Random Mucosal Biopsies Research Articles

S3711 Gastric Lipoma in a Patient With Symptomatic GERD

Introduction: Gastric lipomas are very rare, accounting for 5% percent of all gastrointestinal lipomas, and 3% of all benign gastric tumors. Clinical manifestations range from completely asymptomatic to abdominal pain, dyspepsia, intussusception, obstruction, and bleeding. In asymptomatic patients, these tumors are usually found incidentally on endoscopy, and are managed expectantly. When they become symptomatic, options for treatment include surgical resection or enucleation. The following is a case of an incidentally found gastric lipoma. Case Description/Methods: A 57-year-old man was seen in clinic complaining of a 3 week history of nausea and cough. He described feeling like he wanted to vomit but couldn’t. He denied abdominal pain, bloating, reflux, regurgitation, dysphagia, melena, hematemesis, and weight loss. Medications included wheat dextrin for mild constipation. No family history of colon, esophageal, or gastric cancer. Physical exam was unremarkable. A presumptive diagnosis of GERD was made and he was scheduled for endoscopic evaluation. EGD revealed antral gastritis and a gastric lipoma in the distal body, identified by a positive “pillow sign.” Random mucosal biopsies were taken with a positive “naked fat sign.” Pathology showed antral/oxyntic mucosa with minimal chronic gastritis. Patient was treated with a proton pump inhibitor and symptoms resolved. Discussion: Gastric lipomas are rare, benign tumors of the stomach. They can be differentiated from other solid tumors on endoscopy by 3 signs: the “pillow sign” which is an indentation when compressing the tumor with closed forceps; the “tenting sign” which is grabbing and pulling the mucosa with forceps; and the “naked fat sign”, which is extrusion of fat from the lipoma after biopsy. Conventional biopsies are usually non-diagnostic, as in this case, because they only sample the overlying mucosa. In order to obtain a representative sample of the lipoma, a tunneled biopsy is required, but is not commonly done. Other diagnostic modalities include endoscopic ultrasound, which works best for lesions < 1cm and CT abdomen with contrast (the gold standard). Asymptomatic lipomas are managed expectantly, and do not require surveillance because malignant transformation is rare. In contrast, lipomas that are symptomatic or cause bleeding or obstruction, are usually surgically removed. Our patient was managed conservatively with the recommendation of surgical evaluation if symptoms return.Figure 1.: Endoscopy demonstrating classic pillow sign for Lipoma.

A196 MORE MICROSCOPIC THAN WAS THOUGHT: A RARE CASE OF ISOLATED LYMPHOCYTIC ILEITIS WITHOUT MICROSCOPIC COLITIS

Abstract Background Microscopic colitis (MC) is a chronic inflammatory disease of the colon characterized by lymphocytic infiltration with (collagenous colitis) or without (lymphocytic colitis) the expansion of collagen fibres, and the normal macroscopic appearance of the mucosa on ileocolonoscopy. Recent studies have shown that the ileum may be involved in MC, occurring concurrently with colonic disease, however there is sparse literature on isolated lymphocytic ileitis without colitis. Aims We describe the case of isolated small bowel lymphocytosis without evidence of lymphocytic colitis to highlight the utility of random biopsies of the terminal ileum in cases where microscopic colitis is a diagnostic consideration. Methods A 70-year-old female known for cutaneous mastocytosis presented with six weeks of abdominal pain, non-bloody diarrhea, intolerance to oral intake and significant weight loss. Computed-tomography showed evidence of possible mesenteric panniculitis. Colonoscopy revealed a normal colon and normal-appearing mucosa of the terminal ileum. Random mucosal biopsies were taken to assess for microscopic colitis, with terminal ileal biopsies revealing significant lymphocytic infiltration consistent with lymphocytic ileitis. Biopsies throughout the colon revealed normal colonic mucosa without evidence of concurrent microscopic colitis. Gastroscopy was macroscopically unremarkable and random biopsies in the stomach and duodenum were negative for Helicobacter pylori and lymphocytosis. Immunostaining of the gastric, duodenal, terminal ileal and colonic biopsy specimens were negative for CD25, CD117 and tryptase, indicating the absence of gastrointestinal mastocytosis. Results The patient was diagnosed with lymphocytic ileitis and given the known response of MC to budesonide, she was treated with eight weeks of budesonide with clinical improvement leading to remission of her symptoms. Conclusions This case illustrates a rare incidence of isolated ileal microscopic ileitis without colitis that responded well to standard MC treatment, thereby underscoring the utility of random biopsies in the terminal ileum and throughout the colon when microscopic colitis is on the differential diagnosis. Funding Agencies None

Histologic Normalization Occurs in Ulcerative Colitis and Is Associated With Improved Clinical Outcomes.

