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Aims: Fundic gland polyps (FGPs) comprise 66% of all gastric polyps. Although they are usually non-syndromic, they may be associated with various syndromes, including familial adenomatous polyposis (FAP) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). We aimed to evaluate how histological features relate to distinct FGP subtypes., Methods and Results: We performed a retrospective analysis of 118 FGPs from 109 patients for the architecture of fundic glands, microcyst lining, parietal cell hyperplasia and surface foveolar epithelial changes. Age, gender and history of FAP or GAPPS were collected. Based on combinations of histological features, three distinct patterns (A, B and C) of FGPs were delineated and correlated to the aetiologies. Non-syndromic FGPs were well-formed polyps composed of disordered fundic glands with intermediate-sized microcysts typically lined by a mixture of oxyntic and mucin-secreting cells (73%). Parietal cell hyperplasia (80%) and foveolar surface hyperplasia (78%) were common. FAP-associated cases demonstrated small microcysts that were predominantly lined by fundic epithelium (77%), with limited parietal cell hyperplasia (27%); foveolar hyperplasia was uncommon. GAPPS-related polyps were the largest, with prominent, mucin-secreting epithelium-lined microcysts (73%). Hyperproliferative aberrant pits were universally present, whereas parietal cell hyperplasia was uncommon. Pattern A was identified in most non-syndromic FGPs (74%) and in a minority of FAP-related FGPs (26%). The majority (82%) of FAP-related FGPs showed pattern B, but only 18% of non-syndromic FGPs did. Pattern C consisted exclusively of GAPPS-associated polyps., Conclusions: We conclude that, although FGPs share similar histomorphology, subtle differences exist between polyps of different aetiology. In the appropriate clinical setting, the recognition of these variations may help to consider syndromic aetiologies., (© 2022 John Wiley & Sons Ltd.)

Background & Aims: Chronic liver disease is a major health burden that produces significant liver-related morbidity and mortality. We aimed to evaluate liver-related outcomes of patients with different causes of chronic liver disease in Australia., Methods: We collected data from 10,933 patients with chronic liver disease assessed by Hepascore (a serum fibrosis model) in Western Australia from 2004 through 2015. We obtained records of liver-related death, transplantation, decompensation, and hepatocellular carcinoma from WA Data Linkage Unit databases. Competing risk analysis was used to calculate the cumulative risk of each clinical endpoint, and risks for clinical endpoints were compared among all causes of chronic liver disease., Results: In our final cohort for analysis, 5566 patients had hepatitis C virus (HCV) infection, 1989 had HBV infection, 119 were infected with HBV and HCV, 955 had alcohol-associated liver disease, 1597 had non-alcoholic fatty liver disease (NAFLD), 123 had alcohol-associated liver disease and metabolic risk factors, 561 had autoimmune liver disease without overlap syndrome, and 23 autoimmune overlap syndrome. Significant differences among chronic liver diseases were observed in risk of all-cause death (P < .001), liver-related death (P < .001), liver transplantation (P < .001), and decompensation (P < .001) but not hepatocellular carcinoma (P=.095). Patients with alcohol-associated liver disease had the highest 5-year cumulative risk of liver-related death (17.1%) and the second-highest 5-year cumulative risk of decompensation (29.2%). Multivariate analysis found patients with alcohol-associated liver disease had significantly higher risks of liver-related death and decompensation than patients with HCV infection with hazard ratios (HRs) of 2.39 (95% CI, 1.88-3.03) and 3.42 (95% CI, 2.74-4.27), respectively. Patients with NAFLD had a significantly lower risk of liver related death and decompensation than patients with HCV infection, with HRs of 0.67 (95% CI, 0.48-0.95) and 0.70 (95% CI, 0.52-0.94) respectively., Conclusions: In an analysis of patients in Western Australia, we found patients with alcohol-associated liver disease to have significantly higher risk of decompensation and liver-related death than patients with HCV infection, whereas patients with NAFLD have significantly lower risks of either outcome., (Copyright © 2020. Published by Elsevier Inc.)

Neoplastic lesions of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) are gastric phenotype. GAPPS was reported in 2011 as a new autosomal dominant gastric polyposis syndrome characterized by involvement of the gastric body/fundus with sparing of the antrum by multiple polyps, reported to be primarily fundic gland polyps (FGPs), with progression to dysplasia and adenocarcinoma of intestinal type. Our series consists of 51 endoscopic biopsies and 5 gastrectomy specimens from 25 patients belonging to a previously defined GAPPS family. Slides were reviewed and further stains performed. Endoscopy was abnormal in 15 of the 25 patients: carpeting polyposis of the gastric body and fundus in 14 and a gastric mass without polyposis in one. The most common polypoid lesion (seen in 12 patients) was a disorganized proliferation of specialized/oxyntic glands high up in the mucosa involving the attenuated foveolar region around the gastric pits, which we have termed "hyperproliferative aberrant pits". Well developed FGP were seen in 10 patients. Established neoplastic lesions seen in 9 patients were: (1) discrete gastric adenomas, (2) multifocal "flat" dysplasia in the setting of hyperproliferative aberrant pits +/- FGPs, (3) adenomatous tissue associated with adenocarcinoma. All cases of dysplasia were of gastric phenotype based on morphology and mucin immunohistochemistry., In Conclusion: (1) the spectrum of gastric pathology associated with GAPPS is wider than previously reported, (2) the earliest microscopic clue is the finding of hyperproliferative aberrant pits, and (3) the dysplasia is gastric phenotype and the subsequent adenocarcinoma may follow the gastric pathway of carcinogenesis.

