Exophytic condyloma: are they as benign as we think?

AIM: As the understanding of anal dysplasia continues to develop, controversy remains regarding treatment of these lesions. The purpose of this study was to evaluate lesion type (flat vs exophytic) and the association between morphology and dysplasia. METHODS: This was a single-centre retrospective analysis of a prospectively collected pathological database of patients > 17 years old who underwent operative excision/biopsies for presumed anal condyloma or dysplasia from 2009 to 2018. The analysis includes comparisons between patient factors, phenotype and grade of dysplasia. RESULTS: Sixty-nine patients had 423 lesions. The mean age of the study population was 48.2 years. 62.3% were men and 46.4% of patients were black. 47.8% of patients were human immunodeficiency virus (HIV) positive and 39.1% were men who have sex with men (MSM). There were 176 (41.6%) flat lesions and 234 (55.3%) exophytic lesions. Exophytic lesions were 2.5-fold more likely to be associated with a higher grade of dysplasia than flat lesions (OR 2.63, 95% CI 1.09-6.32). Neither lesion type nor dysplasia severity was associated with human papillomavirus, lesion location or patient characteristics, including race, MSM or HIV status. DISCUSSION: Exophytic lesions were more than twice as likely to have advanced dysplasia compared with flat lesions. A clearer understanding of the association between gross lesion appearance and dysplasia will allow more appropriate counselling of patients and the development of better screening and treatment guidelines for anal condylomata and dysplasia.

Negative surveillance endoscopy occurs frequently in patients with short-segment non-dysplastic Barrett's esophagus.

Surveillance endoscopy of non-dysplastic Barrett's esophagus (NDBE) that fails to detect intestinal metaplasia (IM), or negative surveillance, is known to occur in clinical practice, although the frequency and possible outcomes in a large cohort in clinical practice is not well described. The goals of this study were to define frequency in which negative surveillance occurs and endoscopic outcomes in a screening cohort of short segment NDBE. A retrospective cohort (n = 184) of patients newly diagnosed with short segment NDBE at an outpatient academic tertiary care center between 2003 and 2011 were reviewed. Only those with one or more surveillance endoscopies were included to define a frequency of negative surveillance. Included patients were further assessed if they had two or more surveillance endoscopies and were classified into groups as sampling error or negative IM on consecutive surveillances based on the results of their surveillance endoscopies. The frequency of a negative surveillance endoscopy in all short-segment NDBE patients was 19.66% (92 endoscopic exams were negative for IM of 468 total surveillance exams). A negative surveillance endoscopy occurred in 40.76% (n = 75) patients. Sampling error occurred in 44.12% and negative IM on consecutive surveillance endoscopies in 55.88% of those with ≥ 2 surveillance endoscopies and an initially negative surveillance exam. The frequency of negative IM on consecutive surveillances was 19.00% of all patients who had two surveillance endoscopies. When the index diagnostic Barrett's esophagus segment length was < 1 cm, 32.14% (18/56) of all patients (with ≥ 2 surveillance endoscopies) had negative IM on consecutive surveillance endoscopies. Negative surveillance occurs frequently in short-segment NDBE. When an initial negative surveillance endoscopy occurs, it may be due to either a sampling error or lack of detectable IM on surveillance exam. When a <1 cm segment of NDBE is diagnosed, a significant proportion of patients may go on to have continuously undetected IM on consecutive surveillance endoscopic exams without intervention.

Dysplasia detection rate of confirmatory EGD in nondysplastic Barrett's esophagus.