Mucosal healing, determined by histologic analysis, is a potential therapeutic target for patients with ulcerative colitis (UC). However, the histologic features of tissue normalization, as an outcome of treatment, have not been well described. We examined the prevalence and predictive values of normalization of the colonic mucosa, based on histologic analysis (histologic normalization) in patients with UC, and determined its association with risk of clinical relapse, compared with histologic disease quiescence and endoscopic mucosal healing. We performed a retrospective study of 646 patients with confirmed UC who underwent colonoscopy at a tertiary medical center from August 2005 through October 2013. We reviewed reports from pathology analyses of random mucosal biopsies from each colon segment, and categorized them into 3 groups based on histology findings: (1) normalization (completely normal mucosa with no features of chronicity present), (2) quiescence (crypt atrophy or branching without signs of active inflammation including erosions, abscesses, or focal neutrophil infiltration), or (3) active disease (epithelial infiltration by neutrophils, crypt abscesses, erosions, or ulceration). Histology findings were compared with clinical and endoscopic findings. We assessed variables associated with histology findings and, in patients in clinical remission (Simple Clinical Colitis Activity Index score ≤2 and subscore of ≤1 for stool frequency or rectal bleeding), predictive values for clinical relapse at follow-up evaluations 6months later or more were calculated. Of the 646 patients included in the study, 60% had endoscopic mucosal healing, 40% had histologic quiescence, and 10% had histologic normalization. The level of agreement between mucosal and histologic activity was moderate (agreement for 68% of samples; κ= 0.50; P<.001). On multivariate analysis, only proctitis associated with histologic normalization (P=.002). Of 310 patients in clinical remission at initial review, 25% had a clinical relapse, after a median time of 16 months (interquartile range, 10-23 months). Histologic normalization was independently associated with increased odds of relapse-free survival compared with histologic quiescence (hazard ratio, 4.31; 95% confidence interval, 1.48-12.46; P=.007) and histologic activity (hazard ratio, 6.69; 95% confidence interval, 2.16-20.62; P= .001); mucosal healing was not associated with increased odds of relapse-free survival compared with no mucosal healing (hazard ratio, 1.02; 95% confidence interval, 0.56-1.85; P= .954). Histologic normalization of colonic mucosa can be used as a clinical endpoint for patients with UC. We associated histologic normalization with increased odds of relapse-free survival compared with endoscopic healing or histologic quiescence. Further studies are needed todetermine whether histologic normalization should be a goal of treatment for patients with UC.

Esophageal Squamous Dysplasia is Common in Asymptomatic Kenyans: A Prospective, Community-Based, Cross-Sectional Study

Esophageal squamous cell carcinoma (ESCC) is endemic in east Africa and is a leading cause of cancer death among Kenyans. The asymptomatic precursor lesion of ESCC is esophageal squamous dysplasia (ESD). We aimed to determine the prevalence of ESD in asymptomatic adult residents of southwestern Kenya. In this prospective, community-based, cross-sectional study, 305 asymptomatic adult residents completed questionnaires and underwent video endoscopy with Lugol's iodine chromoendoscopy and mucosal biopsy for detection of ESD. Study procedures were well tolerated, and there were no adverse events. The overall prevalence of ESD was 14.4% (95% confidence interval (CI): 10-19%), including 11.5% with low-grade dysplasia and 2.9% with high-grade dysplasia. The prevalence of ESD was >20% among men aged >50 years and women aged >60 years. Residence location was significantly associated with ESD (Zone A adjusted odds ratio (OR) 2.37, 95% CI: 1.06-5.30 and Zone B adjusted OR 2.72, 95% CI: 1.12-6.57, compared with Zone C). Iodine chromoendoscopy with biopsy of unstained lesions was more sensitive than white-light endoscopy or random mucosal biopsy for detection of ESD and had 67% sensitivity and 70% specificity. ESD is common among asymptomatic residents of southwestern Kenya and is especially prevalent in persons aged >50 years and those living in particular local regions. Lugol's iodine chromoendoscopy is necessary for detection of most ESD but has only moderate sensitivity and specificity in this setting. Screening for ESD is warranted in this high-risk population, and endoscopic screening of Kenyans is feasible, safe, and acceptable, but more accurate and less invasive screening tests are needed.

