Preferred location for the development of esophageal adenocarcinoma within a segment of intestinal metaplasia.

BACKGROUND: Barrett's metaplasia is the predominant precursor for the development of esophageal adenocarcinoma. This precancerous lesion has become the focus of various surveillance programs aimed at detecting earlier and therefore potentially curable lesions. However, sampling error by missing invasive cancer lesions is a common problem. This study aimed to identify preferred locations within a segment of Barrett's mucosa for the development of esophageal adenocarcinoma. METHODS: The study group consisted of 213 patients with histologically proven esophageal adenocarcinoma. Of those, there were 134 cases of early cancer and 79 cases of locally advanced lesions. These patients received neoadjuvant chemotherapy. The frequency of intestinal metaplasia and the location of the tumor occurrence within the segment of intestinal metaplasia were assessed. RESULTS: Intestinal metaplasia was found in 83% of the early lesions and in 98% of the advanced tumors after neoadjuvant chemotherapy. In 82.2% of the cases, the tumor was located at the distal margin of the intestinal metaplasia in patients with early tumor manifestations. The remaining tumor mass after neoadjuvant therapy also was located predominantly at the distal margin of the segment of intestinal metaplasia (85% of the cases). CONCLUSIONS: The results demonstrate that almost all adenocarcinomas of the esophagus are based on the development of a segment of intestinal metaplasia. The distal margin of Barrett's mucosa seems to be the most vulnerable location for the development of invasive cancer.

Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging.

PURPOSE: Preoperative chemotherapy in patients with gastroesophageal cancer is hampered by the lack of reliable predictors of tumor response. This study evaluates whether positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may predict response early in the course of therapy. PATIENTS AND METHODS: Forty consecutive patients with locally advanced adenocarcinomas of the esophagogastric junction were studied by FDG-PET at baseline and 14 days after initiation of cisplatin-based polychemotherapy. Clinical response (reduction of tumor length and wall thickness by > 50%) was evaluated after 3 months of therapy using endoscopy and standard imaging techniques. Patients with potentially resectable tumors underwent surgery, and tumor regression was assessed histopathologically. RESULTS: The reduction of tumor FDG uptake (mean +/- 1 SD) after 14 days of therapy was significantly different between responding (-54% +/- 17%) and nonresponding tumors (-15% +/- 21%). Optimal differentiation was achieved by a cutoff value of 35% reduction of initial FDG uptake. Applying this cutoff value as a criterion for a metabolic response predicted clinical response with a sensitivity and specificity of 93% (14 of 15 patients) and 95% (21 of 22), respectively. Histopathologically complete or subtotal tumor regression was achieved in 53% (eight of 15) of the patients with a metabolic response but only in 5% (one of 22) of the patients without a metabolic response. Patients without a metabolic response were also characterized by significantly shorter time to progression/recurrence (P =.01) and shorter overall survival (P =.04). CONCLUSION: PET imaging may differentiate responding and nonresponding tumors early in the course of therapy. By avoiding ineffective and potentially harmful treatment, this may markedly facilitate the use of preoperative therapy, especially in patients with potentially resectable tumors.

P53 mutational status improves estimation of prognosis in patients with curatively resected adenocarcinoma in Barrett's esophagus.

The incidence of adenocarcinomas in Barrett's esophagus has been rising in the last two decades in the United States and Western Europe for yet unknown reasons. We reported previously a large multi-institutional trial implicating p53 mutations as being involved in the pathogenesis of Barrett's cancer and representing an early marker for the malignant potential of Barrett's epithelium. A prospective study was performed to evaluate the prognostic impact of p53 mutations on survival in 59 patients with Barrett's cancer. Tissue for DNA analysis was obtained by endoscopic biopsy or immediately after surgical resections from the tumor, Barrett's epithelium, and normal stomach and esophagus. p53 mutation analysis was performed by PCR-single strand conformational polymorphism screening of exons 5-9 and DNA sequencing to unequivocally prove the presence of a mutation. p53 mutations were identified in 30 of 59 (50.8%) patients. The presence of a p53 mutation in the tumor had a significant impact on survival after curative resections (RO-resections) with cumulative 5-year survival probabilities of 68.8+/-9.7% for mutation-negative tumors and 24.3+/-9.9% for mutation-positive tumors (log rank: P < 0.001). By Cox proportional hazard analysis, including the parameters of gender, age, Union International Contre Cancer tumor stage, grading, and p53 mutation status, only Union International Contre Cancer tumor stage (P < 0.0001) and p53 mutation status (P < 0.02) were of significant independent prognostic importance. p53 mutation analysis by DNA sequencing is of significant independent prognostic importance next to histopathological tumor stage in patients with curatively resected (RO-resection) Barrett's cancer. It appears that p53 mutational status is a valuable parameter to define low-risk (p53 mutation-negative) and high-risk (p53 mutation-positive) groups for treatment failure after curative resections.

