Laser and brachytherapy in the palliation of adenocarcinoma of the oesophagus and cardia.

BACKGROUND: Palliation of malignant dysphagia is possible by a variety of methods although all have significant drawbacks. Laser therapy is an effective and safe treatment but has to be repeated at four to five weekly intervals to maintain palliation. A means of augmenting the benefits while reducing the need for repeat treatments would be highly beneficial to these patients. AIMS: To prospectively explore the safety and efficacy of intraluminal radiotherapy (brachytherapy) when used to augment laser recanalisation for malignant dysphagia. PATIENTS: Nineteen patients with dysphagia due to advanced adenocarcinoma of the oesophagus or cardia were recruited. METHODS: All patients received laser recanalisation until able to swallow a soft diet or better, before the application of a single dose of brachytherapy (10 Gy at 1 cm from the source). Patients were followed up and treated promptly by further endoscopic means in the event of their dysphagia worsening. RESULTS: Six patients (32%) required no further treatment until death at a median of 10 weeks (range 1-20 weeks). Further therapy was required at a median of 11 weeks (range 4-37 weeks) after brachytherapy for those 13 patients with recurrent dysphagia. Subsequent symptom control required endoscopic intervention at an average of once every nine weeks. There was no mortality associated with laser or brachytherapy. Median survival from initial treatment and including the one survivor was 36 weeks (range 5-132 weeks). CONCLUSIONS: Laser plus brachytherapy offers a safe and effective means of palliating malignant dysphagia due to adenocarcinoma, with a longer dysphagia free interval than historical controls treated with laser alone.     

Outcome of surgical treatment of adenocarcinoma in Barrett''s oesophagus.

A retrospective study was performed of an 11 year period (1978-88) to analyse the survival of 112 patients (85 men and 27 women, mean age 63 years) with adenocarcinoma in a columnar lined (Barrett's) oesophagus in respect of surgical treatment, tumour staging, and histological grading. Presenting symptoms were dysphagia (60%) and pain (25%). Only six patients were previously known to have a columnar lined oesophagus. Eighty five patients (76%) underwent partial resection of the oesophagus and cardia. Postoperative mortality was 6%. After resection (n = 85), the 5 year survival was 24%. Survival was significantly better for patients without regional lymph node metastases (stage 0, I, IIA (n = 61): 5 year survival 30%) and even better if the tumour was restricted to the submucosa (stage 0, I (n = 12): 5 year survival 63%). Survival was not influenced by the histological grade of the tumour. Staging based on infiltration of the oesophageal wall and lymph node spread is valuable in determining the prognosis for patients with adenocarcinoma in Barrett's oesophagus.     

Epidemiological differences between adenocarcinoma of the oesophagus and adenocarcinoma of the gastric cardia in the USA

BACKGROUND AND AIMS: It has been suggested that gastric cardia adenocarcinoma (GCA) is a distinct entity from oesophageal adenocarcinoma (OA). We examined several epidemiological features of GCA and OA in the USA to elucidate differences/similarities between these malignancies. METHODS: Using the database of Surveillance, Epidemiology, and End Results (SEER) program, we examined incidence rates for temporal changes, and ethnic and age distributions, and performed birth cohort analyses for cases with morphologically and histologically confirmed OA or GCA. RESULTS: The age adjusted incidence rates of OA rose progressively, reaching 1.8 per 100 000 (95% confidence interval 1.7-1.9) during 1987-1991 and 2.5 per 100 000 (2.3-2.6) during 1992-1996. In 1992-1996, Whites were affected five times more than Blacks, and men eight times more than women. A significant increase in incidence occurred among younger persons aged 45-65 years. Irrespective of age, OA was characterised by higher incidence rates among more recent birth cohorts: a 40% increase in incidence for each five year increase in the date of birth--a "birth cohort effect". On the other hand, the incidence rates of GCA reached their highest level of 3.3 per 100 000 (3.2-3.4) in 1987-1991 and subsequently declined during 1992-1996 to 3.1 per 100 000 (3.0-3.3). Whites were affected twice more than blacks and men five times more than women. Most patients with GCA were older than 60 years with no increase among younger persons and no birth cohort effect (p=0.99). CONCLUSION: Several significant epidemiological differences exist between OA and GCA. These differences suggest that these two malignancies are separate entities with different risk factors.     