Inflammatory Bowel Disease Affects the Outcome of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection

A significant fraction of patients with recurrent Clostridium difficile infections (CDI) have inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) can break the cycle of CDI recurrence and can be performed without evaluation of the colon. We evaluated the efficacy of colonoscopic FMT in patients with and without IBD, and whether we could identify IBD in patients during this procedure. We collected clinical meta-data and colonoscopy results from 272 consecutive patients that underwent FMT for recurrent CDI at the University of Minnesota from 2008 through 2015. Patients had at least 2 spontaneous relapses of CDI following their initial episode and did not clear the infection after 1 extended antibiotic regimen. We collected random mucosal biopsies from patients' right colons to identify lymphocytic or collagenous colitis during the FMT procedure. Failure or success in clearing CDI was determined within or at 2 months after the FMT. Of patients undergoing FMT, 15% had established IBD and 2.6% were found to have IBD during the FMT procedure. A single colonoscopic FMT cleared CDI from 74.4% of patients with IBD and 92.1% of patients without IBD (P= .0018). Patients had similar responses to FMT regardless of immunosuppressive therapy. More than one-quarter of patients with IBD (25.6%) had a clinically significant flare of IBD after FMT. Lymphocytic colitis was documented in 7.4% of patients with endoscopically normal colon mucosa; only 3 of these patients (20%) required additional treatment for colitis after clearance of CDI. Based on an analysis of 272 patients, FMT is somewhat less effective in clearing recurrent CDI from patients with IBD, compared with patients without IBD, regardless of immunosuppressive therapy. More than 25% of patients with IBD have a disease flare following FMT. Lymphocytic colitis did not affect the outcome of FMT, but a small fraction of these patients required pharmacologic treatment after the procedure.

Fluorescence cystoscopy: the end of biopsies for carcinoma in situ detection?

The present prospective study by Palou et al. 1, conducted in eight Spanish centres, documents the use of hexaminolevulinate fluorescence cystoscopy (FC)-guided bladder tumour resection and biopsies in 283 patients with non-muscle-invasive bladder cancer (NMIBC). It is an inpatient comparison between white-light cystoscopy and FC. The study presents data from routine practice in Spain and the results show an improvement in diagnosis of NMIBC, especially Ta tumours and carcinoma in situ (CIS) with FC-guided resections. These results are confirmation of reports in the literature, including a number of randomized controlled trials and a recent large meta analysis 2. Although the magnitude of the difference between FC and white-light cystoscopy was somewhat lower in the present study, apparently even in normal daily practice the difference was significant. Moreover, as the rate of CIS in Spain is very high, up to 19% in a large Spanish series 3, I can imagine that the use of FC is of specific interest in this country. Apart from the confirmation of the better detection rate (75.5 and 93.2% for white-light cystoscopy and FC, respectively, figures similar to those in the recent literature) and confirmation of safety of hexaminolevulinate FC, there are two particular points regarding the present study that I would like to highlight. The first item that deserves some discussion is mucosal biopsies. In this study the number of false-positive results (948/1569; 60.4%) was very high. This was predominantly explained by the inclusion or mucosal biopsies from ‘normal appearing urothelium’ in these calculations. Only 36 lesions were detected with biopsies, which suggests a very low detection rate. Assuming that >800 random biopsies were taken (apparently six biopsies were taken per patient, and biopsies were taken in 49.1% of the 283 patients), the detection rate was <4%, and one might ask whether it was still worthwhile to take these biopsies. Even though 26.7% of patients with CIS were only diagnosed by biopsies in this study, the number was small. The authors also indicate that it was surprising that CIS was not found more often with FC, but they blame it on the learning curve for FC. The value of mucosal biopsies was also questioned by some reviewers, and in fact by the present authors too. In their introduction they explain the biopsy policy by the high rate of CIS in Spain; however, they also indicate that this incidence seems to be decreasing. Taking together the disappointing detection rate of mucosal biopsies and the high detection rate of CIS with FC, the message should be clear: stop taking mucosal biopsies from normal-looking urothelium. As a matter of fact, this had already been suggested before the era of FC by the authors of other large studies, such as an analysis by the European Organisation for the Research and Treatment of Cancer 4 and a large Dutch study 5. The false-positive rate for FC was not very high (15.7%, similar to the more recent studies with hexaminolevulinate FC). And I assume that these figures would even be much lower if biopsies of normal urothelium were to be excluded from these calculations. The second point that deserves attention is the learning curve for FC and its impact on the results. The authors indeed mention as an important limitation of this study ‘the investigators’ lack of experience’ with FC. They point out that this might be the reason that the advantage of FC for the detection of CIS seemed to be less pronounced than in published series, although still significantly better than with white light. In their cohort, 27 of 36 patients with CIS (75%) were detected with FC. The impact of the learning curve and the limited experience of some of the centres is also illustrated by the wide range between centres in, for example, the false-positive rates. Indeed, some training with this FC technique is mandatory. Unfortunately, however, the authors were not able to provide details of the relationship between experience and detection of CIS or false-positive rates. In conclusion, even in routine practice, FC significantly improves the detection of NMIBC. The advantage is seen especially in Ta tumours and CIS, similarly to recent publications. The use of FC can, in my view, replace the use of random mucosal biopsies of normal-looking urothelium with white light because the detection rate of these biopsies is only a few percent. Finally, the present study also shows that a learning curve significantly improves the detection rate of NMIBC with FC and decreases the rate of false-positives. This should probably be somewhere between 5 (the number used in some of the registration studies for hexaminolevulinate) and 20 as suggested by a recent Canadian study 6. J.A.W. has been an investigator for Photocure and has been an advisor for and has received honoraria from Photocure and Ipsen.

