Asbestos exposure and histological subtype of malignant mesothelioma.

BACKGROUND: Malignant mesothelioma (MM) has distinct histological subtypes (epithelioid, sarcomatoid and biphasic) with variable behaviour and prognoses. It is well recognised that survival time varies with the histological subtype of MM. It is not known, however, if asbestos exposure characteristics (type of asbestos, degree of exposure) are associated with different histological subtypes. AIM: To determine if the pathological MM subtype is associated with the type of asbestos or the attributes of asbestos exposure. METHODS: Cases of MM for the period 1962 until 2012, their main histological subtype and their most significant source of asbestos exposure were collected from the Western Australian Mesothelioma Registry. Exposure characteristics included, degree of asbestos exposure (including total days exposed, years since first exposure and, for crocidolite only, calculated cumulative exposure), source of exposure (occupational or environmental), form of asbestos handled (raw or processed) and type of asbestos (crocidolite only or mixed fibres). RESULTS: Patients with the biphasic subtype were more likely to have occupational exposure (OR 1.83, 1.12 to 2.85) and exposure to raw fibres (OR 1.58, 1.19 to 2.10). However, differences between subtypes in the proportions with these different exposure characteristics were small and unlikely to be biologically relevant. Other indicators of asbestos exposure were not associated with the histological subtype of mesothelioma. CONCLUSIONS: There was no strong evidence of a consistent role of asbestos exposure indicators in determining the histological subtype of MM.

Predicting survival in malignant mesothelioma.

Malignant mesothelioma (MM) of the pleura or peritoneum is a universally fatal disease attracting an increasing range of medical interventions and escalating healthcare costs. Changes in survival and the factors affecting survival of all patients ever diagnosed with MM in Western Australia over the past five decades and confirmed by the Western Australian Mesothelioma Registry to December 2005 were examined. Sex, age, date and method of diagnosis, site of disease and histological type were recorded. Date of onset of symptoms and performance status were obtained from clinical notes for a sample of cases. Cox regression was used to examine the association of the clinical variables and the 10-yr periods of disease onset with survival after diagnosis. Survival was inversely related to age, being worse for males (hazard ratio (HR) 1.4, 95% CI 1.2-1.6), and those with peritoneal mesothelioma (HR 1.4, 95% CI 1.1-1.7). Patients with sarcomatoid histology had worse prognosis than patients with epithelioid and biphasic histological subtypes. Survival improved after the 1970s and has made incremental improvements since then. Median (interquartile range) survival by decade, from 1960 until 2005, was 64 (0-198), 177 (48-350), 221 (97-504), 238 (108-502) and 301 (134-611) days; ~4 weeks of this apparent improvement can be attributed to earlier diagnosis. With increasing resources and treatment costs for MM over the past 40 yrs, there have been modest improvements in survival but no complete remissions.

Banff schema for grading liver allograft rejection: utility in clinical practice.

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.

Reactive mesothelial hyperplasia vs mesothelioma, including mesothelioma in situ: a brief review.

In biopsy tissue, discrimination between reactive mesothelial hyperplasia and epithelial mesothelioma can pose a major problem for the surgical pathologist. Confidence in the diagnosis is often proportional to the amount of tissue available for study and depends largely on findings of invasion and the extent and cytologic atypia of the lesion, because there is no marker specific for the mesothelium and that discriminates consistently among normal, hyperplastic, and neoplastic mesothelial tissue. Therefore, mesothelioma in situ is diagnosable only when invasive epithelial mesothelioma is demonstrable in the same specimen, in a follow-up biopsy specimen, or at autopsy. Comparison of 22 cases of mesothelioma in situ that fulfill these requirements for diagnosis with 141 invasive mesotheliomas and 78 reactive mesothelioses indicates that strong linear membrane-related labeling for epithelial membrane antigen and silver-labeled nucleolar organizer region-positive material that occupies 0.6677 microm2 or more of the nucleus in an atypical in situ mesothelial lesion of the pleura are found consistently in neoplastic mesothelial cells. Although these findings may engender suspicion of mesothelioma in situ in high-risk persons, the criteria for diagnosis of pure mesothelial lesions of this type are still under study. Mesothelioma in situ should be considered proved only when unequivocal invasion is identified in a different area of the pleura or at a different time; a diagnosis of pure mesothelioma in situ should not be made in patients not exposed to asbestos.

Cellular expression and regulation of iron transport and storage proteins in genetic haemochromatosis.