Only patients with dysplasia progress to adenocarcinoma in Barrett''s oesophagus.

Columnar lined oesophagus (Barrett's oesophagus) carries a risk for the development of adenocarcinoma. Epithelial dysplasia appears to be a precursor but the utility of this marker for predicting subsequent adenocarcinoma is unsettled. We therefore prospectively studied 81 patients with histologically proven columnar epithelium of at least the distal 3 cm of the tubular oesophagus with regular endoscopic biopsies for a total of 289.2 patient years (mean 3.6 years, range 0.5-8). Twenty three patients (28%) had epithelial dysplasia detected during follow up. Both patients with persistent high grade dysplasia present on initial biopsies developed adenocarcinoma after 2.6-4.5 years, despite the absence of gross macroscopic change. The initial single layer pleomorphic high grade dysplasia in one patient regressed to low grade dysplasia which has persisted for 1.5 years. Of 10 patients with initial low grade dysplasia, one progressed to adenocarcinoma in 4.3 years. The low grade dysplasia persisted unchanged in seven patients for 1.5-7 years and appears to have regressed in two patients after three to five years. Ten patients developed low grade dysplasia during the surveillance period. This has persisted unchanged in six patients from 0.5-5 years, regressed in three for 0.5-5 years and has appeared after the first yearly biopsy in one patient. No patient without dysplasia has developed adenocarcinoma. The incidence of adenocarcinoma in Barrett's oesophagus in this study is one case per 96 patient years. This is 61 times (95% confidence limits 12-176) the age adjusted incidence of oesophageal cancer in Australia. Persistent high grade dysplasia appears to be a sensitive indicator for the development of subsequent adenocarcinoma.     

Length of Barrett''s oesophagus: an important factor in the development of dysplasia and adenocarcinoma.

In a 15 year prospective study of endoscopic surveillance of columnar lined oesophagus, 102 patients with a mean follow up of 54 (12.5) months and total follow up of 462 years have been evaluated. Of all the sets of biopsies taken, 59 in 21 patients were found to exhibit dysplasia or carcinoma. Four male patients had carcinoma of the oesophagus, indicating a 30 times increased risk of development of adenocarcinoma in columnar lined oesophagus. The length of columnar lined oesophagus in subjects with dysplasia was significantly longer as compared with the whole group (p = 0.01) and when compared with the patients without dysplasia (p = 0.005). None of the patients with dysplasia had a columnar lined oesophagus of less than 8 cm. Length of columnar lined oesophagus therefore seems to be a significant risk factor in the development of dysplasia and subsequent carcinoma and intensive follow up of patients with columnar lined oesophagus greater than 8 cm in length is recommended.     

Detection of adenocarcinoma in Barrett's oesophagus by means of laser induced fluorescence.

PATIENTS: Seven patients with Barrett's metaplastic epithelium and oesophageal adenocarcinoma were investigated by means of laser induced fluorescence after low dose intravenous injection (0.35 mg/kg bw) of Photofrin (QLT, Vancouver, Canada). Laser induced fluorescence measurements were performed immediately after resection of the oesophagus. METHODS: Laser induced fluorescence spectra were recorded from 15-30 locations in each surgical specimen from normal mucosa, Barrett's epithelium, and tumour tissue. Histological examination was performed on each location to correlate the fluorescence spectral characteristics with histological status of the epithelium (normal, metaplastic or malignant). Measurements were also performed during endoscopy in five patients to test the applicability of the method in a clinical setting. Fluorescence spectra were recorded and evaluated at characteristic wavelengths, and biopsy specimens were collected. Fluorescence ratios were calculated as the quotient of Photofrin fluorescence divided by autofluorescence. RESULTS: The mean (SD) fluorescence ratio values were 0.10 (0.058) for normal oesophageal mucosa, 0.16 (0.073) for normal gastric mucosa, 0.205 (0.17) for Barrett's epithelium with moderate dysplasia, 0.79 (0.54) for severe dysplasia, and 0.78 (0.56) for adenocarcinoma. The highest fluorescence ratios were obtained for adenocarcinoma tissue, which could generally be distinguished from all nonmalignant tissue. Metaplastic Barrett's epithelium also yielded higher fluorescence ratios than did normal mucosa. CONCLUSIONS: The results suggest that the technique can be used during endoscopy for real time tissue characterisation in the oesophagus, as an aid in detecting malignant transformation not macroscopically apparent at endoscopy.     