Successful treatment of enteropathy associated with common variable immunodeficiency

Successful treatment of enteropathy associated with common variable immunodeficiency

Colonoscopy with Random Mucosal Biopsies for Chronic Diarrhea: Practice Pattern Differences between Gastroenterologists and Surgeons

Colonoscopy with Random Mucosal Biopsies for Chronic Diarrhea: Practice Pattern Differences between Gastroenterologists and Surgeons

Lymphocytic Colitis: A Spectrum of Inflammatory Bowel Disease: A Case Series

Introduction: Lymphocytic colitis (LC) is characterized by chronic diarrhea and specific microscopic changes in a macroscopically normal colonic mucosa. Lymphocytic colitis progressing to ulcerative colitis (UC) has been previously reported, however there is limited data on UC evolving into LC. Here we present a series of five cases with UC subsequently developing into lymphocytic colitis suggesting LC could be a part of the spectrum of inflammatory bowel disease (IBD). Case Report: A total of five cases of UC evolving into LC were identified using a retrospective database study of 876 UC patients diagnosed during years 2001-2011 at the Cleveland Clinic. The median age at the time of UC diagnosis was 34 years. All five patients had a chronic history of UC for a median duration of 15 years prior to being diagnosed with LC by histopathology. Three out of five patients were on treatment for UC with either mesalamine or salfasalazine and the other two patients were treated with either prednisone, mesalamine or 6-mercaptopurine at the time of diagnosis of LC. All patients were under complete remission with medications. On subsequent follow up three out of five people relapsed with intermittent watery diarrhea prompting a colonoscopy which suggested no evidence of active UC but had histological pattern of LC on their random mucosal biopsies. The other two patients were asymptomatic from UC and had evidence of LC during routine surveillance colonoscopic biopsies. Discussion: Lymphocytic colitis, a subtype of microscopic colitis, with chronic inflammatory infiltrates in the colonic mucosa without specific abnormalities noted on endoscopy. We found five patients with longstanding UC who subsequently developed LC. We noted complete histological and/or symptomatic remission in three out of the five cases while two of these patients reverted back into ulcerative colitis suggesting that LC could present as a continuum of UC. There have been case reports of collagenous colitis evolving into ulcerative colitis and vice versa. Literature reveals NF- kB activation occurs early in both collagenous colitis and ulcerative colitis but downstream cellular programs appear different in both. However, in LC the exact molecular mechanism of this histological transformation or the prognostic implications is lacking and requires further evaluation on prospective studies. Until then, it might be prudent to follow up these patients with LC to assess for relapse of UC. We therefore suggest lymphocytic colitis could be part of the spectrum of inflammatory bowel disease.Table: [1160] Cases of ulcerative colitis subsequently developing lymphocytic colitis

A Case of Steroid Dependent Eosinophilic Gastroenteritis Presenting as a Huge Gastric Ulcer

