Is the etiology of eosinophilic esophagitis in adults a response to allergy or reflux injury? Study of cellular proliferation markers.

Recent research suggests that allergy may be the key factor in the etiology of eosinophilic esophagitis (EE); however, historically, the condition was hypothesized as related to reflux injury to the esophageal mucosa. We studied this hypothesis by comparing markers of inflammation and cellular proliferation in EE and reflux esophagitis. Lower esophageal biopsies of adult patients with EE (n = 10), reflux esophagitis (n = 8), and normal controls (n = 13) were assessed quantitatively for the expression of the cyclooxygenase-2 (COX-2) enzyme, cellular proliferation, and oncogenic resistance to apoptosis using monoclonal antibodies for COX-2, Ki-67, and Bcl-2, respectively. Normal esophageal epithelium demonstrated weak diffuse uptake of COX-2 stain in the basal layer. No COX-2 expression was demonstrated in the EE group, significantly less than the control and reflux groups (P < 0.01 and P < 0.001, respectively). Cellular proliferation measured by Ki-67 expression was higher in EE and reflux compared with control (P < 0.001 and P < 0.01). Ki-67 expression, and thus degree of hyperplasia, appeared greater in EE than reflux, but was not statistically significant (P = 0.228). The degree of apoptosis was similar in all study groups. EE and reflux esophagitis are proliferative conditions expressing Ki-67 in higher concentrations than control. Mucosal proliferation in reflux esophagitis is COX-2 dependent. This novel research in EE has demonstrated downregulation of COX-2 expression compared with reflux esophagitis and control. We hypothesize that the allergy-related cytokine IL-13 known to inhibit COX-2 expression and found in high concentrations in EE as responsible for this. The pathogenesis of EE is likely dependent on allergy rather than reflux injury to the esophagus.

Reciprocal relationship between expression of hypoxia inducible factor 1alpha (HIF-1alpha) and the pro-apoptotic protein bid in ex vivo colorectal cancer.

Hypoxia inducible factor 1 (HIF-1) represses the transcription of pro-apoptotic bid in colorectal cancer cells in vitro. To assess the clinical relevance of this observation, HIF-1alpha and Bid were assessed in serial sections of 39 human colorectal adenocarcinomas by immunohistochemistry. In high HIF-1alpha nuclear-positive cell subpopulations, there was a significant reduction in Bid expression (ANOVA, P=0.04). Given the role of Bid in drug-induced apoptosis, these data add impetus to strategies targeting HIF-1 for therapeutic gain.

Intra-operative pathological diagnosis of chronic ulcerative colitis in the two stage ileal pouch anal anastomosis.

OBJECTIVE: The definitive diagnostic biopsy for chronic ulcerative colitis (CUC) is the colon itself. Simultaneous colectomy and ileal pouch anal anastomosis (IPAA) means that the colon only becomes available for pathological assessment intra-operatively. We examined the role of intra-operative pathological assessment including frozen section in distinguishing between CUC and Crohn's colitis, inpatients undergoing simultaneous colectomy and IPAA. METHOD: Prospective study of 13 patients undergoing simultaneous colectomy and IPAA between Jan 1992 and April 1999. Resected colon was sent for pathological assessment intra-operatively in all 13 patients. Comparison was made between final histology and frozen section. Patient outcome and pouch function was recorded prospectively. RESULTS: Thirteen patients, M:F 5:8, mean age 41 years (range 20-56). Intra-operative pathological assessment including frozen section diagnosed CUC in nine patients, Crohn's disease in two patients and indeterminate colitis in two patients. The two Crohn's patients had subtotal colectomy and ileostomy. The nine CUC patients and two indeterminate colitis patients underwent IPAA. There was complete agreement between intra-operative assessment including frozen section and the final histopathology. At a median follow up of 31 months (8-58 months) all pouches were intact with good function. There has been no evidence of Crohn's disease on subsequent pouchoscopy and pouch biopsy. CONCLUSIONS: Pathological assessment, including frozen section of the colon, intra-operatively is a useful adjunct to surgical decision making in those patients undergoing simultaneous colectomy and IPAA.