Management of Barrett's oesophagus, dysplasia and early adenocarcinoma

There has been a dramatic increase in recent years in the incidence of Barrett's oesophagus and the oesophageal adenocarcinoma associated with it. Adequate monitoring strategies and improved diagnostic procedures are therefore essential. Alongside conventional video-endoscopy with four-quadrant biopsies, many additional diagnostic procedures are now available to improve monitoring. These allow the early diagnosis of dysplastic areas and early carcinomas. Both thermal procedures (argon plasma coagulation, multipolar electrocoagulation and KTP laser and Nd∶YAG laser treatment) and non-thermal ablation procedures (photodynamic therapy) are used for the endoscopic ablation of Barrett's mucosa without dysplasia, being employed in addition to acid suppression treatment. On the basis of the data currently available, it is, however, not yet possible to offer a general recommendation in favour of endoscopic ablation. Alongside surgical treatment for high-grade dysplasia and early carcinoma, endoscopic treatment procedures, which have a much lower complication and mortality rate, will probably play an important role in the future. Endoscopic mucosal resection and photodynamic therapy are particularly promising. Long-term results with these procedures are, however, still awaited.     

Flow-cytometric analysis of growth-regulatory peptides and their receptors in Barrett's oesophagus and oesophageal adenocarcinoma.

The conventional assessment of the premalignant potential of Barrett's oesophagus is unsatisfactory. However, it has recently been shown that abnormalities of growth-regulatory peptides and their receptors may be important in the pathogenesis of this condition. In an attempt to improve the diagnostic and prognostic criteria we have studied 21 consecutive patients with Barrett's oesophagus and 7 others with adenocarcinoma of the oesophagus. In each patient biopsy specimens were taken from the columnarlined oesophagus or the adenocarcinoma and from the gastric cardiac mucosa for routine histologic evaluation. Immediately adjacent specimens were taken from both the Barrett's mucosa or adenocarcinoma and from the gastric mucosa for flow-cytometric study. The latter samples were disaggregated and labelled with antibodies to epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and epidermal growth factor receptor (EGF-R). The flow cytometer selected cells labelled with each antibody and expressed them as a percentage of the total number of disaggregated cells (average, 5500 cells). Epidermal growth factor receptors were expressed in a greater number of cells from Barrett's mucosa, with the intestinal type or those with dysplasia, than in gastric cardiac mucosa (p less than 0.05). All seven adenocarcinoma had many more cells expressing EGF, TGF-alpha, and EGF-R than normal gastric mucosa (p less than 0.01). We conclude that flow-cytometric evaluation of EGF-R can help in the understanding of the pathogenesis of Barrett's oesophagus.     