[Barrett's esophagus]. / Barrett-Osophagus Verhältnis zwischen Ausmass der intestinalen Metaplasie, Funktion des unteren Osophagussphinkters und Säure- bzw. Gallereflux.

INTRODUCTION: It is widely accepted that long segments of Barrett's esophagus are caused by end-stage gastroesophageal reflux disease (GERD), but little is known about the correlation of severity of GERD and extent of metaplasia. METHODS: Twenty normal volunteers and 142 patients with different extent of intestinal metaplasia (39 with intestinal metaplasia limited to the esophagogastric junction, 48 with short segments of Barrett's esophagus, and 55 with long segments) underwent manometry and combined pH-bilirubin monitoring. RESULTS: The extent of intestinal metaplasia correlated to the exposition of gastric and duodenal juice in the esophagus and inversely with a competent lower esophageal sphincter. CONCLUSIONS: The extent of intestinal metaplasia is related to the severity of GERD.

Mutations of p53 in Barrett's esophagus and Barrett's cancer: a prospective study of ninety-eight cases.

We had previously identified p53 mutations in Barrett's esophagus and therefore began a multiinstitutional study to determine their significance as a marker for malignancy. Ninety-eight patients from four institutions were studied. Forty-eight patients (37 men and 11 women, mean age 56.2 years) had Barrett's esophagus with metaplasia or dysplasia but no evidence of malignancy at a mean follow-up of 2.2 years. Barrett's esophagus was classified as metaplasia with no evidence of dysplasia in 32 patients, as low-grade dysplasia in 13, and as high-grade dysplasia in three. The other 50 patients (46 men and four women, mean age 60.2 years) had adenocarcinoma arising in Barrett's esophagus. Tissues from normal stomach or esophagus, tumor, and Barrett's esophagus were obtained for deoxyribonucleic acid analysis by endoscopic biopsy from patients with Barrett's esophagus or cancer or during operations on some patients with Barrett's cancer. Exons 5 through 9 of the p53 gene were studied for mutations by single-strand conformational polymorphism analysis after polymerase chain reaction amplification. Mutations detected by single-strand conformational polymorphism analysis were confirmed by deoxyribonucleic acid sequencing. None of the tissue samples from patients with Barrett's esophagus alone and no dysplasia or low-grade dysplasia had any p53 mutations, but one of the three patients with high-grade dysplasia and no evidence of invasive malignancy did have a p53 mutation. Of the 50 patients with Barrett's cancer, however, 23 (46%) had p53 mutations in Barrett's epithelium, tumors, or both. Twenty of these patients had p53 mutations in the tumor only (n = 16) or in both tumor and Barrett's epithelium (n = 4), suggesting that the mutation plays a direct role in carcinogenesis. Mutations in Barrett's epithelium were found in one patient in the group without malignancy and in seven patients with cancer (one with no dysplasia, two with low-grade dysplasia, and five with high-grade dysplasia). In three patients with cancer, mutations occurred only in Barrett's epithelium, suggesting that such mutations may also be a marker for genomic instability. Mutations were predominantly found in exons 5, 7, and 8, and transitions from guanine to adenine were the most frequent changes. Mutations of p53 are clearly involved in the pathogenesis of Barrett's cancer for a subset of patients (46%), and the fact that we could detect mutations in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk for development of invasive cancer.

Responders benefit from neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma: results of a prospective phase-II trial.