The assumption that intestinal metaplasia is a prerequisite for intraepithelial neoplasia/dysplasia and adenocarcinoma in the distal esophagus has been challenged by observations of adenocarcinoma without associated intestinal metaplasia. This study describes our experience of intestinal metaplasia in association with early Barrett neoplasia in distal esophagus and gastroesophageal junction. We reviewed the first endoscopic mucosal resection of 139 patients with biopsy-proven neoplasia. In index endoscopic mucosal resection, 110/139 (79%) cases showed intestinal metaplasia. Seven had intestinal metaplasia on prior biopsy specimens and three had intestinal metaplasia in subsequent specimens, totaling 120/139 (86%) patients showing intestinal metaplasia at some point supporting the theory of sampling error for absence of intestinal metaplasia in some cases. Those without intestinal metaplasia (13%) were enriched for higher stage disease (T1a Stolte m2 or above) supporting the assertion of obliteration of intestinal metaplasia by the advancing carcinoma. All cases of intraepithelial neoplasia and T1a Stolte m1 carcinomas had intestinal metaplasia (42/42). The average density of columnar-lined mucosa showing goblet cells was significantly less in shorter segments compared to those ≥3 cm (0.31 vs 0.51, P=0.0304). Cases where segments measured less than 1 cm were seen in a higher proportion of females and also tended to lack intestinal metaplasia. We conclude that early Barrett neoplasia is always associated with intestinal metaplasia; absence of intestinal metaplasia is attributable to sampling error or obliteration of residual intestinal metaplasia by neoplasia and those with segments less than 1 cm show atypical features for Barrett-related disease (absent intestinal metaplasia and female gender), supporting that gastroesophageal junction adenocarcinomas are heterogeneous.

Aim: To establish if serial Hepascore tests (referred to as delta Hepascore) in those with chronic hepatitis C (CHC) correlate with the increase and/or decrease in risk of liver related complications., Methods: Three hundred and forty-six CHC patients who had two Hepascore tests performed were studied. During 1944 patient years follow-up 28 (8.1%) reached an endpoint. The Hepascore is a serum test that provides clinically useful data regarding the stage of liver fibrosis and subsequent clinical outcomes in chronic liver disease., Results: Patients with a baseline Hepascore > 0.75 had a significantly increased rate of reaching a composite endpoint consisting of hepatocellular carcinoma, liver death, and/or decompensation ( P < 0.001). In those with an initial Hepascore > 0.75, a subsequent improved Hepascore showed a significantly decreased risk for the composite endpoint ( P = 0.004). There were no negative outcomes in those with a stable or improved delta Hepascore. The minimum time between tests that was found to give a statically significant result was in those greater than one year ( P = 0.03)., Conclusion: In conclusion, Hepascore is an accurate predictor of liver related mortality and liver related morbidity in CHC patients. Of note, we have found that there is a decreased risk of mortality and morbidity in CHC patients when the patient has an improving delta Hepascore. Repeat Hepascore tests, when performed at a minimum one-year interval, may be of value in routine clinical practice to predict liver related clinical outcomes and to guide patient management., Competing Interests: Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript.

HER2 is amplified/overexpressed in a subset of gastric and gastro-oesophageal junction cancers. Addition of anti-HER2 therapy has been shown to provide survival benefit in this setting. However, there are limited data assessing the concordance of HER2 status between primary and metastatic sites.A total of 113 samples from 43 paired primary and metastatic tumours were tested for HER2 status, by immunohistochemistry (IHC) for protein expression and silver in situ hybridisation (SISH) for gene amplification.Primary sites tested included endoscopic biopsies (n = 30) and resections (n = 24). Metastatic samples included lymph nodes (n = 29), peritoneal effusions (n = 21) and miscellaneous sites (n = 9). The overall HER2+ rate was 11%. Of 41 (95%; 95% CI 88.5-100%) concordant cases, 38 were HER2- and three were HER2+. There were two (5%) discordant cases, one of which showed heterogeneity of HER2 expression.This series confirms a high concordance rate of 95%, supporting that testing of primary tumours and metastases is equally valid and providing clinical rationale for the addition of anti-HER2 therapy in HER2+ disseminated disease.