Familial aggregation of Barrett's oesophagus,oesophageal adenocarcinoma,and oesophagogastric junctional adenocarcinoma in Caucasian adults

BACKGROUND: Although familial clusters of Barrett's oesophagus and oesophageal adenocarcinoma have been reported, a familial predisposition to these diseases has not been systematically investigated. AIMS: To determine whether Barrett's oesophagus and oesophageal (or oesophagogastric junctional) adenocarcinoma aggregate in families. PATIENTS AND METHODS: A structured questionnaire eliciting details on reflux symptoms, exposure history, and family history was given to Caucasian case (n=58) subjects with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma, and to Caucasian control (n=106) subjects with symptomatic gastro-oesophageal reflux disease without Barrett's oesophagus. Reported diagnoses of family members were confirmed by review of medical records. RESULTS: The presence of a positive family history (that is, first or second degree relative with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma) was significantly higher among case subjects compared with controls (24% v 5%; p<0.005). Case subjects were more likely to be older (p<0.001) and male (74% v 43% male; p<0.0005) compared with control subjects. In a multivariate logistic regression analysis, family history was independently associated with the presence of Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma (odds ratio 12.23, 95% confidence interval 3.34-44.76) after adjusting for age, sex, and the presence of obesity 10 or more years prior to study enrollment. CONCLUSIONS: Individuals with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma are more likely to have a positive family history of Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma than individuals without Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma. A positive family history should be considered when making decisions about screening endoscopy in patients with symptoms of gastro-oesophageal reflux.     

Endoscopic ultrasonography in the preoperative staging of adenocarcinoma of the distal oesophagus and oesophagogastric junction

BACKGROUND: Endoscopic ultrasonography is considered to be the most accurate procedure in the preoperative staging of oesophageal carcinoma. Its accuracy was evaluated in the preoperative staging of adenocarcinoma of the distal oesophagus and oesophagogastric junction. Methods: Thirty-two consecutive patients with adenocarcinoma of the distal oesophagus and oesophagogastric junction were preoperatively examined and staged by means of endoscopic ultrasonography. All patients underwent radical en bloc resection of the oesophagus and proximal stomach (or total gastrectomy) with standard lymphadenectomy including thoracic duct and mediastinal fat tissue. The postoperative histopathologic TNM stage was taken as reference. RESULTS: An endoscopic ultrasonography examination could be completed in 26 of the patients; the other 6 had obstructive tumour. In two patients infiltration of the tumour into the vital organs (in one patient aortic infiltration and in a second patient pericardial infiltration) was incorrectly suspected. The ability to predict T stage was 65.6%. T stage was overstaged in 31.2% and understaged in 3.1% of the cases. The ability to predict N stage was 71.9%. N stage was overstaged in 25.0% and understaged 3.1% of the cases. CONCLUSIONS: In adenocarcinoma of the oesophagus and oesophagogastric junction endoscopic ultrasonography helps in predicting resectability, but the exact TN staging is not accurate. Since early detection of tumour and aggressive surgical intervention constitute the only curative treatment, caution must be exercised when judging a patient to be inoperable solely on the basis of endoscopic ultrasonography findings without proven distant metastases.     

Barrett oesophagus and adenocarcinoma: an overview of epidemiologic, conceptual and clinical issues.

A steady increase in the incidence of adenocarcinoma of the oesophagus and oesophagogastric junction has been observed in Western countries. Patients with distinctive-type Barrett oesophagus are predisposed to developing adenocarcinoma of the oesophagus. Distinctive-type Barrett oesophagus is defined by the presence of intestinal-like goblet cells anywhere in the oesophagus. Adenocarcinomas of the oesophagogastric junction may be associated with short segments of intestinal-type columnar epithelium in the distal oesophagus. Prognosis after surgical resection for cancer of the oesophagus or oesophagogastric junction is strongly affected by the extent of the disease at the time of diagnosis. The identification of Barrett oesophagus as a premalignant condition, the recognition of a stepwise neoplastic progression, along with the poor survival rates of advanced oesophageal adenocarcinoma have initiated the practice of endoscopic biopsy surveillance for patients with Barrett oesophagus. There is supporting evidence that endoscopic biopsy surveillance of Barrett oesophagus permits detection of malignancy at an early stage with favourable results after oesophageal resection. Endoscopic treatment modalities should at this time not be generally adopted in the management of patients with early invasive adenocarcinoma of the oesophagus or oesophagogastric junction.     