BACKGROUND: We present the results of a prospective phase-II-study of neoadjuvant combined radiochemotherapy followed by surgical resection in patients with histological proven locally advanced squamous cell carcinoma of the esophagus located at or above the level of the tracheal bifurcation. METHODOLOGY: Between February 1995 and March 2000 a total of 76 patients with esophageal squamous cell carcinoma (uT3/4N0/+-categories) received simultaneous combined neoadjuvant radiochemotherapy consisting of a continuous intravenous infusion of 5-fluorouracil (300 mg/m2/day) 7 day per week concurrently with conventional fractioned external beam radiation therapy (2 Gy/day), five fractions per week up to a total dose of 30 Gy. RESULTS: Radiochemotherapy related acute severe toxicity rate (CTC-grade-III) occurred in 34 patients, two patients died. Sixty-four patients underwent surgery with a complete resection in 48 patients. Three patients died during a 90-day post-operative course. The histopathological workup revealed no viable residual tumour cells in eight patients (ypCR) and according to the modified criteria of Mandard in 26 patients a histopathological response. Twenty-two of these patients underwent a R0-resection. The median follow-up time was 5.4 years with an overall median survival time of 20.6 months. The median survival in the 26 responders was 32.3 months versus 19.5 months in 38 non-responders (p=0.03). CONCLUSIONS: Patients with locally advanced squamous cell carcinoma of the esophagus, who respond to preoperative neoadjuvant combined radiochemotherapy, seem to have more benefit from subsequent resection than non-responding patients.

Assessment of resectability of gastrointestinal cancers by endoscopic ultrasonography.

The general principle in the treatment of malignancy is complete tumor removal. Meticulous preoperative staging determines whether the complete resection is technically possible. Should radical resection prove to be impossible, palliative methods are applied that aim at restitution of the intestinal passage without any effect on survival.

The value of endosonographic rectal carcinoma staging in routine diagnostics: a 10-year analysis.

BACKGROUND: Endosonography is currently the gold standard for the local staging of rectal carcinoma, but its accuracy varies from 62% to 91%. This study aimed to determine the accuracy of endosonography, to evaluate the interobserver variability, and to compare the performance of the 7.5-MHz and the 10-MHz ultrasound scanners. METHODS: Between 1990 and 2000, 458 patients with rectal cancer were included in the study. All the patients had undergone rectal endosonography with a 7.5-MHz scan (period 1: 1990-1996) or a 10-MHz scan (period 2: 1997-2000). Endosonographic staging was compared with pathologic staging. RESULTS: The overall rate for correctly classified patients was 69% with respect to the T category and 68% with respect to the N category. There was no difference between the two scanners. In terms of accuracy, the T3 category tumors were the most (86%) and the T4 tumors the least (36%) accurately classified. Overstaging of tumors (19%) was much more frequent than understaging (12%). A high interobserver variability of 61% to 77% was noted. For pT1 tumors, the 10-MHz scan was almost two times more accurate than the 7.5-MHz scan (71% vs 36%). CONCLUSIONS: The accuracy of endosonographic staging of rectal carcinoma very much depends on the T category. A high-resolution scanner and an experienced examiner can help to ensure that endosonography remains an important tool in the staging process of patients with rectal carcinoma, especially early carcinoma.

Preoperative chemotherapy unmasks underlying Barrett's mucosa in patients with adenocarcinoma of the distal esophagus.

BACKGROUND: Intestinal metaplasia of the distal esophagus frequently cannot be detected in patients with esophageal adenocarcinoma. It has therefore been questioned whether Barrett's esophagus is the primary precursor lesion of such lesions. We hypothesized that the underlying Barrett's mucosa may be masked by tumor overgrowth in the majority of these patients. METHODS: The pretherapeutic endoscopy and biopsy records of 79 patients with locally advanced esophageal adenocarcinoma who had undergone preoperative chemotherapy were reviewed and compared to findings on restaging endoscopy/biopsy and subsequent resection and histopathologic analysis of the resected specimen. RESULTS: Pretherapeutic endoscopy and biopsy showed associated Barrett's esophagus in 59/79 patients, whereas there was no evidence of associated intestinal metaplasia in 20/79 patients on extensive biopsies. Following neoadjuvant chemotherapy, Barrett's mucosa was unmasked and later documented by biopsy or histopathologic assessment of the resected specimen in 18 of the latter 20 patients. This resulted in an overall association of Barrett's mucosa with adenocarcinoma in the distal esophagus of 97.4% CONCLUSION: Underlying Barrett's mucosa is frequently masked by tumor overgrowth in patients with locally advanced adenocarcinoma of the distal esophagus.

Adenocarcinoma of the gastro-esophageal junction: CT for monitoring during neoadjuvant chemotherapy.