Background and Aims: Rates of long-term clinical outcomes of chronic hepatitis C in patients with none, mild or severe liver fibrosis are required to determine benefits of anti-viral therapies. This study evaluated long-term outcomes for chronic hepatitis C stratified by all Metavir fibrosis stages., Methods: Clinical outcomes were determined using population-based data linkage methodology for 880 hepatitis C patients who had a liver biopsy performed from 1992 to 2012., Results: During 9386 person-years of follow up, 28 patients developed hepatocellular carcinoma, 58 developed liver decompensation and 122 died or underwent liver transplantation. There was no significant difference in liver-related death for those with F0-F2 with an 18-year survival probability >94%. Hazard ratio of liver-related death for F3 compared with F0-F2 was 4.24 (P = 0.003), with no significant difference in the first 13-year follow up. The 15-year decompensation-free survival for F0, F1 and F2 was 100%, 96% and 94% respectively and for hepatocellular carcinoma-free survival was 100%, 99% and 98%. Hazard ratio of liver complication (hepatocellular carcinoma or decompensation)-free survival for F3 compared with F0-F2 was 3.22 (P = 0.001), with no significant difference during the first 7-year follow up. F4 had significantly higher risk of liver-related death, decompensation and hepatocellular carcinoma than F3 (P < 0.001)., Conclusions: Chronic hepatitis C patients with F2 or less had few liver complications after 15 years. For F3 patients, the significant increase in liver-related death occurred after 13 years and for liver complications after 7 years., (© 2014 Royal Australasian College of Physicians.)

HER2 testing on effusions of metastatic gastric carcinoma may provide a valuable alternative to testing on primary biopsies. This study assessed the feasibility of this method by immunohistochemistry (IHC) and silver in situ hybridization (SISH). Cell blocks from 46 effusions from metastatic gastric carcinoma were examined. IHC was scored using the modified criteria of Hofmann et al. An average of ≥6 signals per nucleus was considered amplification on SISH. Results were compared with histological specimens to assess HER2 status concordance. Cell blocks showed a poorly cohesive pattern in 30 (65%), aggregates in 7 (15%), and mixed pattern in 9 (20%). Seven (15%) showed an IHC 2+/3+ reaction with a membranous pattern, appearing more granular than in histology. Three (7%) showed HER2 amplification on SISH. In 18 cases (39%), HER2 status was compared with histological specimens, showing 100% concordance. Difficulties were encountered in distinguishing malignant cells from reactive mesothelial cells in 12 (26%). This study supports the feasibility of HER2 assessment on effusions. The incidence of HER2 positivity (7% with SISH+ and IHC 2+/3+) was lower than reported in histological samples. Further refinement and validation will enhance the use of this method in clinical practice and overcome difficulties encountered., (© 2014 Wiley Periodicals, Inc.)

Endoscopic resection (ER) is considered the therapy of choice for intraepithelial neoplasia associated with visible lesions and T1a adenocarcinoma. Pathologists are bound to encounter specimens collected via these techniques more frequently in their practice. A standardised protocol for handling, grossing, and assessing ER specimens should be adopted to ensure that all prognostic information and characteristics influencing treatment are included in reports (see Supplementary Video Abstract, http://links.lww.com/PAT/A22). The entire specimen should be appropriately oriented, processed and assessed. An ER specimen will commonly show intraepithelial neoplasia or invasive carcinoma. There are essential features that should be recorded if invasive carcinoma is found as they dictate further management and follow-up. These features are the margin status, depth of invasion, degree of differentiation and presence or absence of lymphovascular invasion. Important features such as duplication of muscularis mucosae should be recognised to avoid misinterpretation of depth of invasion. Key diagnostic and prognostic elements that are essential for optimal clinical decisions have been included in the reporting format proposed by the Structured Pathology Reporting committee of the Royal College of Pathologists of Australasia (RCPA).

Background & Aims: Histopathological scoring of liver fibrosis mainly measures architectural abnormalities and requires a minimum biopsy size (⩾ 10 mm). Liver collagen quantification may allow use of small size biopsies and improve the prediction of clinical outcomes. This study evaluated the ability of the collagen proportional area (CPA) measurement to predict clinical outcomes., Methods: Clinical outcomes were determined using population based data-linkage for chronic hepatitis C (CHC) patients from 1992 to 2012. Quantitative digital image analysis of liver biopsies was used for CPA measurement., Results: 533 patients with a biopsy size ⩾ 5 mm were included. Median follow up was 10.5 years. 26 developed hepatocellular carcinoma (HCC), 39 developed liver decompensation and 33 had liver related death. 453 had Metavir F0-F2 and 80 had F3-F4. CPA ranged from 1.3% to 44.6%. CPA and Metavir stage were independently associated with liver related death. Metavir stage, CPA stage and age were independently associated with HCC. CPA stage (C1: 0%-5%, C2: 5%-10%, C3: 10%-20%, C4: >20%) stratified risk and a significant difference in outcomes was present between all CPA stages for HCC and between C2-C3 and C3-C4 for decompensation and liver related death. The 15 year composite endpoint-free survival was 97% for C1, 89% for C2, 60% for C3, 7% for C4. C4 had significantly worse survival than ⩽ C3 (p<0.001) in cirrhotic patients., Conclusions: CPA stage gave additional information regarding risk stratification for adverse clinical outcomes independent of Metavir stage., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The aim of this study was to compare HER2 amplification, as determined by the HER2 copy number (CN) and the HER2/CEP17 ratio, with protein expression in gastric and gastro-oesophageal junction (G/GOJ) adenocarcinoma.HER2 immunohistochemistry (IHC) and silver in situ hybridisation (SISH) were performed in 185 cases. Modified gastric criteria were used for IHC scoring. HER2 and CEP17 CNs were counted in at least 20 cancer cells and the ratio calculated as per previously defined protocols. These two SISH methods were statistically compared against the different IHC scores.Thirty-four cases showed amplification, by both methods in 29, and either method in five. IHC score was 3+ in 29 cases; 26 showed amplification by both methods, one by ratio only and two were not amplified. IHC score was 2+ in 24 cases; three showed amplification by both methods and two by either. One each of IHC 1+ and 0 showed an increased ratio but not CN. The HER2 CN and ratio for IHC score 3+ compared to scores 2+, 1+ and 0 were significantly different (all p < 0.01). The CN for IHC 2+ vs IHC 1+ and IHC 0 was significantly different (both p < 0.01) but the ratio was not (p = 0.5711 and p = 0.2857, respectively). The CN and the ratio for scores 1+ and 0 were not significantly different (p = 0.9823 and p = 0.9910, respectively).The HER2 CN differentiates between the different IHC scores better than the HER2:CEP17 ratio. Cases that show IHC3+ and high CN may not require calculation of the ratio. Furthermore, consideration should be given to the CN when IHC negative cases appear amplified by the ratio only.