Current guidelines for endoscopic surveillance of Barrett's esophagus (BE) recommend that patients with newly diagnosed BE undergo confirmatory esophagogastroduodenoscopy (EGD) to exclude the presence of dysplasia. The extent to which confirmatory endoscopy alters management and detects missed dysplasia in newly diagnosed BE has not been reported. The frequency with which confirmatory endoscopy changed surveillance management in patients with newly diagnosed BE was assessed. A two center cohort analysis was conducted on patients newly diagnosed with BE. The rate of dysplasia on confirmatory endoscopy for patients who had nondysplastic BE was obtained. Demographic and endoscopic variables were assessed for association with dysplasia detection using Firth logistic regression model. Out of the 146 patients newly diagnosed with BE and initially determined to be without dysplasia, 12 had dysplasia on the confirmatory second EGD (8.2%). Eleven of 12 cases with dysplasia on confirmatory endoscopy had long-segment BE (LSBE). Among all the LSBE cases in our cohort, 11 had newly diagnosed dysplasia on confirmatory EGD, 29.7% (11/37). The average number of biopsies obtained from the 11 LSBE cases with dysplasia was comparable with the rest of the LSBE cases without dysplasia (6.73 and 5.42, respectively, P-value 0.205). The rate of dysplasia detection in short-segment BE (SSBE) was much lower, 0.95% (1 out of 105). There were no cases of high-grade dysplasia (HGD) or cancer detected in any SSBE case. HGD was detected on confirmatory EGD in two cases, both were LSBE. Segment length was the only statistically significant factor to predict the presence of dysplasia on confirmatory endoscopy (odds ratio 9.158, P. 0.008). Confirmatory EGD in newly diagnosed LSBE had significant rate of dysplasia detection (29.7%) in this cohort. Among patients with SSBE, there was a low rate of dysplasia detection with confirmatory EGD, less than 1% of cases. No additional cases of HGD or esophageal carcinoma in SSBE cases were detected. This suggests that the yield of confirmatory EGD is greater in patients with LSBE.

Diagnostic yield of a novel jumbo biopsy "unroofing" technique for tissue acquisition of gastric submucosal masses.

BACKGROUND AND STUDY AIMS: Adequate tissue acquisition for the diagnosis of gastric submucosal masses (GSMs) has been challen ging for gastroenterologists. The use of standard biopsy forceps generally recovers non-diagnostic overlying mucosa. Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) provides a significant improvement, but is often still inadequate for diagnosis. The aim of the current study was to assess the efficacy of a novel jumbo biopsy unroofing technique (JUT) for tissue acquisition in GSM. PATIENTS AND METHODS: This prospective study recruited patients who were referred for EUS for the evaluation of GSM between 2006 and 2009. All patients underwent EUS with FNA when feasible followed by JUT. The primary outcome was diagnostic yield of JUT. RESULTS: A total of 93 patients were enrolled, 72 of whom were included in the investigation; 16 patients were excluded with no evidence of a submucosal mass or extrinsic compression, and five patients were further excluded by pathology confirming mucosal lesions. Of the 72 jumbo biopsies 66 (92%) provided diagnostic tissue without significant complications and 42 (58%) had lesions amenable to FNA. Although 34 of the 42 lesions were deemed adequate at the time of on-site cytological evaluation, only 28 (67%) provided sufficient tissue for final diagnosis. More importantly, only 37/72 (52%) of all patients had lesions that required any further intervention. CONCLUSIONS: Utilization of JUT is safe and effective for diagnosis of GSM. The data suggest that the jumbo biopsy unroofing technique should be considered as an initial diagnostic strategy for GSMs found during upper endoscopy.

Pseudomelanosis duodeni: associated with multiple clinical conditions and unpredictable iron stainability - a case series.

Pseudomelanosis duodeni is seen endoscopically as dark spots in the duodenal mucosa and is generally considered to be local deposition of iron from oral iron intake. However, pseudomelanosis duodeni may be identified histologically even before it becomes endoscopically evident; iron stainability within the mucosa is uneven and unpredictable, and multiple clinical conditions other than oral iron intake may be associated. We reviewed 17 adult patients with histologically detected pseudomelanosis duodeni, their endoscopic appearances, iron stainability, and clinical findings including oral iron and drug intake. Only 6/17 (35 %) had endoscopically apparent dark spots. Perl's iron stain was entirely positive in 18 %, partially positive in 64 %, and negative in 18 % of cases. History of oral iron was present in 76 % of patients, but other clinical conditions consistently associated were hypertension in 88 %, end stage renal disease in 59 %, and diabetes mellitus in 35 % of patients.