OBJECTIVE: A clinical study was performed to assess the diagnostic value of spiral CT for evaluation of response during neoadjuvant chemotherapy (CTx) in patients with adenocarcinoma of the gastro-esophageal-junction (GEJ). Results were compared to those of endoscopy. METHODS AND MATERIAL: Twenty-five patients with histologically proven adenocarcinoma of the GEJ scheduled to undergo neoadjuvant CTx were studied. Before CT examination, 1200 ml of a vanilla flavoured paraffin emulsion were applied orally to the fasting patients and 40 mg BuscopanR or 2 mg glucagon were injected i.v. for hypotonia. Iodine (100 ml) was injected automatically (3 ml/s) and the CT scan was started 10 s after complete administration of CM. For response evaluation to CTx, four standardized parameters were measured by two experienced, blinded radiologists. The results were categorized according to the WHO classification of 1981 and compared to those of endoscopy. RESULTS: In 24 of 25 patients endoscopic and computed tomographic response evaluation showed a close correlation (r = 0.96). CONCLUSION: Spiral CT with negative oral contrast agent is a suitable technique for monitoring of GEJ masses. In combination with standardized metric parameters it offers a quantitative response evaluation in patients with GEJ masses during neoadjuvant CTx.

Multiple hollow organ dysplasia in Ehlers-Danlos syndrome.

We report a case of Ehlers-Danlos syndrome with a number of rare, hazard-creating organ dysplasias such as colon diverticula causing spontaneous perforation, bladder diverticula, bile duct diverticula, and multiple aneurysma formations of the arteries.

Preoperative staging and risk analysis in esophageal carcinoma.

In esophageal cancer surgery a preoperative risk analysis of the patient and staging of the tumor are necessary to reduce postoperative mortality and to identify those patients who will benefit from primary surgery. A risk analysis includes the recording of cardiac, pulmonary, renal, hepatic and cerebral functions, and defines the functional limits of the various systems. Preoperatively it is most important to assess whether the primary tumor is completely resectable or not, because only patients undergoing complete tumor resection benefit from surgery with respect to the long-term prognosis. It is necessary to undertake a classification on the basis of tumor localization and local infiltration, which today can most reliably be evaluated by endoscopic ultrasonography. Advanced tumors above the bifurcation are associated with early infiltration of the tracheobronchial system, and should therefore receive preoperative treatment with combined radiotherapy and chemotherapy. Below the bifurcation, only T4-tumors invading neighboring structures should receive this pretreatment, whereas all others can be resected primarily.

[Surgical endoscopy for staging and the selection of procedure]. / Chirurgische Endoskopie für Staging und Verfahrenswahl.

The outcome in the treatment of malignant tumors of the gastrointestinal tract can be improved in two ways: by early recognition, and possibly also by multimodal treatment concepts. Endoscopic methods are can serve two purposes: firstly, the diagnosis and recognition of early and flat lesions; here high resolution video-endoscopy, in some cases supplemented by magnification and chromo-endoscopy and other extended methods (e.g. autofluorescence), are likely to improve the diagnostic accuracy. Another purpose endoscopy and endoscopic ultrasound is to select patients suitable for local therapy of early cancers. In advanced tumors, endoscopy and especially endosonography are the standard methods for predicting the locoregional tumor stage, in order to select patients who may benefit from neoadjuvant treatment to select patients for curative treatment or palliation. The role of endoscopy and endosonography for the diagnosis and treatment of oesophageal, gastric and rectal carcinoma is discussed in the following review.

[Laser and afterloading therapy: esophageal cancer]. / Laser- und Afterloading-Therapie: Oesophaguscarcinom.

In the palliative treatment of malignant esophageal stenosis endoscopic laser therapy and intracavitary radiation currently represent the best alternative. The results achieved with elimination of dysphagia, duration of the complaint-free interval, survival period, and complications are presented from a group of 167 patients. Referring to the quality of life, an evolving tendency towards the use of laser therapy instead of endoscopic intubation is reported.

Role of endoscopic ultrasonography in esophageal carcinoma.

One hundred and sixty seven consecutive patients with esophageal carcinoma (squamous cell carcinoma: n = 108, adenocarcinoma: n = 59) who underwent surgery were preoperatively examined by endoscopic ultrasonography (EUS), and the results were compared with intraoperative exploration and histopathological evaluation of resection specimens. The T and N stage were correctly determined by EUS in 86% and 73%, respectively. The assessment of the T stage for cases with traversable (n = 124) versus non-traversable (n = 43) tumor stenoses was 85% and 70%, respectively. Prediction of resectability by EUS (89%) was correct for adenocarcinoma (82% actual R0 resection rate), but not for squamous cell cancer (64%). This was due to the high incidence of submucosal microscopic tumor spread of squamous cell cancer not detectable on EUS. We consider EUS an indispensable diagnostic tool in the local staging of esophageal cancer since it provides important information in the assessment of resectability, aids in therapeutic decisions and in determining the prognosis. Our comparably low rate of primary surgery (66%) and the high resection rate of 95% are due to the exact preoperative staging by EUS.