Background: Collagen proportional area (CPA) determined by quantitative digital image analysis better quantifies liver fibrosis than histological stage; however, its clinical use has been limited by non-standardized methods., Aim: This study aimed to compare CPA obtained using different staining methods, magnifications and biopsy sizes., Methods: Two hundred and forty-nine patients with chronic hepatitis C who had a liver biopsy and serum fibrosis markers performed were included. CPA was measured either using a sirius red (CPAs) or a trichrome (CPAt) stain., Results: CPAs measured at 20× and 40× magnifications generated similar outcomes with interclass correlation (ICC) coefficient of 0.98. Compared with trichrome, sirius red staining had much less variation with an ICC coefficient of 0.99 for slides stained in the same batch and 0.92 in different batches. Mean CPAs was higher than mean CPAt by 3.53%, P < 0.001. Morphological analysis found that sirius red detected delicate fibrous septa and spurs better than trichrome. Both CPAs and CPAt correlated well with Metavir stage, whereas CPAs had better ability to detect cirrhosis with the area under ROC curve of 0.95. Overall CPA had superior correlation with serum markers of fibrosis in Metavir F2-F4 than that in F0-F1 and CPAs correlated better with serum fibrosis markers than CPAt in Metavir F0-F1. Multivairate analysis found that HA, α2-macroglobulin, platelet count and albumin were independently correlated with CPAs and only HA was independently correlated with CPAt., Conclusions: Sirius red staining for CPA determination was more accurate and reliable for quantifying hepatic collagen compared with trichrome staining., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The objective of this study was to develop a triage algorithm to optimize diagnostic yield from cytology, carcinoembryonic antigen (CEA), and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) testing on different components of a single pancreatic cyst fluid specimen. The authors also sought to determine whether cell block supernatant was suitable for CEA and KRAS testing., Methods: Fifty-four pancreatic cysts were triaged according to a volume-dependent protocol to generate fluid (neat and supernatant) and cell block specimens for cytology, comparative CEA, and KRAS testing. Follow-up histology, diagnostic cytology, or a combined clinicopathologic interpretation was recorded as the final diagnosis., Results: There were 26 mucinous cystic lesions and 28 nonmucinous cystic lesions with volumes ranging from 0.3 mL to 55 mL. Testing different components of the specimens (cell block, neat, and/or supernatant) enabled all laboratory investigations to be performed on 50 of 54 cyst fluids (92.6%). Interpretive concordance was observed in 17 of 17 cases (100%) and in 35 of 40 cases (87.5%) that had multiple components tested for CEA and KRAS mutations, respectively. An elevated CEA level (>192 ng/mL) was the most sensitive test for the detection of a mucinous cystic lesion (62.5%) versus KRAS mutation (56%) and "positive" cytology (61.5%). KRAS mutations were identified in 2 of 25 mucinous cystic lesions (8%) in which cytology and CEA levels were not contributory., Conclusions: A volume-based protocol using different components of the specimen was able to optimize diagnostic yield in pancreatic cyst fluids. KRAS mutation testing increased diagnostic yield when combined with cytology and CEA analysis. The current results demonstrated that supernatant is comparable to neat fluid and cell block material for CEA and KRAS testing., (Copyright © 2012 American Cancer Society.)