Herpes simplex virus hepatitis: expanding the spectrum of disease.

We describe 2 transplant patients with herpes simplex virus (HSV) hepatitis who were minimally symptomatic throughout their illness. The spectrum of disease caused by HSV hepatitis is more variable than previously reported in this population. HSV hepatitis should be considered in immunocompromised hosts with elevated transaminases without evidence of fulminant hepatic necrosis.

Insulinoma presenting with hyperandrogenism: a case report and a literature review.

An 18-year-old woman presented with a 6-month history of amenorrhoea and hyperandrogenism. Three months later she developed several episodes of fasting hypoglycaemia and was subsequently diagnosed with an insulinoma. Hyperinsulinaemia was observed in association with an elevated serum testosterone level. Surgical removal of the insulinoma resulted in resolution of the clinical and biochemical features of the polycystic ovarian syndrome (PCOS). Polycystic ovarian syndrome is unusual in a patient having an insulinoma. The rarity of this association may be the result of the late age of onset of this type of tumour, intermittent secretion of excessive insulin by the tumour, the degree of hyperinsulinism or other factors extrinsic to the insulin receptor that may facilitate insulin activity. However, we could not discover how our patient differs in having had PCOS from the majority of women with insulinoma who do not. If other patients with insulinoma are subsequently found to have hyperandrogenism, then this tumour might be added to the differential diagnosis of causes of anovulatory cycles and hyperandrogenaemia, although rare the association would be uncommon.

Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats.

Only 30% of alcoholics develop liver disease (ALD) suggesting that additional factors are needed. Endotoxin is one such factor, but its etiology is unclear. Since the gut is the main source of endotoxin, we sought to determine whether an increase in intestinal permeability (leaky gut) is required for alcohol-induced endotoxemia and liver injury and whether the gut leakiness is preventable. For 10 weeks, rats received by gavage increasing alcohol doses (to 8 g/kg/day) and either oats (10 g/kg) or chow b.i.d. Intestinal permeability was then assessed by urinary excretion of lactulose and mannitol. Liver injury was evaluated histologically, biochemically (liver fat content), and by serum aminotransferase. Alcohol caused gut leakiness that was associated with both endotoxemia and liver injury. Oats prevented these changes. We conclude that chronic gavage of alcohol in rats is a simple experimental model that mimics key aspects of ALD, including endotoxemia and liver injury, and can be useful to study possible mechanisms of endotoxemia in ALD. Since preventing the gut leakiness by oats also prevented the endotoxemia and ameliorated liver damage in rat, our results suggest that alcohol-induced gut leakiness 1) may cause alcohol-induced endotoxemia and liver injury and 2) may be the critical cofactor in the 30% of alcoholics who develop ALD. Further studies are needed to determine whether ALD in humans can be prevented by preventing alcohol-induced gut leakiness, studies that should lead to the development of useful therapeutic agents for the prevention of ALD.

Differential expression of metallopanstimulin/S27 ribosomal protein in hepatic regeneration and neoplasia.

We have previously shown that human metallopanstimulin-1 (MPS-1) is a ubiquitous 9.4-kd multifunctional ribosomal S27/nuclear "zinc finger" protein that is expressed at high levels in a wide variety of actively proliferating cells and tumor tissues. In this study, we examined the expression of MPS-1 in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Tissue samples were obtained at the time of tumor resection, needle biopsy, or liver transplantation. MPS- 1 was studied by immunohistochemistry by use of specific antibodies to the N-terminus of MPS-1 in a biotin/streptavidin-amplified system. In chronic hepatitis, hepatocytes had very weak MPS-1 immunostaining. In contrast, hepatocytes in regenerating cirrhotic nodules stained strongly for MPS-1. In well-differentiated hepatocellular carcinoma, MPS-1 presence was intense at the periphery of the malignant nodule. In poorly differentiated hepatocellular carcinoma, MPS-1 presence was notably intense in malignant hepatocytes invading the septal tissues, in close contact with neovascular structures. These results suggest that MPS-1 may be involved in both progression toward malignancy in regenerating cirrhotic nodules and in subsequent steps of hepatocarcinogenesis.