Eosinophilic oesophagitis: a novel treatment using Montelukast.

BACKGROUND: Eosinophilic oesophagitis is a rarely diagnosed condition involving eosinophil infiltration of the oesophageal mucosa and creating significant symptoms of dysphagia. Failure to diagnose this disorder relates to reluctance to biopsy an apparently normal oesophagus. This is essential for histological diagnosis. To date, treatment success has been achieved only with corticosteroids. We describe here the use of an eosinophil stabilising agent Montelukast for the symptomatic relief of these patients. PATIENTS AND METHODS: Twelve patients have been identified with this condition in our unit since 1995, after thorough investigation of their dysphagia. We commenced eight of these patients on the leukotriene receptor antagonist Montelukast to symptomatically improve their swallowing while avoiding the use of long term corticosteroids. RESULTS: Many of these patients had been previously misdiagnosed, and therefore inappropriately and unsuccessfully treated for an extensive period prior to referral to our unit. All patients were unresponsive to acid suppression therapy alone but showed improvement in their swallowing on Montelukast. Six of eight reported complete subjective improvement, five patients remaining completely asymptomatic on a maintenance regimen. CONCLUSIONS: Eosinophilic oesophagitis is a disease that is often misdiagnosed due to lack of awareness and reluctance of clinicians to biopsy an apparently normal oesophagus in dysphagic patients, and therefore obtain a histological diagnosis. Investigation of these patients adds further evidence to this condition being a separate pathological state from gastro-oesophageal reflux and eosinophilic enteritis. Montelukast has been found to be of significant help in the symptomatic control of these patients while avoiding long term corticosteroids use.

Diffuse esophageal leiomyomatosis with localized dense eosinophilic infiltration.

Diffuse esophageal leiomyomatosis is a rare cause of dysphagia. There is frequently a chronic inflammatory infiltrate, but here we present the first reported case in association with a dense infiltration of eosinophils and mast cells confined to the affected muscularis propria. This was successfully managed by long esophageal myotomy, with resolution of dysphagia and no symptomatic recurrence after 3 years.

Prevention of the neoplastic progression of Barrett's oesophagus by endoscopic argon beam plasma ablation.

BACKGROUND: Patients with Barrett's oesophagus have a risk of approximately 1 per 100 patient-years for the development of oesophageal adenocarcinoma. Endoscopic ablation of Barrett's oesophagus has been shown to lead to the regrowth of a 'neo' squamous epithelium if gastro-oesophageal reflux is controlled, but the incidence of subsequent tumour formation is unknown. METHODS: The follow-up of 55 patients who underwent endoscopic ablation of Barrett's oesophagus by argon beam plasma coagulation (ABPC) is reported. Of the 55 patients, nine had low-grade dysplasia, nine had high-grade dysplasia and the remainder had non-dysplastic Barrett's metaplasia. Twelve patients had reflux control by antireflux surgery and the remainder received proton pump inhibitor therapy. Barrett's metaplasia was ablated by ABPC to within 2 cm of the gastro-oesophageal junction. RESULTS: To date, one patient has died and one patient was unable to complete treatment. The remaining patients were followed by regular endoscopic surveillance for a mean of 38.5 months to give a total follow-up of 173.5 patient-years. No malignancy has developed in any patient during follow-up. CONCLUSION: The absence of malignant complications in this study of prophylactic ablation of long-segment Barrett's oesophagus strengthens the argument for endoscopic ablation in the prevention of oesophageal adenocarcinoma.

Value and accuracy of cytology in addition to histology in the diagnosis of lung cancer at flexible bronchoscopy.

