An additional Delphi survey documented consensus regarding critical quality parameters recommended for routine inclusion in databases. These quality parameters were documentation on mortality, comorbidities, completeness of data collection, blood transfusion, grading of complication severity, changes in level of care, discharge location, and readmission rates. CONCLUSIONS The proposed system for defining and recording perioperative complications associated with esophagectomy provides an infrastructure to standardize international data collection and facilitate future comparative studies and quality improvement projects.

MUC1 and Nuclear β-Catenin Are Coexpressed at the Invasion Front of Colorectal Carcinomas and Are Both Correlated with Tumor Prognosis

Purpose: Overexpression of MUC1 and cytosolic interaction of the mucin with β-catenin are claimed to be involved in colorectal carcinogenesis. In vitro data published recently suggest that MUC1 overexpression results in an increase of steady state levels of nuclear β-catenin. We tried to elucidate the coexpression of both molecules in colorectal cancer to demonstrate possible correlations with clinical, pathological, and prognostic data. Experimental Design: An immunohistochemical double staining study was performed to characterize the expression and subcellular distribution of MUC1 and β-catenin in a series of 205 patients with colorectal carcinoma. The results were correlated with clinicopathological variables as well as overall survival. Results: MUC1 was strongly expressed in the tumor center and at the invasion front in ∼50% of the cases. Similar results were obtained with regard to nuclear accumulation of β-catenin at the invasive tumor parts. MUC1 protein expression in the tumor center correlated significantly with a low grade of differentiation, and nuclear β-catenin in the tumor periphery was more frequent in carcinomas of the left colon and rectum. Overexpression of MUC1 and β-catenin, as well as their nuclear coexpression at the invasion front correlated with a worse overall survival in an univariate analysis. However, only pathological tumor-node-metastasis staging and MUC1 at the invasion front revealed as independent prognostic factors. Conclusions: These results suggest that MUC1 and β-catenin are coexpressed at the invasion front of colorectal carcinomas and that this feature is associated with an accelerated course of disease and worse prognosis.

Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival

Methylation of 5′ CpG islands in promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of this study was to determine whether hypermethylation of the adenomatous polyposis coli (APC) gene promoter occurs in primary non-small cell lung cancer (NSCLC), and whether hypermethylated APC has any relationship with survival. APC promoter 1A methylation was determined in normal and corresponding tumor tissue from 91 NSCLC patients and in a control group of 10 patients without cancer, using a quantitative fluorogenic real-time PCR (Taqman®) system. APC promoter methylation was detectable in 86 (95%) of 91 tumor samples, but also in 80 (88%) of 91 normal samples of NSCLC patients, and in only two (20%) of 10 normal lung tissues of the control group. The median level of APC promoter methylation was 4.75 in tumor compared to 1.57 in normal lung tissue (P<0.001). Patients with low methylation status showed significantly longer survival than did patients with high methylation status (P=0.041). In a multivariate analysis of prognostic factors, APC methylation was a significant independent prognostic factor (P=0.044), as were pT (P=0.050) and pN (P<0.001) classifications. This investigation shows that APC gene promoter methylation occurs in the majority of primary NSCLCs. High APC promoter methylation is significantly associated with inferior survival, showing promise as a biomarker of biologically aggressive disease in NSCLC.