Resolution of cirrhosis in autoimmune hepatitis with corticosteroid therapy.

Successful therapy for liver diseases, including autoimmune hepatitis, primary biliary cirrhosis, and hepatitis C, has been associated with a reduction in hepatic fibrosis. Recently, a study of needle liver biopsy specimens documented resolution of cirrhosis in a small group of patients with autoimmune hepatitis who responded to corticosteroid therapy. We describe a woman with autoimmune hepatitis who had cirrhosis on a wedge biopsy of the liver in 1985 and who attained a biochemical response with immunosuppressive therapy. A repeat wedge liver biopsy performed 14 years later was normal, providing unequivocal evidence that cirrhosis can reverse completely in autoimmune hepatitis.

Daily interferon therapy for hepatitis C virus infection in liver transplant recipients.

BACKGROUND: Hepatitis C virus infection persists after liver transplantation and causes recurrent liver injury in the majority of patients. Standard dose interferon therapy has been largely unsuccessful for hepatitis C in transplant recipients. METHODS: Twelve patients, at least 7 months posttransplant, with detectable hepatitis C virus RNA in serum and features of hepatitis C on liver biopsy were randomized to interferon-alpha2a, 3 mU daily for 12 months (n=8) or no treatment (n=4). The tolerability of daily interferon dosing in liver transplant recipients was evaluated and effects on hepatitis C virus RNA level, quasispecies evolution, and liver histology were studied. RESULTS: Treated patients had an improvement in histological activity index at the end of therapy relative to controls (median reduction of 2 versus median increase of 1.5) (P=0.04). Four treated patients had a virological response (all bDNA negative, one qualitative polymerase chain reaction negative) compared with none of the untreated patients. Only two of six treated patients tested had evidence of quasispecies diversification on therapy. Seven of eight patients in the treatment group required dose reduction for fatigue and/or depression. They tolerated 1.5 mU of interferon-alpha2a daily. Two treated patients developed graft dysfunction, one of who had histological evidence of rejection and subsequent graft loss. CONCLUSIONS: Low daily doses of interferon were tolerated by liver transplant recipients and provided histological benefit without associated quasispecies diversification in most cases. These findings provide a rationale to study low dose daily or pegylated interferon maintenance therapy for the management of hepatitis C posttransplant.

Multifocal granular cell tumor of the esophagus and proximal stomach with infiltrative pattern: a case report and review of the literature.

The granular cell tumor is a solitary painless nodule that arises most commonly on the skin or the tongue. The vast majority are benign. Approximately 5% to 9% of granular cell tumors have been reported in the gastrointestinal tract, most commonly in the esophagus. We report a case of a 45-year-old African American woman with multifocal granular cell tumors of the esophagus and proximal stomach. Two lesions within the distal esophagus and proximal stomach were characteristic nodular granular cell tumors. Within the mid esophagus there was poorly defined transmural involvement by benign-appearing granular cells. This pattern of infiltration by benign cells is uncharacteristic. A review of the literature with emphasis on the determination of malignancy is also presented.

Mechanical, histologic, and biochemical effects of canine rectal formalin instillation.