Eosinophilic gastroenteritis is defined as primary eosinophilic infiltration of the gastrointestinal tract. Endoscopic findings of this disease entity are non-specific, and huge gastric ulceration as initial presentation is extremely rare. We experienced a case of eosinophilic gastroenteritis presenting with abdominal pain in a 38 year-old-woman. Deep and huge ulceration in gastric antrum and body looked like advanced gastric cancer. Surgical resection was performed and histopathological examination showed dense infiltration of eosinophil without malignant cells. 5 years after surgery, diffuse abdominal pain and generalized edema developed and computed tomography showed entire wall thickening of the gastrointestinal tract. Random mucosal biopsy of the remnant stomach and terminal ileum showed mucosal eosinophilic infiltrations. She was treated with steroids and azathioprine but experienced frequent relapses and was dependent on steroids to maintain remissions. After 3 years, she died from infective endocarditis due to the prolonged use of immunosuppressive agents. (Korean J Helicobacter Up Gastrointest Res 2012; 12:103-107)

Insight into long-term histological, proliferative and apoptotic modifications in ileal orthotopic neobladder and conduit mucosa

To assess the long-term histological, apoptotic and proliferating alterations of the intestinal mucosa of ileal conduits and orthotopic neobladders. Fifty patients (46 males, 4 females), aged 52-78 years, who underwent urinary diversion with either ileal orthotopic neobladder (group ON, 20 patients) or conduit (group IC, 30 patients) from 2001 to 2005, were included in this prospective study. Ileal samples were collected during surgery (controls) and by random mucosal biopsies 6, 12, 24, 36 and 48 months later. Histological (villi height, crypt depth, eosinophil cell count), proliferation (Ki67 immunochemistry), and apoptotic (Bcl-2 immunochemistry, TUNEL) parameters were assessed. During the 4-year follow-up, we recorded progressive villi area, height and crypt depth reduction, mucosa flattening, and inflammatory and eosinophilic infiltration. Villi height: crypt depth ratio showed a statistically significant difference (P < 0.05) between the two groups from the 6th month. Dysplasia, metaplasia, and neoplasia were not observed. Bcl-2 values showed a progressive increase until 24 months in group ON and 12 months in group IC, followed by a decline thereafter. Ki-67 values showed a progressive increase after 6 months in group ON and an increase until 24 months followed by a decline thereafter in group IC. TUNEL showed two peaks, at 24 and 48 months. Histological adaptation was revealed in both groups, with statistically significant differences in favor of orthotopic substitution. Proliferative and apoptotic pathways are implicated as demonstrated by relevant modifications of Bcl-2, Ki-67 and TUNEL, in accord with the histological adaptation.

S‐phase fraction in superficial urothelial carcinoma of the bladderA prospective, long‐term, follow‐up study

To study, in addition to traditional tumor characteristics at diagnosis, the significance of DNA ploidy and S-phase fraction for tumor progression and tumor-related death in superficial carcinoma of the urinary bladder. Newly detected superficial bladder carcinomas (stage Ta-T1), from 195 consecutive patients were characterized according to stage, grade, tumor size, multiplicity, growth pattern, cytologic evaluation and random mucosal biopsies, as well as DNA ploidy and S-phase fraction as determined by means of DNA flow cytometry. The outcome of disease was evaluated using hospital charts and death certificates. During a median follow-up period of 98 months (range 1-160 months), 28 patients (14%) progressed to muscle-invasive or metastatic disease and 24 (12%) died from disease. In univariate analysis all factors studied, with the exception of the size and number of tumors at diagnosis, were significantly related to progress and tumor-specific survival. In multivariate analysis, however, S-phase fraction was the most significant prognostic factor. When 21 high-risk patients with T1G3 tumors who underwent early cystectomy were excluded, S-phase fraction remained the most important prognostic factor. DNA ploidy failed as an independent predictor of survival. High S-phase fraction at diagnosis of superficial urothelial carcinoma of the bladder identifies patients at high risk of progression and death from disease.

RECURRENCE, PROGRESSION AND SUCCESS IN STAGE TA GRADE 3 BLADDER TUMORS TREATED WITH LOW DOSE BACILLUS CALMETTE-GUERIN INSTILLATIONS