There is still disagreement as to the value and reliability of wash and brush cytology, in comparison with histology, for the diagnosis of malignancy at flexible bronchoscopy. The present study compares the yield and concordance of findings from the two modalities for visible tumours at flexible bronchoscopy. A single-centre study of 514 consecutive flexible bronchoscopy procedures, in which a lesion suspicious of cancer was seen and bronchial wash cytology, brush cytology and forceps biopsy samples were taken. All equivocal or suspicious results were taken as negative. An overall yield of 89.3% was achieved using a combination of all three tests. This was greater for endobronchial than submucosal (95% vs. 86%) tumours. Cytology alone diagnosed 17.7% of cases. Use of all three modalities allowed tumours to be differentiated between small and non-small cell types in all but 5/459 positive cases (98.9%). There were only 3/313 cases in which there was a difference in cell type (small cell vs. non-small cell) between the two modalities. We conclude that wash and brush cytology are valuable tools, in addition to forceps biopsy, at flexible bronchoscopy. All three tests should be performed routinely in cases of suspected malignancy.

Cyclooxygenase-2 expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence.

OBJECTIVE: Increased expression of the inducible cyclooxygenase 2 (COX-2) enzyme has been detected in esophageal and colonic adenocarcinoma, and intake of aspirin and non-steroidal anti-inflammatory drugs, known COX-2 inhibitors, have been associated with reduced tumor formation. Elevated COX-2 mRNA but variable protein expression has been demonstrated in Barrett's epithelium, and we have, therefore, sought to evaluate the expression of COX-2 protein throughout the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. METHODS: Paraffin-embedded esophageal biopsies from 56 different patients with Barrett's esophagus were analyzed for COX-2 expression by immunohistochemistry. Twenty contained nondysplastic intestinal and gastric metaplasia, 12 demonstrated low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 12 contained invasive adenocarcinoma. RESULTS: Epithelial expression of COX-2 protein was detected in 75% (15/20) of benign cases, 83% (10/12) of cases with LGD, and 100% of cases with HGD or adenocarcinoma. Using a semiquantitative analysis, median staining scores for the groups were 2, 3, 14, and 13, respectively (scale 0-16), with the expression being significantly higher in the HGD and cancer groups compared to benign and LGD groups (p < 0.001). CONCLUSIONS: This study demonstrates clear COX-2 expression in the epithelial cells in Barrett's metaplasia, confirms elevated expression in adenocarcinoma, and shows that the elevation in expression occurs in the progression from LGD to HGD.

Lymphoepithelioid cell lymphoma (Lennert's lymphoma) presenting as atypical granuloma annulare.

We describe a case presenting as atypical granuloma annulare where the underlying diagnosis, confirmed by lymph node biopsy, was lymphoepithelioid cell lymphoma (Lennert's lymphoma). Lennert's lymphoma is a peripheral T-cell lymphoma which may follow a variable course and transform into an aggressive phase. Cutaneous manifestations of this condition have only rarely been reported in the literature. The presence of granulomas in the skin may have either obscured the lymphoma infiltrate or may have reflected a more generalized immune response to the underlying malignancy.

Pasteurella multocida meningitis in an adult: case report.

Pasteurella multocida is known to form part of the normal flora in the nasopharynx or gastrointestinal tract in many domestic and wild animals. Most human P multocida infections are soft tissue infections caused by dog or cat bites. Less commonly this bacterium is associated with infections affecting other organ systems of man. A case of fatal P multocida meningitis discovered at the necropsy of a 52 year old man is described. P multocida is an unusual causative agent of meningitis which tends to affect those at the extremes of age.

Anal intraepithelial neoplasia in an inflammatory cloacogenic polyp.

A rare case of anal intraepithelial neoplasia arising in an inflammatory cloacogenic polyp is reported. While the occurrence of neoplasia complicating benign anal conditions is recognised, this case re-emphasises the need for careful histological examination of all perianal lesions.

Comparative study of intestinal metaplasia and mucin staining at the cardia and esophagogastric junction in 225 symptomatic patients presenting for diagnostic open-access gastroscopy.