UNLABELLED: Instillation of 4 percent formalin effectively treats radiation hemorrhagic proctitis; however, little is known regarding its side effects. PURPOSE: The study contained herein was undertaken to determine rectal compliance and collagen content, mucosal and vascular histologic changes, and kinetics of formalin absorption following instillation. METHODS: Fifteen mongrel dogs (50-60 pounds) were randomized into five experimental groups according to time elapsed from formalin treatment: control, acute, one week, two weeks, and four weeks. Formalin was instilled in 30-ml aliquots to a total volume of 400 ml. Rectal compliance (closed manometry system) was assessed pre-formalin and post-formalin at the designated time interval. Serum formalin metabolites were determined at time 0, 0.5, 1, and 3 hours. A segment of rectal wall was analyzed for collagen content, mucosal injury, and blood vessel density. RESULTS: Serum formalin levels peaked within 30 minutes, returning to normal by 3 hours. With the exception of one dog, toxic levels were not reached at any time during the study. No dogs experienced sepsis, fever, or altered gastrointestinal function. Acute and one-week dogs showed mild diffuse proctitis and mucosal slough, which healed within two weeks. Rectal compliance and collagen content were unchanged. Mucosal blood vessels decreased in number early (P = 0.03). CONCLUSIONS: Instillation of 4 percent formalin in sequential aliquots of a small volume that is kept in contact for a short period of time is safe. Serum formalin levels generally do not reach toxic levels, and the slight elevation in formalin concentration that was seen returns to normal within three hours. Formalin-induced proctitis heals within two weeks, and no long-term changes in rectal compliance or collagen content were seen.

Myoepithelial hamartoma of the duodenal wall.

A rare case of myoepithelial hamartoma of the duodenal wall is presented, and previous case reports found in the literature are reviewed. Myoepithelial hamartomas are thought to arise from displaced pancreatic anlage present along the gastrointestinal tract during embryogenesis, which can differentiate into various pancreatic elements; the most highly differentiated form is heterotopic pancreas. An alternative theory is pancreatic metaplasia of endodermal tissues. We describe a 41-year-old man who presented with abdominal pain and vomiting. CT scanning revealed a mass at the head of the pancreas. A pancreaticoduodenectomy was performed for presumed cystadenoma. Histology of the mass revealed a disorderly arrangement of smooth muscle, dilated and nondilated ducts, pancreatic acinar tissue and mucus glands. The relationship of myoepithelial hamartomas involving the small bowel to similar lesions in the stomach, bile ducts and gallbladder is discussed.

Absorption kinetics of rectal formalin instillation.

Formalin instillation has become an accepted treatment of radiation-induced hemorrhagic cystitis and proctitis since the initial report by Brown in 1969 (Med. J. Aust. 1:23, 1969). Although its use is widespread, no studies have been performed to determine the safest, volume or duration of formalin exposure. The purpose of our study was to determine the optimum technique for instillation and the safety margin regarding the maximum time that formalin can be in contact with the rectal mucosa without causing serum toxicity. In a pilot canine study, 4% neutral buffered formalin was instilled into the rectum in 30 ml aliquots for 60 seconds each after which each aliquot was withdrawn; a total volume of 400 ml was used. Our subsequent experiment involved rectal instillation of a single formalin bolus of 100 ml for 1 hour without removal during this time. Formalin metabolites were measured in the blood and urine to assess toxicity. Results indicate that with the latter technique serum formic acid reaches toxic levels within 15 minutes of instillation and may stay elevated for several hours. Metabolites in the urine similarly increase within 15 minutes, lagging only shortly behind the rise in serum levels. Performing formalin instillation in a series of 30 ml aliquots appears to be a safer treatment, as toxic serum levels were not reached and their slight rise above baseline returned to normal within 3 hours.

Tumor angiogenesis in primary and metastatic colorectal cancers.