Bacillus Calmette-Guerin (BCG) therapy is considered to be an effective prophylactic and therapeutic agent for high risk superficial transitional cell carcinoma of the bladder. Nevertheless, in a select uncommon population of stage Ta grade 3 superficial lamina-free tumors the results of this treatment have not yet been well established. We evaluated recurrence and progression rates, and the success of BCG therapy in a population with stage Ta grade 3 transitional cell carcinoma of the bladder. Of the 605 patients treated at our institution from 1982 to 1996 for the histopathological diagnosis of primary bladder cancer 32 (5.3%) with stage Ta grade 3 noninvasive primary bladder tumor were treated with intravesical instillations of 75 mg. Pasteur strain BCG in 50 ml. saline weekly for 6 weeks. At a followup of 2 to 13 years (mean 58.4 months) patients were evaluated with urinary cytology, cystoscopy, transurethral resection and random mucosal biopsies. Recurrence, grade and stage progression, death and causality were analyzed. Of the 32 patients 9 (28%) responded positively to BCG without recurrence, while disease recurred as stage Ta in 8 (25%) and T1 in 7 (22%), and progressed to muscle layer infiltration in 8 (25%). Four patients (12%) died of bladder cancer. The number of tumors at primary resection, gross examination, the mitotic index or an association with carcinoma in situ did not appear to be predictive factors of progression to muscle invasion. Urine cytology (I to II versus III to IV) appeared to correlate highly with progression and BCG response (p<0.001) with excellent sensitivity (1) but low specificity (0.67). Our study demonstrates the high progression potential of stage Ta grade 3 tumors, since nearly 50% recurred and 25% progressed to invasive disease. These results may be closely compared with the results of previous trials of stage T1 grade 3 disease. We suggest that recurrence should be detected at an early stage using long-term followup with strict observance of the surveillance protocols during a minimum 5-year tumor-free period.

Clinical significance of urothelial dysplasia concomitant with superficial bladder cancer

Retrospective analysis was carried out to evaluate the prognostic value of urothelial dysplasia with superficial bladder cancer. 62 patients with bladder cancer of pTa or pT1 who had been treated by transurethral resection (TUR-Bt), underwent random mucosal biopsies in the urinary bladder. The results of random biopsies were classified into 3 groups: negative group, dysplasia group and CIS group. The recurrence rate, progression rate and type of recurrences (true recurrence/new occurrence) were compared among the 3 groups. The results of random biopsies were as follows; negative group was found in 42 (68%), dysplasia group in 17 (27%) and CIS group in 3 (5%). There were no significant difference in the characteristics of the patients among the 3 groups. The recurrence rates at 1, 2 and 5 years after TUR-Bt were 3%, 12% and 21%, respectively, for negative group, and 37%, 51% and 67%, respectively, for dysplasia group (p < 0.01). For CIS group, 2 of 3 cases (67%) recurrenced within 1 year after TUR-Bt. Non of negative group progressed to muscle invasion, whereas 57% of dysplasia group invaded bladder muscle after 6 years post operatively (p < 0.001). No significant relationship was observed between the absence or presence of concomitant dysplasia and the rate of true recurrence. Dysplasia group revealed a higher rate (47.1%) of new occurrence than negative group (2.4%) (p = 0.0001). The presence or absence of concomitant dysplasia of superficial bladder cancer seems to be an important prognostic factor for future new ocurrence and progression after TUR-Bt.

THE INFLUENCE OF THE LEVEL OF LAMINA PROPRIA INVASION AND THE PREVALENCE OF P53 NUCLEAR ACCUMULATION ON SURVIVAL IN STAGE T1 TRANSITIONAL CELL BLADDER CANCER

Purpose We assessed the influence of the level of lamina propria invasion and the prevalence of p53 nuclear immunoreactivity on the survival of patients with stage T1 transitional cell bladder cancer. Materials and Methods All patients with stage T1 bladder cancer were prospectively and routinely grouped according to the level of lamina propria invasion. Invasion of the tumor stalk was defined as stage T1a, invasion of the lamina propria proper superficial to the level of muscularis mucosa as stage T1b and into or deeper than the muscularis mucosa as stage T1c. The p53 nuclear immunoreactivity was determined with antibody PAB 1801. Results The study comprised 143 patients including 31 (22%) with stage T1a disease, 60 (42%) with stage T1b and 52 (36%) with stage T1c. Mean patient age was 67 years (range 38 to 92) and mean followup was 4.7 years (range .4 to 9.7). Tumor grade related to the depth of lamina propria invasion (p <0.05) and the prevalence of dysplasia in random mucosal biopsies was higher in stage T1b and T1c tumors than in stage T1a. Of all tumors 42% expressed p53 nuclear reactivity which correlated with tumor grade (p <0.05). Also the prevalence of nuclear p53 was higher in stages T1b and T1c compared with T1a disease. Of the patients 115 were treated with transurethral resection alone and 28 underwent radical cystectomy. Overall survival was 60.1%. Age was the only independent predictor of survival in patients older than 75 years. For patients up to 75 years old survival related to age, level of lamina propria invasion and presence of p53 nuclear accumulation. For this subpopulation overall survival was 67%, and 79% for stage T1a, 70% for stage T1b and 57% for stage T1c (p <0.05). Survival was higher in patients with p53 negative (73%) than in those with p53 positive (61%) tumors (p <0.05). A multivariate analysis of the influence of lamina propria invasion and nuclear p53 status on survival histology was found to be the only independent predictor of survival. Conclusions Immediate radical cystectomy should be considered for patients with stage T1c tumors and for some patients with stage T1b disease, particularly those with tumors expressing p53 nuclear reactivity and with dysplasia in the random mucosal biopsies.

