Andries H. Mulder

Grading of dysplasia in Barrett's oesophagus: Substantial interobserver variation between general and gastrointestinal pathologists

Aims:  To determine interobserver variation in grading of dysplasia in Barretts oesophagus (BO) between non‐expert general pathologists and expert gastrointestinal pathologists on the one hand and between expert pathologists on the other hand.

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 (Barretts) 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 Barretts oesophagus.

Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study

OBJECTIVES:Patients with Barretts esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors.METHODS:We included 713 patients with BE (≥2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance.RESULTS:After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3–7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01–1.2), esophagitis (RR 3.5; 95% CI 1.3–9.5), and LGD (RR 9.7; 95% CI 4.4–21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18–40%).CONCLUSIONS:In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Cytogenetic analysis of Barrett's mucosa and adenocarcinoma of the distal esophagus and cardia

We performed flow cytometry and cytogenetic analysis of 37 adenocarcinomas of the distal esophagus and cardia, of which 22 arose in Barretts mucosa. Two of eight analyzed specimens of Barretts mucosa had clonal chromosomal abnormalities. In 19 cases clonal chromosomal abnormalities were found in tumor tissue. The complex pattern of cytogenetic changes did not differ among the adenocarcinomas arisen in Barretts esophagus, and those in the distal esophagus without Barretts mucosa or cardia. Abnormal karyotypes with multiple and complex rearrangements were seen in 11 cases and with single or a few numeric changes in eight. Losses of chromosomes 4, 18, 21, and Y were the most frequent numeric changes. Loss of the Y chromosome was observed in eight of 26 tumors of males (31%). Gains of chromosomes 14 and 20 were also frequent numeric changes. Structural abnormalities were observed in 13 of the abnormal karyotypes (68%). The chromosome arms most frequently rearranged were 1p, 3q, 11p and 22p. The chromosome arm most frequently contributing to losses was 1p, with the shortest region of overlap being 1p22-33. The chromosome arms most often involved in gains were 11p and 22p, and i(3q) was the isochromosome that was most frequently identified.

Dysplasia and aneuploidy as markers of malignant degeneration in Barrett's oesophagus. The Rotterdam Oesophageal Tumour Study Group.

The role of dysplasia and aneuploidy as markers in columnar epithelium for malignant degeneration in Barretts oesophagus was compared in a case control study comprising 38 patients with benign Barretts oesophagus and 50 patients with Barretts oesophagus associated with adenocarcinoma. Tissue specimens of columnar epithelium were reviewed for the presence of specialised columnar epithelium and the grade of dysplasia. Ploidy was determined using the method for formalin fixed paraffin wax embedded tissue described by Hedley. There was no significant difference in the frequency of specialised columnar epithelium between both groups. Dysplasia was found more often in columnar epithelium associated with adenocarcinoma compared with benign Barretts oesophagus (p < 0.001). Multivariate analysis using logistic regression showed an increased risk of malignancy in Barretts oesophagus in case of dysplasia (odds ratio 9.4, p = 0.003 for mild dysplasia and 33.1, p < 0.001 for moderate or severe dysplasia). Ploidy was not statistically significantly correlated with dysplasia. Aneuploidy or increased G2/tetraploidy proved to be an independent risk factor for younger patients (age < 65 years: odds ratio 44.7, p = 0.003). In conclusion, dysplasia and aneuploidy or increased G2/tetraploidy in columnar epithelium are independent risk factors for malignant degeneration. Patients with these risk factors should be offered a more intensive screening programme.

Chronic rejection of concordant aortic xenografts in the hamster-to-rat model

Several groups have demonstrated that it is possible to obtain long-term graft survival of concordant xenografts. One of the important questions that remains is whether xenografts are susceptible to chronic rejection. To answer this question we used the aorta transplantation model. One centimetre of hamster aorta was interposed in the abdominal aorta of Lewis rat recipients. The recipients were either untreated (group 1), or treated with 10 mg/kg cyclosporine (CsA), given intramuscularly three times a week (group 2). Rats were sacrificed at day 7, 14, 21, 28, 56 and 84 and the thickness of the intima, the media and the adventitia was measured. Furthermore, the cellularity of the media and the adventitia was assessed by counting the number of nuclei per 0.05 mm2 and immunohistochemistry of the aortic grafts was performed. Graft arteriosclerosis developed in aortic xenografts of both group 1 and group 2. In group 1, intimal lesions were already present from day 21 onwards in all rats, whereas in group 2 they were present only in 33% (2/6) of the rats. At day 84 all the grafts in group 1 were totally occluded, while those in group 2 were still open. The thickness of the media was slightly increased in both groups during the whole observation period, mainly due to edema. Although a few infiltrating macrophages could be seen, the number of nuclei per 0.05 mm2 of the media remained constant during the first 21 days, but declined sharply from day 21 onwards, as a consequence of disappearing myocytes. Thickness of the adventitia in both groups increased after transplantation due to infiltrating macrophages and T cells, reaching a peak at day 14. After day 14 the adventitial thickness in group 1 decreased rapidly to reach values comparable to group 2 from day 28 onwards. In conclusion, graft arteriosclerosis, as a sign of chronic rejection, occurs in concordant aortic xenografts. The lesions in the xenografts develop extremely rapidly, and compared to data from the literature, faster than in aortic allografts. The process of chronic rejection in aortic xenografts can be reduced by CsA.

Abnormal glomerular basement membrane in idiopathic multicentric osteolysis

The primary cause of nephropathy in idiopathic multicentric osteolysis is as yet unknown. We report a young girl with idiopathic multicentric osteolysis and nephropathy. An abnormal glomerular basement membrane was the only abnormality found in a renal biopsy taken 2 years before the development of end-stage renal failure. We believe that this biopsy finding represents or is related to the unknown primary lesion causing nephropathy in idiopathic multicentric osteolysis.

Phlegmonous gastritis: an unusual presenting symptom of Sjögren's syndrome.

This case report describes the histological and macroscopic changes seen within a few months in the gastric mucosa of a 28 year old woman patient with upper abdominal symptoms. With hindsight these changes were the first signs of Sjögrens syndrome.