Role of endoscopic ultrasonography in gastric carcinoma.

Two hundred and fifty four consecutive patients with gastric adenocarcinoma who underwent surgery were preoperatively evaluated with endoscopic ultrasonography (EUS). The results were compared with the post-operative histo-pathological staging. EUS was correct in determining the T and N stage in 83% and 66%, respectively. Although EUS was accurate in determining the absence of lymph node metastases (accuracy in stage N0: 93%), it was not reliable in determining stages N1 and N2 (64% and 52%, respectively). Since 88% of all T3 and T4 tumors had lymph node metastases, the concomitant T stage may be an important criterion for assessing the nature of endosonographically visualized lymph nodes. The actual R0-resection rate (78%) was almost identical to the rate predicted preoperatively by EUS (81%). We therefore consider EUS a valuable pretherapeutic procedure in patients with gastric carcinoma.

Staging of squamous esophageal cancer: accuracy and value.

Endoscopic ultrasonography (EUS) and computed tomography (CT) should be used as complementary methods for TNM staging of esophageal cancer. EUS is the most accurate modality for staging primary tumor and mediastinal lymph node metastases. CT should be used to detect infiltration of other mediastinal organs and distant metastases. For esophageal cancer staging magnetic resonance imaging (MRI) is not superior to CT. For detection of cervical lymph node metastases percutaneous ultrasonography is appropriate. In patients with advanced distal carcinoma of the esophagus, hepatic and peritoneal metastases and intraabdominal lymph node infiltration should be ruled out by laparoscopy prior to surgery. The results of preoperative staging are relevant if the management of esophageal cancer comprises not only surgery but also endoscopic mucosectomy, primary palliative procedures, and especially neoadjuvant radiochemotherapy. Within therapeutic trials the precise staging prior to treatment is essential for analysis of the results. The value of routine postoperative staging during a follow-up program is yet unproved for esophageal cancer.

[What is the value of endosonography in the preoperative staging of esophageal carcinoma?]. / Was leistet die Endosonographie im präoperativen Staging des Osophaguskarzinoms?

The value of endosonography (ES) for diagnosing the stage of oesophageal carcinoma was analysed in 180 patients with this form of cancer (161 men and 19 women; mean age 57 [41-73] years). The tumour stenosis could not be passed in 54 patients (30%). Primary resection of the tumour was possible in 97 patients (53.9%). It is in these latter cases that the results of endosonography and histological findings in the resected specimen were compared. The sensitivity of ES for the depth of infiltration of the primary tumour was 85%, while for involvement of regional lymph nodes it was 75%. In those cases in which ES could be applied only at the tumour stenosis but not beyond, the staging sensitivity was 72%. According to the ES findings, R0-resection should have been possible in 87 of 97 patients (89.7%), but on the basis of the histological findings in only 65 patients (67%). Nonetheless, ES is at present the most accurate method of judging resectability and thus of formulating a multimodal preoperative treatment concept.

Endoscopic classification of esophageal cancer: correlation with the T stage.

Staging of esophageal squamous cell carcinoma is a prerequisite to assessing prognosis and deciding on appropriate treatment. Endoscopy provides one means of predicting the extent of tumor growth. Using the classification of the Japanese Society for Esophageal Diseases, which differentiates superficial (type 0) from more advanced stages of esophageal carcinoma, we studied 273 patients with squamous cell cancer of the esophagus. Histopathologic examination of resected specimens (N = 81) or endosonography (N = 128) served to correlate the endoscopically defined categories with the otherwise determined T stages. Not classifiable by endoscopy were 64 patients (23.4%), 42 of whom were pre-treated by means of chemo- or radiation therapy. In the remaining 209 patients, it could be shown that endoscopic assessment was both sensitive (78%) and specific (93%) in predicting the local extent of tumor (overall accuracy, 89%). Detailed analysis showed good sensitivity for stage 0 (83%) which corresponds to T-1 carcinoma and for stages 3 and 4 (82% and 83%) which represent T-3 and T-4 tumors. Only in endoscopic stages 1 and 2 was the concordance with the T stage (T-2) weaker, with a sensitivity of 52%. We conclude that prediction of local tumor extent by endoscopic observation is a generally reliable means of pre-operative staging esophageal cancer.