OBJECTIVE: Adenocarcinoma around the esophagogastric junction (EGJ) is increasing in incidence, and is frequently associated with areas of macroscopic or microscopic intestinal metaplasia (IM). The aim of this study was to define the incidence and type of metaplastic changes in the cardia and at the EGJ in symptomatic patients in whom there was no endoscopic columnar segment. METHODS: Patients attending for open-access gastroscopy had three sets of endoscopic biopsies taken at 3-cm intervals, from cardia, EGJ, and distal esophagus. Hematoxylin and eosin, Alcian blue/PAS (AB/PAS), and high-iron diamine/Alcian blue (AB/HID) were used to define and characterize IM. RESULTS: Of 225 patients, eight (4%) had carcinoma, eight (4%) had conventional long-segment Barrett's esophagus, 15 (7%) showed endoscopic short-segment Barrett's change, with no endoscopic Barrett's in 194 (86.2%). Of the latter, 34 (17.5%) had IM at the EGJ, and nine (4.6%) had IM at the cardia on hematoxylin and eosin. Acid mucin stains were positive at the EGJ in 135 (69.6%) and at the cardia in 75 (38.7%). Metaplasia at the EGJ was associated with sulphomucins (p < 0.0001) and involved the surface glandular epithelium (p < 0.0001) more frequently than the cardia. Metaplasia was not related to reflux symptoms, hiatus hernia, or endoscopic esophageal inflammation. Ninety percent of those with IM detectable by hematoxylin and eosin were taking acid suppression, compared with 72.8% overall. CONCLUSIONS: Intestinal metaplasia is very common at the esophagogastric junction and gastric cardia, with marked differences in incidence and characteristics of mucin staining between the two sites. The relationship of intestinal metaplasia to the development of carcinoma is yet to be determined.

Restoration of the normal squamous lining in Barrett's esophagus by argon beam plasma coagulation.

OBJECTIVE: Barrett's esophagus is associated with significantly increased risk of development of esophageal adenocarcinoma. Replacing columnar epithelium with the normal squamous lining in this condition offers the possibility of decreasing the risk of degeneration to invasive adenocarcinoma. This study aimed to establish the feasibility of argon beam plasma coagulation (ABPC), in conjunction with control of gastroesophageal reflux, to restore the squamous lining. METHODS: Thirty patients with Barrett's esophagus (four low-grade dysplasia, three high-grade) were recruited from our surveillance program, and underwent endoscopic ABPC. RESULTS: Twenty-seven patients completed treatment, with macroscopic replacement of their columnar lining by squamous epithelium, histologically confirmed in all 27, and followed up for a median of 9 months (range, 6-18 months). Two patterns of squamous replacement were identified: 70% of patients showed squamous epithelium with no persistent intestinal metaplasia, and in 30% the new squamous epithelium covered areas of underlying intestinal metaplasia. One patient has withdrawn from the study. Two esophageal perforations, with one death, occurred early in the study. CONCLUSION: ABPC, in conjunction with control of gastroesophageal reflux, allows squamous regrowth in both benign and dysplastic Barrett's esophagus. Despite the theoretical safety advantages of ABPC over techniques such as laser, esophageal perforation may occur with this technique. It is too soon to recommend ABPC for dysplastic or nondysplastic Barrett's because follow-up is too short to show a decreased incidence of and mortality from adenocarcinoma.

Fatal Serratia marcescens meningitis and myocarditis in a patient with an indwelling urinary catheter.

Serratia marcescens is commonly isolated from the urine of patients with an indwelling urinary catheter and in the absence of symptoms is often regarded as a contaminant. A case of fatal Serratia marcescens septicaemia with meningitis, brain abscesses, and myocarditis discovered at necropsy is described. The patient was an 83 year old man with an indwelling urinary catheter who suffered from several chronic medical conditions and from whose urine Serratia marcescens was isolated at the time of catheterisation. Serratia marcescens can be a virulent pathogen in particular groups of patients and when assessing its significance in catheter urine specimens, consideration should be given to recognised risk factors such as old age, previous antibiotic treatment, and underlying chronic or debilitating disease, even in the absence of clinical symptoms.