Aims: Mycophenolate-associated colitis has been previously reported to show patterns of colonic mucosal injury mimicking a host of conditions, including graft-versus-host disease, ischaemia and inflammatory bowel disease (IBD). The aim of this study is to characterise, semiquantitatively, pathological changes of mycophenolate mofetil (MMF) mucosal injury., Methods: Seven transplant patients receiving MMF who underwent colonoscopic examination and biopsy were identified retrospectively over a 2-year period. Multiple histologic parameters, including architectural distortion, cryptitis, stromal active inflammation, individual damaged crypts (IDC) and crypt apoptotic figures were evaluated in the biopsies semiquantitatively. Where biopsy site was identified, the parameters were assessed separately in biopsies from right and left colon., Results: All cases showed mixed patterns of mucosal injury. All seven cases showed focal architectural distortion (in 58% of fragments per case), focal cryptitis (mean 3.0 foci per case), increased crypt apoptosis (mean 26.5/100 crypts) and IDC (mean 3.0 foci). Focal changes resembling acute self-limited colitis were noted in three cases. Possible proximal accentuation of some changes was noted with right side biopsies tending to show greater crypt apoptotic activity and more foci of architectural distortion. Three cases showed dual pathology (two with cytomegalovirus (CMV) infection and one with IBD)., Conclusions: Although a wide spectrum of changes may be seen in MMF-associated colitis, important microscopic clues include a mixed pattern of injury (typically a combination of crypt apoptosis, isolated crypt damage and architectural distortion), and possible proximal accentuation of pathologic changes. The need for clinical correlation and follow-up is emphasised by the occurrence of dual pathology in patients treated with MMF.

Background and Goals: Liver fibrosis influences treatment and surveillance strategies in chronic hepatitis B (CHB). This multicenter study aimed to examine the accuracy of serum fibrosis models in CHB patients including those with low alanine aminotransferase (ALT) levels and serially in those undergoing treatment., Method: We examined noninvasive fibrosis models [Hepascore, Fibrotest, APRI, hepatitis e antigen (HBeAg)-positive and -negative models] in 179 CHB patients who underwent liver biopsy and fibrosis assessment by METAVIR and image morphometry. Serial Hepascore measurements were assessed in 40 subjects for up to 8.7 years., Results: Hepascore was more accurate than Fibrotest [area under the curve (AUC) 0.83 vs. 0.72, P = 0.05] and HBeAg-positive model (AUC 0.83 vs. 72, P = 0.03) for significant fibrosis but was not significantly different to APRI or HBeAg-negative scores. Fibrosis area assessed by morphometry was correlated with Hepascore (r = 0.603, P < 0.001), Fibrotest (r = 0.392, P = 0.03), and HBeAg-positive (r = 0.492, P = 0.001) scores only. Among 73 patients with an ALT <60 IU/L, noninvasive models were useful to predict fibrosis (PPV 80-90%) or exclude significant fibrosis (NPV 79-100%). Hepascore increased significantly among patients monitored without treatment and reduced among patients undergoing therapy (0.05/year ± 0.03 vs. -0.04/year ± 0.02, P = 0.007)., Conclusions: Serum fibrosis models are predictive of fibrosis in CHB and assist in identifying subjects with low-normal ALT levels for treatment.

Aims: To assess human epidermal growth factor receptor 2 (HER2) status and heterogeneity using immunohistochemistry (IHC) and silver in-situ hybridization (SISH) in gastric carcinoma and dysplasia, and to correlate HER2 status between biopsy and resection specimens of gastric carcinoma., Methods and Results: Immunohistochemistry for HER2 was performed in 178 cases of gastric carcinoma, and SISH in cases showing at least 1+ reaction. HER2 positivity [European Medicines Agency (EMA) guidelines] was identified in 20.2% of carcinomas and 12.9% of high-grade dysplasia, and HER2 heterogeneity noted in 50% and 33% of these cases, respectively. IHC negative/positive reactivity and SISH results were concordant in 96.2%. SISH amplification was seen in 35.3% of IHC 2+ and in a case with previously unrecognized staining pattern. Concordance of IHC HER2 status on biopsies and gastrectomies was seen in 74.1%. False negative IHC results on either the biopsy or gastrectomy were seen in 19.4% of HER2 amplified cases., Conclusions: Human epidermal growth factor receptor 2 status in gastric carcinoma is comparable to previous studies with good concordance between IHC and SISH; all IHC 2+ and unusual patterns should be assessed with ISH studies; heterogeneity of tumour HER2 overexpression/amplification is common with possible implications for HER2 testing; and HER2 overexpression appears sufficiently specific to be considered a potential diagnostic biomarker of dysplasia., (© 2011 Blackwell Publishing Limited.)

Background: According to American Gastroenterological Association Institute criteria, the diagnosis of eosinophilic oesophagitis (EOE) requires clinicopathological correlation. In the appropriate clinical context, a high eosinophil count (HEC, defined as >or=15/HPF) is considered pathological evidence of EOE. However, HEC may not always be identified in biopsies given its patchy distribution, and there may be histological overlap between EOE and gastro-oesophageal reflux disease (GORD) in the distal oesophagus., Aims: To evaluate the utility of subepithelial sclerosis and HEC in proximal oesophageal biopsies as additional diagnostic criteria., Methods: Cases between 2004 and 2008 with paired proximal and distal oesophageal biopsies and the mention of eosinophils in the reports were retrieved from PathWest Queen Elizabeth II Medical Centre archives. Biopsies were reviewed and assessed for eosinophilic count and presence of subepithelial stroma and sclerosis. A final diagnosis was made after review of both biopsy and clinical details., Results: There were 23 cases of EOE and 20 cases of GORD in an adult cohort. In comparison to GORD, cases of EOE had significantly higher eosinophil counts in proximal (39.4 vs 0.6 eosinophils/HPF) and distal biopsies (35.6 vs 1.9), with HEC in proximal biopsies a feature exclusive to EOE (83% vs 0%). Subepithelial sclerosis was identified in at least one biopsy in 74% of EOE and in only a single case of GORD., Conclusions: HEC in proximal oesophageal biopsies and subepithelial sclerosis should be considered major diagnostic findings in EOE.