Management of gastric remnant carcinoma based on the results of a 15-year endoscopic screening program.

Partial gastrectomy for benign peptic ulcer disease is associated with an increased risk of adenocarcinoma of the gastric remnant, especially in patients who are at least 15 years' postgastrectomy. Increasing evidence of mucosal dysplasia is noted on random gastric biopsy and may serve as a histologic marker in the identification of early cancer of the gastric stump. From an initial group of 233 patients who underwent gastrectomy for benign peptic ulcer disease between 1960 and 1975, 163 patients began yearly flexible gastroscopy and random mucosal biopsy. Routine histologic studies identified either normal or dysplastic epithelium as well as adenocarcinoma. An average of eight biopsies were taken per endoscopic study. All endoscopic studies were performed by surgical residents under the supervision of one surgical attending. From July 1980 to June 1995, 145 patients completed annual gastroscopy and random biopsy. A total of 2287 endoscopic studies were performed. Fifteen patients were found to have severe dysplasia. Nine (60%) had associated microscopic evidence of adenocarcinoma. Four additional patients had macroscopic adenocarcinoma on endoscopic examination. All 13 patients with cancer were asymptomatic. Six patients continue surveillance who display moderate-to-severe dysplasia alone. The 13 patients with carcinoma underwent completion gastrectomy (R2 nodal dissection) with no evidence of cancer found beyond the gastric wall. These patients averaged 29 years since their original partial gastrectomy. A prospective screening program for gastric remnant cancer was begun to assess the ability to discover early neoplastic changes on random biopsy and to make treatment decisions regarding the efficacy of completion gastrectomy after discovery of carcinoma. Aggressive annual screening using flexible endoscopy and multiple random biopsy may discover cancer in the gastric remnant and can lead to completion curative gastrectomy in asymptomatic people. Patients who are at least 20 years postpartial gastrectomy for benign disease should be considered for annual endoscopic surveillance.

Expression of Markers for Transitional Cell Carcinoma in Normal Bladder Mucosa of Patients with Bladder Cancer

Purpose Because we have found that random mucosal biopsies have no additional prognostic value to conventional histopathology, we studied biopsies of histologically normal bladder mucosa with several molecular markers believed to be associated with the development of transitional cell carcinoma. Materials and Methods Six groups of patients with an increasing stage of bladder tumor were selected: (1) benign disease (for example, benign prostatic hyperplasia, n = 8); (2-4) low (n = 10), intermediate (n = 9) and high risk (n = 7) superficial tumors; (5) progressive superficial tumors resistant to optimal conservative therapy (n = 6); (6) invasive or disseminated tumors at presentation (n = 5). We studied the expression of cytokeratin (used as an epithelial marker), fibronectin, E-cadherin (HECD-1), I-CAM, human leukocyte antigen (HLA)-I, HLA-II and epidermal growth factor receptor (EGF-R) in cold-cup biopsies of normal mucosa. Results Fibronectin, HECD-1, I-CAM and HLA-II expression showed no significant changes in the different groups. There was a significant increase in the expression of HLA-I (p = .003) and EGF-R (p = .0001) with a higher stage of the tumor. Conclusion An increasing EGF-R expression in normal looking mucosa of patients with increasing stages of bladder tumors could be a prognostic factor or might indicate that this increase in expression is not tumor specific but is seen in the whole bladder.