Adenomyoepithelioma of the skin: a case report with immunohistochemical and ultrastructural observations.

AIMS: The histological, immunohistochemical and electron microscopic features of a primary adenomyoepithelioma of skin, a rare sweat gland tumour, are reported. METHODS AND RESULTS: The tumour occurred on the back of a 92-year-old woman. It was composed of well-formed tubules lined by epithelial cells surrounded by clear or spindled myoepithelial cells. Immunohistochemically, the epithelial cells exhibited strong cytokeratin (CAM5.2) and weak carcinoembryonic antigen positivity. The myoepithelial cells showed diffuse positivity for smooth muscle actin and focal positivity for S100 protein. Ultrastructurally, the myoepithelial cells contained myofilaments with focal densities and hemidesmosomes. They were limited by well-formed basal lamina. The tumour was associated with a small eccrine spiradenoma. CONCLUSION: We predict that the tumour will behave in a benign fashion. There is no evidence of recurrence or metastasis 28 months later.

Fine needle aspiration of palpable breast lumps: a 1-year audit using the Cytospin method.

A fine-needle aspiration (FNA) service for the diagnosis of palpable breast lumps was started at the Royal Preston Hospital, Preston, UK, in November 1989. Over the subsequent year, 407 FNAs were taken from 393 women. A simple technique was used which involved the surgeon flushing the aspirate into 10 ml of Cytospin collection fluid; cytocentrifuge preparations were then safely and conveniently prepared in the laboratory. Slides were stained with Papanicolaou and H&E. The method detected 112 out of a total of 121 cancers (92.6%); of the nine that were undetected, five aspirates were inadequate and four were falsely reported as negative. There were no false positives. The overall inadequate rate was 11.0%. Excluding inadequate samples, the absolute sensitivity was 89.7% and complete sensitivity 96.6% with 94.4% specificity. This 1-year audit has shown the Cytospin method of FNA in palpable breast disease to have a favourable sensitivity and specificity, and therefore to be an alternative to conventional FNA using direct smears.

Propagation and properties of Kaposi's sarcoma-derived cell lines obtained from patients with AIDS: similarity of cultured cells to smooth muscle cells.

Cells derived from Kaposi's sarcoma (KS) were propagated in vitro using conditions which resulted in elimination of contaminating fibroblasts and the emergence of homogeneous cell populations which morphologically resembled smooth muscle cells and had neoplastic characteristics. In long-term culture, they differentiated into large ribbon-like cells with longitudinal fibrillarity of their cytoplasm. These fibrils stained red by Masson trichrome staining, and were reactive with antibodies to desmin. Dense bodies typical of myoblasts were observed in some cells by electron microscopy. The cells did not form capillary structures like endothelial cells, they lacked Weible-Palade bodies, and did not express the blood-clotting Factor VIII-related antigen or receptors for the lectin Ulex europaeus agglutinin I. They did express four other antigens, however, in common with endothelial cells. The cells did not form tumors in athymic nude mice; however, they formed colonies in soft agar, manifested tumor-like growth on muscle organ cultures, and were invasive in an artificial basement membrane invasion assay. The results indicate that a component of KS is closely related to leiomyoblasts and and has neoplastic properties.

Endocardial fibroelastosis in infants with hydrops fetalis.

Endocardial fibroelastosis, defined as an endocardium in excess of 30 microns thick, was found in 10 out of 34 cases of hydrops fetalis in a review of 1589 perinatal necropsies carried out between 1976 and 1989. The infants comprised 16 cases of rhesus haemolytic disease, of whom three had endocardial fibroelastosis, and 18 cases of non-rhesus hydrops, of whom seven had endocardial fibroelastosis. Intrauterine congestive heart failure was thought to have been the probable cause of hydrops in eight of the 10 infants with endocardial fibroelastosis. None of an age matched control group without endocardial fibroelastosis had evidence of congestive cardiac failure. These observations support the hypothesis that endocardial fibroelastosis is an endocardial response to chronic prenatal myocardial stress.