Differentiation of recurrent hepatitis C virus (HCV) disease from acute cellular rejection (ACR) following liver transplantation can be difficult. Previously, we have found that MxA protein, a specific and sensitive marker for type 1 interferon production, is strongly expressed in chronic HCV disease. Here, we investigate MxA expression as a marker for recurrent HCV disease in the livers of 14 adult HCV patients who underwent liver transplantation. Serial liver biopsies available for 12 of these patients were stained for MxA protein and scored using a semi-quantitative approach. Hepatocellular MxA protein levels were significantly up-regulated (p = 0.025) in recurrent HCV disease in comparison to ACR. In biopsies that showed histological changes consistent with recurrent HCV disease, strong hepatocellular MxA staining was present in 14/18 (78%). In the liver biopsies with histological evidence of ACR, strong MxA hepatocellular staining was present in only three of 10 (30%). Thus, assessment of hepatocellular MxA protein expression can contribute to the differential diagnosis of ACR and recurrent HCV disease following liver transplantation. In conclusion, analysis of intrahepatic MxA levels has the potential to reduce the inappropriate use with high-dose pulsing of steroids post-operatively.

Aim: To assess the severity of hepatic iron loading in patients with a compound heterozygous C282Y/H63D HFE genotype., Methods: A total of 246 patients were referred to the Hepatology Clinic at a tertiary hospital for HFE genotyping and further assessment of elevated serum transferrin saturation and/or ferritin results, either with or without abnormal liver function tests. Subjects of the study were 19 patients compound heterozygous for HFE who had liver biopsy, quantitative liver iron estimation and liver histopathology., Results: Mild iron overload [hepatic iron concentration between 30 and 100 micromol/g dry weight], was present in 16/19 compound heterozygous patients, three patients had values within the reference range. As well as the compound heterozygous HFE genotype, 18/19 patients were found to have had at least one additional risk factor for developing either iron loading or liver disease., Conclusion: Compound heterozygous patients show no more than mild liver iron loading. The decision whether or not to recommend liver biopsy in C282Y/H63D patients with abnormal serum iron indices and/or liver function tests should be based on the need to evaluate liver damage rather than solely to assess liver iron loading.

The therapeutic effect of interferon-alpha and ribavirin in the treatment of chronic hepatitis C viral infection is limited. To identify patient characteristics that may predict responsiveness to treatment, the intrahepatic protein expression of two directly induced IFN-alpha effector proteins, MxA and PKR, were studied. Forty liver biopsy samples from patients with a variety of chronic liver diseases were stained for MxA and PKR protein using immunohistochemical techniques. In a HCV patient cohort, 30 liver biopsies were stained for MxA and PKR protein prior to treatment with IFN-alpha and ribavirin. PKR protein expression was not upregulated in viral liver disease. In contrast, MxA protein expression was significantly upregulated in viral liver disease (P = 0.005). In chronic HCV liver disease, moderate to strong cytoplasmic expression of MxA protein was observed in hepatocytes and monocytes, indicating endogenous hepatocellular IFN-alpha pathway activation. In the HCV patient cohort treated with combination therapy, strong pre-treatment MxA hepatocyte expression was predictive of a non-response to treatment (odds ratio 9.33; P = 0.01; 95% confidence interval 1.63-53.2). This effect was independent of HCV genotype and viral load. It is concluded that pretreatment hepatocellular MxA expression may become a useful predictor of response to combination treatment with IFN-alpha and ribavirin., (Copyright 2002 Wiley-Liss, Inc.)

Background and Aim: Orthotopic liver transplantation (OLT) is now the accepted therapy for end-stage chronic liver disease. Long-term survival is now expected in the majority of patients and, consequently, disease recurrence has emerged as a major concern. Our aim was to document the rate of disease recurrence after liver transplantation for conditions other than hepatitis C, in patients followed up by the Western Australian Liver Transplant Service (WALTS)., Methods: The case notes of all post-OLT patients followed up by WALTS were reviewed. Patients were excluded if survival was less than 3 months post-OLT; OLT was performed for hepatitis C alone or follow up was unavailable. Detection and definition of disease recurrence depended on pretransplant diagnosis, and were based on patient interview, biochemical, immunological and serological tests. Radiological and histological confirmation were obtained where clinically indicated., Results: Eighty-seven patients were identified (89 OLTs performed). The overall rate of recurrence was 10%. Recurrence rates by disease were: primary sclerosing cholangitis (17%), primary biliary cirrhosis (12%), autoimmune hepatitis (17%), hepatitis B (40%) and alcoholic liver disease (4%). Alcohol use relapse after transplantation occurred in 25%. The overall survival post-OLT was 87%, with a mean follow up of 53 months. Survival in patients with recurrent disease was 89%., Conclusions: Disease recurrence after OLT does occur, but overall, it is relatively uncommon. Recurrence rates vary significantly and depend, in part, on indication for OLT. With medium-term follow up, recurrent disease does not have an effect on mortality.