Intramucosal adenocarcinoma arising under squamous re-epithelialisation of Barrett's oesophagus

BACKGROUND: Eradication of Barrett's mucosa by thermal or photoablation combined with high doses of proton pump inhibitors is a potentially attractive strategy in the management of this preneoplastic condition. However, major concerns of this method are the persistence of residual metaplastic glands beneath the new squamous epithelium and the absence of any knowledge of its impact on long term outcome. CASE REPORT: The case of an intramucosal adenocarcinoma diagnosed 18 months after apparently complete squamous re-epithelialisation achieved using argon plasma coagulation and high dose omeprazole (40 mg/daily) is reported in a 68 year old patient presenting initially with a Barrett's oesophagus without dysplasia. Intramucosal adenocarcinoma was located under the new squamous layer and presented as a bulging area covered by the squamous epithelium. It probably originates from residual metaplastic glands after therapy although a pre-existing tumour cannot be definitely excluded. CONCLUSION: This observation might question future application of this experimental endotherapy in non-dysplastic Barrett's oesophagus. It suggests that the residual glands might still be premalignant and that the early diagnosis of neoplastic changes might be compromised by the squamous re-epithelialisation.     

Barrett食管粘蛋白表达及意义

目的检测Barrett食管中粘蛋白的表达，探讨粘蛋白表达的意义。方法采用免疫组化方法检测Barrett食管上皮中MUC1、MUC2、MUC3、MUC5AC及MUC6粘蛋白的表达，分析粘蛋白表达与Barrett食管组织病理学分型及放大内镜下小凹分型间的关系。结果Barrett食管胃型化生上皮以及肠化上皮均可见MUC1的弱阳性表达；肠化上皮中见MUC2的强阳性表达，阳性表达主要位于杯状细胞胞浆中；MUC3不仅在Barrett食管肠化上皮表层的柱状细胞及杯状细胞浆表达，而且在肠化上皮的无肠化区的柱状细胞内也可见阳性表达；MUC5AC不仅在Barrett食管胃、肠上皮化生的表层柱状上皮胞浆内强阳性表达，而且在杯状细胞亦见阳性表达；在Barrett食管胃、肠两型上皮化生的深层腺体均可见MUC6的阳性表达，抗原定位于细胞浆内，杯状和柱状细胞均有阳性反应物质；在不同分型小凹中，绒毛状及不规则型小凹上皮MUC2、MUC3的阳性表达显著高于点状和棒状（P〈0．01）；MUC2、MUC3仅在肠化上皮中表达，在胃底及交界型上皮中无表达；MUC1、MUCSAC及MUC6在胃型及肠型化生上皮中均呈阳性表达，阳性表达率在各组织病理分型间差异无统计学意义（P〉0．05）。结论Barrett食管肠化生上皮中特异表达MUC2与MUC3；MUC3的表达可能是肠化形成的早期事件；绒毛状及不规则型小凹中MUC2与MUC3高表达提示两型小凹的肠型分化特点，检测其表达有助于Barrett食管特殊肠上皮化生的识别。     

NSAIDs and the oesophagus.

There have been many studies documenting the deleterious effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal tract, and it is widely accepted that these agents cause mucosal damage in the stomach, duodenum, jejunum, ileum and colon. The mechanism of this toxicity is at least partly due to inhibition of endogenous prostaglandin synthesis. Prostaglandins, especially PGE2, PGI2 and the synthetic PGE1 analogue misoprostol, protect the stomach from these harmful effects. There is good theoretical evidence that the opposite is the case in the oesophagus, with prostaglandins causing relaxation of the lower oesophageal sphincter, increasing acid reflux and acting as mediators of the inflammatory response. NSAIDs have beneficial effects in some models of oesophagitis and have even been proposed as treatment for oesophagitis. In spite of these theoretical benefits, there are many reports implicating NSAIDs in the pathogenesis of oesophagitis, oesophageal ulceration and stricture formation.