Mucosal recipient-type mononuclear repopulation and low-grade chronic rejection occur simultaneously in indefinitely surviving recipients of small bowel allografts

Abstract Lewis rat recipients of long-term, surviving, orthotopic Brown-Norway rat intestinal allografts, initially treated with cyclosporin A (CyA) or FK 506, were evaluated for their functional capacity and morphology over 1 year after the immunosuppressive therapy had been discontinued. Functional parameters such as nitrogen and fat balances, maltose absorption, blood chemistry, hematologic studies, and the weight gained by the allografted animals did not differ from those of syngeneically grafted or age-matched normal animals. Immuno-histochemical studies showed that the lamina propria of the allografts was repopulated with recipient MHC class 11 + mononuclear cells and that a normal distribution of T helper, T suppressor/killer, and IgA + plasma cells had occurred. IIowever, fibrous replacement of the mesenteric lymph nodes and Peyer's patches were detected in all, and an inflammatory obliterative arteriolo-pathy developed in the mesenteric vasculature of half of the allografted animals. No such findings were observed in recipients of syngeneic grafts. These results demonstrate that the limited use of potent immunosuppressive agents immediately after transplantation averts rejection and is followed by recipient-type mucosal lymphocytic repopulation. Simultaneously, a clinically not recognizable chronic rejection evolves. This suggests that the timely diagnosis of chronic rejection may not be possible with the use of standard tests of gut function and random mucosal biopsies alone.

Mucosal recipient-type mononuclear repopulation and low-grade chronic rejection occur simultaneously in indefinitely surviving recipients of small bowel allografts

Lewis rat recipients of long-term, surviving, orthotopic Brown-Norway rat intestinal allografts, initially treated with cyclosporin A (CyA) or FK 506, were evaluated for their functional capacity and morphology over 1 year after the immunosuppressive therapy had been discontinued. Functional parameters such as nitrogen and fat balances, maltose absorption, blood chemistry, hematologic studies, and the weight gained by the allografted animals did not differ from those of syngeneically grafted or age-matched normal animals. Immunohistochemical studies showed that the lamina propria of the allografts was repopulated with recipient MHC class II+ mononuclear cells and that a normal distribution of T helper, T suppressor/killer, and IgA+ plasma cells had occurred. However, fibrous replacement of the mesenteric lymph nodes and Peyer's patches were detected in all, and an inflammatory obliterative arteriolopathy developed in the mesenteric vasculature of half of the allografted animals. No such findings were observed in recipients of syngeneic grafts. These results demonstrate that the limited use of potent immunosuppressive agents immediately after transplantation averts rejection and is followed by recipient-type mucosal lymphocytic repopulation. Simultaneously, a clinically not recognizable chronic rejection evolves. This suggests that the timely diagnosis of chronic rejection may not be possible with the use of standard tests of gut function and random mucosal biopsies alone.

Experimental high-frequency ultrasound can detect graft rejection after small bowel transplantation

Early diagnosis of graft rejection after small bowel transplantation (SBT) can allow prompt institution of vigorous immunosuppressive therapy, with resultant reversal of the rejection process. The current method for graft monitoring is random mucosal biopsy from a stomal site or through an endoscope. However, because early rejection often has a patchy distribution, it could be missed by random biopsy. We hypothesized that the pathological process of rejection would alter acoustic impedance of the tissue and thus change the ultrasonic patterns of the graft intestinal wall. If this hypothesis is correct, then high-frequency endoscopic ultrasound (US) could be used to monitor the entire transplanted bowel and guide the biopsy, with improved yields. This hypothesis was tested in a rat orthotopic SBT model. Sixty-two intestinal specimens (9 isografts, 12 allografts treated with cyclosporine A [CsA], 22 untreated allografts, and 19 intestines from normal rats) were collected for in vitro transluminal US imaging (30 MHz) and histopathologic study. The echo pattern of normal rat intestinal wall consisted of five echo layers that correlated spatially with the histological layers: the innermost hyperechoic layer 1, plus hypoechoic layer 2, corresponded to the mucosa; hyperechoic layer 3, the submucosa; anechoic layer 4, the muscularis propria; and hyperechoic layer 5, the serosa. The isografts and CsA-treated allografts were identical histologically and ultrasonically to normal intestine. However, the echo patterns of the untreated allografts had progressive loss of architectural stratification, with worsening rejection. The change began with patchy indistinctness and disruption of hyperechoic layers 1, 3 and 5, and progressed to total obliteration of the layers, with the intestinal wall becoming a nonstratified hypoechoic structure. In addition, the normal thickness ratio (2–4:1) of layers 1 + 2 to the remaining deeper layers (3, 4, and 5) was decreased or inverted in the rejected intestine. US detected histologically confirmed graft rejection, with a sensitivity and specificity of 100% and 80%, respectively. Furthermore, there was a strong correlation between the US prediction of rejection severity and actual severity determined by histological study (correlation coefficient = 0.91; P < .001). These data confirm our hypothesis and indicate that high-frequency endoscopic US may be a useful method to monitor graft rejection after SBT.