DNA from gastrointestinal biopsy specimens from 28 Australian patients with histologic evidence of intestinal spirochetosis (IS) was subjected to PCRs to amplify segments of the 16S rRNA and NADH oxidase genes of Brachyspira aalborgi and Brachyspira (Serpulina) pilosicoli. B. aalborgi was identified in specimens from 24 (85.7%) patients and B. pilosicoli in those from 4 (14.3%) patients (2 of whom were also positive for B. aalborgi). For two patients, no product was amplified. This study demonstrates that B. aalborgi is much more commonly involved in histologically identified IS in Australian patients than is B. pilosicoli. This is the first report of amplification of B. pilosicoli DNA from humans with IS.

Background: Distinguishing well differentiated hepatocellular carcinoma (HCC) from benign hepatocellular lesions is a well recognized problem in fine-needle aspiration (FNA) cytology. The endothelial cell marker CD34 is negative in normal hepatic sinusoids and stains vessels diffusely in HCC. This feature is useful in distinguishing benign from malignant hepatocytic lesions in histological specimens, although benign lesions may show focal positivity for CD34 confined to periportal and periseptal areas. In this study, we assess the role of CD34 in cell block and thin core biopsy material from benign and malignant hepatocellular lesions, and compare it with reticulin staining., Methods: Cell blocks and thin core biopsies were assessed from 40 cases of HCC and 25 benign hepatocytic lesions. HCCs were scored for nuclear grade. Sections were stained for CD34 antigen and scored semi-quantitatively. Previously performed reticulin stains were reviewed., Results: Thirty three of 40 HCCs (82.5%) showed diffuse positivity for CD34. The other seven cases showed either focal positivity (four cases), minimal positivity (two cases) or negative staining (one case). These results did not correlate with the nuclear grade of the tumor. Two of 25 benign cases (8%) showed diffuse positivity for CD34, 8 showed focal positivity, 11 showed minimal positivity, and 4 showed negative staining. All HCCs showed an abnormal reticulin pattern characterized by expanded trabeculae and islands, or sheets, with decreased or absent reticulin. All of the benign hepatocellular lesions showed a normal trabecular reticulin pattern., Conclusions: Diffusely positive CD34 staining is useful to support a diagnosis of well differentiated HCC, but in our study the reticulin stain distinguished more consistently between benign and malignant lesions.

Background: Distinction of well differentiated hepatocellular carcinoma (HCC) from benign hepatocellular lesions is a well recognized problem in fine-needle aspiration (FNA) cytology, sometimes leading to indeterminate reports. The aim of this study was to critically examine criteria that might allow definitive diagnosis in these cases., Methods: FNA smears and cell blocks from 65 patients with primary hepatocellular lesions were reviewed. Seventy separate samples had been obtained. The initial reports in these samples were: HCC in 34, benign findings in 27, and indeterminate findings in 9. We defined architectural and cytological features seen in the malignant cases but not seen in the benign cases, including an assessment of reticulin in cell blocks. These criteria were then applied to the indeterminate cases., Results: The most specific cytologic criteria of malignancy in well differentiated HCC were (i) numerous stripped atypical nuclei, (ii) macronucleoli, (iii) increased mitoses, and (iv) multinucleation. The most specific architectural criteria in smears were (i) widened trabeculae, (ii) well defined capillaries traversing tissue fragments, and (iii) solid islands of hepatocytes rimmed by endothelial cells. The most valuable architectural criteria in cell blocks were (i) trabeculae greater than two cells thick and (ii) reduced or absent reticulin framework. Using the above criteria a retrospective diagnosis of HCC was possible in eight of the nine indeterminate cases, all but one of which have subsequently been confirmed as malignant., Conclusions: Close attention to architectural features in both smears and cell blocks should allow most well differentiated HCCs to be diagnosed by FNA cytology. A reticulin stain should be part of the routine assessment of cell blocks. Cancer (Cancer Cytopathol), (Copyright 1999 American Cancer Society.)

The magnetic resonance imaging (MRI) features of 11 biopsy-proven lesions of focal nodular hyperplasia (FNH) of the liver were reviewed retrospectively. Only three lesions showed atypical features. It is believed MRI can reliably differentiate FNH from other liver tumours when strict criteria are fulfilled.

An accurate and functional system for grading acute liver allograft rejection is important for patient management, research, and communication. The Banff schema is a consensus document designed to provide an internationally accepted standard for this purpose. The aim of this study is to determine if application of the Banff schema would significantly alter the grading of acute liver allograft rejection compared with the Birmingham system. One hundred twenty-four post-liver transplantation biopsies performed by the Western Australian Liver Transplantation Service between 1992 and 1997 were retrospectively analyzed by a pathologist and a hepatologist. Each was supplied with a brief clinical history before applying the Banff and Birmingham criteria. Results were compared with each other and to the diagnosis made at the time of the biopsy, which was based on the European grading system. Rejection was diagnosed by the reviewers in 61 of 124 biopsy specimens according to the criteria of Snover. The Banff schema and Birmingham system agreed on the grade of rejection in 22 of the 61 biopsy specimens. The Banff schema elevated the grade of rejection in 39 specimens by an increment of one. In no instance did the Banff schema reduce the grade. Comparison between the Banff schema and diagnosis made at the time of biopsy showed agreement in 39 specimens, whereas the Banff schema elevated the grade in 15 specimens and reduced the grade in 23 specimens. In comparison to the Birmingham system, the Banff schema elevated the grade of liver allograft rejection in the majority of biopsy specimens, and this has the potential to alter clinical management with the adoption of the Banff schema or if the systems are used interchangeably.