PURPOSE: Angiogenesis is needed to sustain growth of both primary and metastatic lesions; however, comparisons in microvessel density between a primary tumor and its metastases have not been widely performed. We studied microvessel density in primary colorectal cancers and their liver metastases. METHODS: Sections from 32 primary lesions and 53 hepatic metastases were immunostained with a monoclonal antibody for von Willebrand's factor, an endothelial cell marker. Blood vessels were quantified under x 100 magnification using both conventional light microscopy and computer-assisted image analysis. Primary and metastatic angiogenesis scores (AS), i.e., vessel counts, were analyzed with respect to tumor size, hepatic multicentricity, synchronicity, resectability, and patient survival. Using computer-assisted calculations, the same analyses were performed using blood vessel to tumor surface area ratios, vessel wall thickness, and intensity of immunostaining. RESULTS: Angiogenesis scores were significantly lower in metastatic lesions compared with their primary tumors (P < 0.0001). Primary AS did not correlate with metastatic tumor size, resectability, multicentricity, or patient survival. Metastatic AS strongly predicted patient survival (P < 0.0009) but with a negative coefficient, i.e., higher scores were associated with improved survival. Metastatic AS were higher in resectable than in nonresectable metastases and in solitary than in multiple metastases; however, these trends were not statistically significant. Metachronous liver lesions had significantly higher angiogenesis scores than synchronous metastases (P < 0.04). Similar trends were seen using computer-assisted image analysis. CONCLUSIONS: These results indicate that in presence of an established metastasis, there is a weak angiogenic relationship between a primary tumor and its metastasis. Heterogeneity in metastatic lesions cannot be explained solely by studying angiogenesis in primary tumors. Microvessel density in a primary tumor may not be useful as an independent prognostic indicator in late stages of disease. In such cases, assessment of microvessel density in a metastatic tumor whenever possible may be an indicator of prognosis.

Intestinal anastomotic healing at varying times after irradiation.

The use of preoperative and intraoperative irradiation as surgical adjuncts in cancer management has led to concerns regarding post-operative wound healing. The optimum time to construct an intestinal anastomosis after irradiation has not been determined. The aim of this study was to evaluate anastomotic wound healing at varying times after irradiation. One hundred eighty-seven male Sprague-Dawley rats were randomized into seven experimental groups. Group I (control) had a sutured anastomosis and no irradiation. Groups II-VII received a single dose of 20 Gy intraoperatively. In group II, a sutured anastomosis incorporating irradiated bowel was performed immediately after irradiation. Groups III-VII underwent a second laparotomy to undergo a sutured anastomosis with irradiated bowel at 2 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after irradiation. The rats were sacrificed 7 days after the anastomosis was created and the segment of terminal ileum containing the anastomosis was harvested. Tensile strength, hydroxyproline content, and modified Black irradiation damage scores were determined: [table: see text] The increasing modified Black scores reflect the progressive nature of irradiation damage over time. Increasing hydroxyproline content is seen after irradiation but this does not imply increasing wound strength. There was a return of tensile strength to normal levels by 2 weeks. These findings suggest that normal wound healing can be expected if a minimum of 2 weeks elapses between irradiation and intestinal anastomosis.

Immunohistochemical detection of mutant P53 protein and human papillomavirus-related E6 protein in anal cancers.

PURPOSE: The wild-type P53 protein, a product of the P53 gene, is a normal growth controlling protein. Mutation of the P53 gene generates a mutant P53 protein which promotes tumor formation through loss of growth suppression. Some of the agents responsible for P53 gene mutation are known, one of which may be tumorigenic human papillomavirus (HPV) infection. Anal cancers are demonstrating a changing trend in the affected population, from older females in the older reported series to younger males more recently. This may be a reflection of infection with tumorigenic HPV types 16 and 18. The E6 oncoprotein of these viruses inactivates the growth-controlling wild-type P53 protein. In this study, our purpose was to determine the incidence of mutant P53 and HPV-16 and 18-related E6 protein and their coexpression in anal cancers. METHODS: We examined 29 anal cancers immunohistochemically for mutant P53 protein, HPV 16 and 18 E6 protein, and coexpression of the two. RESULTS: Mutant P53 protein was present in 58.6 percent of anal cancers overall and in 85.7 percent of anal adenocarcinomas. E6 oncoprotein was present in five cases (17.2 percent), all of which were squamous-cell carcinomas. Coexpression of both mutant P53 and E6 proteins was seen in only three cases (10.3 percent). CONCLUSION: Although tumorigenic HPV may be an important cause for P53 gene mutation in anal cancers, perhaps other mutagenic factors play a predominant role.