PCR procedures amplifying portions of the 16S rRNA and NADH oxidase genes of Brachyspira aalborgi and Serpulina pilosicoli were applied to DNA extracted from paraffin-embedded human colonic or rectal tissues from 30 Norwegian, Australian, and U.S. patients, 16 of whom had histologic evidence of intestinal spirochetosis (IS). B. aalborgi-specific sequences were identified by PCR in 10 of the IS patients (62.5%) but none of the others, while S. pilosicoli sequences were not detected in tissues from any patient. Direct sequencing of products from three of the positive samples provided further confirmation of the presence of B. aalborgi. B. aalborgi may be a more common cause of intestinal spirochetosis than has been previously thought.

Purpose: Irrigation of the rectal stump before anastomosis after resection for carcinoma is accepted colorectal surgical practice. However, not all surgeons perform this routinely, and it has never been established conclusively that irrigation of the rectal stump eliminates exfoliated malignant cells or even reduces local recurrence. The patients of a surgeon whose standard surgical practice involved rectal irrigation were compared with those of a surgeon who does not routinely practice rectal irrigation., Method: Ten patients were given rectal washout with 200 to 500 ml of normal saline introduced via a Foley catheter per rectum. Ten patients were not given rectal washout. In both groups the anastomosis was performed with a circular stapler, and the stapler and donuts were rinsed in 200 ml of normal saline. The saline was sent for cytologic examination and classified as malignant cells seen or no malignant cells seen. The cytopathologist was blinded to the washout status., Results: Of the ten patients who had rectal washout performed, none had malignant cells seen. Of the ten patients who did not have rectal washout performed, eight had malignant cells seen in the cytology (P = 0.007; two-tailed Fisher's exact probability test)., Conclusion: Rectal washout eliminates exfoliated malignant cells in the rectum in the vicinity of the anastomosis.

Background: A preoperative diagnosis of medullary carcinoma of the thyroid (MCT) allows for the investigation of associated multiple endocrine neoplasia/ pheochromocytoma, and definitive surgery without the need for frozen section. Criteria for cytodiagnosis are well known but variable patterns of presentation may cause diagnostic difficulty., Methods: This study examines the accuracy of cytodiagnosis and the value of ancillary tests in 17 patients seen between 1976 and 1997. Nine patients underwent thyroid gland aspirations, five patients underwent fine-needle aspiration (FNA) of the thyroid and cervical lymph nodes, and three patients underwent cervical lymph node aspiration alone. Electron microscopy (EM) of aspirated material was performed in nine cases and immunocytochemistry in two cases., Results: In all cases the diagnosis was suggested by FNA. In four cases, diagnosis and management were based on cytology alone. EM of FNA material was confirmatory in nine cases, two of which also showed positive calcitonin immunocytochemistry. In three cases the diagnosis was not proven until surgical resection, and in one case FNA confirmed lymph node metastasis in known MCT. Frozen section in five patients did not change the level of diagnostic confidence over the FNA diagnosis in any case. In four other thyroid tumors (one Hürthle cell follicular carcinoma, two anaplastic carcinomas, and one hyperplastic nodule) MCT was suspected in the FNA differential diagnosis but later excluded. In the Hürthle cell tumor immunoperoxidase staining was positive for calcitonin and in one anaplastic carcinoma, a neuroendocrine phenotype was suggested. In the latter case, additional EM excluded MCT., Conclusions: Although correct diagnosis is made by cytology in the majority of instances, other tumors may show cytologic findings similar to MCT. EM of FNA material was found to be the most definitive method of proving or excluding MCT. Immunocytochemistry may be misleading for rarely performed tests.

The risks of acquisition of hepatitis C infection, the histological spectrum of liver disease, and the presence of viraemia were investigated in anti-hepatitis C virus (HCV) antibody positive blood donors. All 357 (0.64%) blood donors to the South Australian Red Cross Transfusion Service found to have anti-HCV antibody during the first seven months of testing in 1990 were assessed, and 70 (19.6%) were found to have elevated alanine transaminase levels. These subjects were referred for participation in the study; 31 presented for enrollment. Sixteen (52%) of the 31 patients had previously used intravenous drugs, four (13%) had been transfused, two (6%) had a history of occupational exposure to blood, and three (10%) had tattoos and ear-piercing as possible risk factors for acquisition of hepatitis C. There was no history of parenteral exposure in six (16%). None of these donors had clinical evidence of liver disease, but in all 24 of the 31 who had a liver biopsy there was histological evidence of significant liver damage. Twelve had evidence of chronic active hepatitis. All 24 subjects biopsied were viraemic as judged by the presence of HCV RNA in serum.