Genetic haemochromatosis is a common iron overload disorder of unknown aetiology. To characterize the defect of iron metabolism responsible for this disease, this study localized and semi-quantified the mRNA and protein expression of transferrin, transferrin receptor and ferritin in the liver and duodenum of patients with genetic haemochromatosis. Biopsies were obtained from iron-loaded non-cirrhotic patients with genetic haemochromatotic and control patients with normal iron stores. Additional duodenal biopsies were obtained from patients with iron deficiency. Immunohistochemical and in situ hybridization analysis for transferrin, transferrin receptor and ferritin was performed. Hepatic transferrin, transferrin receptor and ferritin protein expression was localized predominantly to hepatocytes and was increased in patients with genetic haemochromatosis when compared with normal controls. Interestingly, hepatic ferritin mRNA expression was not increased in these same patients. In the genetic haemochromatotic duodenum, ferritin mRNA and protein was localized mainly to crypt and villus epithelial cells and the level of expression was decreased compared with normal controls, but similar to iron deficiency. Duodenal transferrin receptor mRNA and protein levels colocalized to epithelial cells of the crypt and villus were similar to normal controls. Early in the course of genetic haemochromatosis and before the onset of hepatic fibrosis, transferrin receptor-mediated iron uptake by hepatocytes contributes to hepatic iron overload. Increased hepatic ferritin expression suggests this is the major iron storage protein. While persisting duodenal transferrin receptor expression may be a normal response to increased body iron stores in patients with genetic haemochromatosis, decreased duodenal ferritin levels suggest that duodenal mucosa is regulated as if the patient were iron deficient.

The use of epithelial membrane antigen and silver-stained nucleolar organizer regions testing in the differential diagnosis of mesothelioma from benign reactive mesothelioses.

BACKGROUND: The accurate diagnosis of pleural lesions obtained from small closed biopsy is difficult. As yet there is no single reliable test to distinguish between malignant and benign mesothelial tissue. METHODS: Immunostaining of epithelial membrane antigen (EMA) and the quantitation of silver stained nucleolar organizer regions (AgNORs) each were applied to benign and malignant histologic sections of pleural and peritoneal biopsies. The usefulness of these stains was tested both individually and in combination in the diagnosis of epithelial malignant mesothelioma. RESULTS: One hundred and three of the 141 malignant lesions (73%) were immunoreactive for EMA but only 3 of the 73 benign lesions (4%) reacted equivocally, and none positively. The average count of AgNORs/cell in malignant lesions (n = 80) was elevated compared with benign cases (n = 26), but a significant overlap was exhibited in the AgNOR count and this form of analysis was considered to be of little value in distinguishing benign from malignant mesothelial processes. Much less overlap was observed when the average AgNOR area was measured. By using the maximum benign AgNOR area of 0.6677 microm2 as the upper threshold, 51 cases (63.8%) were identified as malignant; the test demonstrated 100% specificity and 63.8% sensitivity. By combining the EMA and AgNOR results, 76 of 80 of the malignant mesothelioma cases (95%) tested positive for at least 1 of the tests with no false-positive results identified. CONCLUSIONS: This study confirms the usefulness of EMA in diagnosing malignant and benign mesothelial lesions, and demonstrates the enhanced diagnostic value of combining EMA immunoreaction with the average area of AgNOR per cell, thereby increasing sensitivity in the diagnosis of epithelial malignant mesothelioma.

Comparison of measures of exposure to asbestos in former crocidolite workers from Wittenoom Gorge, W. Australia.

Determinations of exposure-response relationships between crocidolite and the major asbestos-related diseases in the Wittenoom cohort have previously depended on the validity of estimates of airborne exposure to asbestos. This work aims to validate the airborne exposure measurements by obtaining measurements of the concentrations of uncoated crocidolite fibers and asbestos bodies retained in the lungs of individual workers, and to estimate the half-life of crocidolite fibers in the lungs. Samples of lung tissue, excluding tumor, of all former Wittenoom workers known to have died in Western Australia (WA) were sought from teaching hospitals, pathology departments, and the Coroner's pathologist. The lung specimens were processed using Pooley's method with TEM for counts of fibers of all types and using Smith and Naylor's method with conventional light microscopy for asbestos bodies (AB). Multiple linear regression was utilized to examine the associations between crocidolite concentrations in the lung and duration of employment at Wittenoom, time since last employed at Wittenoom, nature of job, estimated average fiber concentration at the worksite, and estimated cumulative crocidolite exposure (CCE) in fiber-years/ml for each subject. Lung tissue from 90 cases was processed and there was good agreement between counts of crocidolite fibers, asbestos bodies, and CCE. Correlations were 0.77 for AB and fibers, 0.54 for AB and CCE, and 0.58 for CCE and fibers, after log transformation. The half-life of crocidolite fibers in the lung was estimated at 92 months (95% CI 55-277 months). Previous estimates of airborne exposure to Wittenoom crocidolite have been reasonably reliable. The relatively simple technique of light microscopy for counting ABs in lung tissue also provides a useful and reliable indication of the level of past occupational exposure to crocidolite in subjects whose exposure has been only to crocidolite. The half-life of crocidolite fibers in the lungs of former Wittenoom workers is about 7-8 years.

Malignant mesothelioma in Pilbara Aborigines.

Malignant mesothelioma occurred in a female Aborigine after environmental exposure to asbestos. All known cases of the disease in Aborigines in Western Australia were reviewed; all occurred in Pilbara residents. Most were exposed while involved in the transport of asbestos from the Wittenoom crocidolite operation. Based on recent estimates of the size of the Aboriginal population in the Pilbara region, their incidence of this disease (250 per million for ages 15 and over) is one of the highest population-based rates recorded.

Asbestos bodies in lung tissue following exposure to crocidolite.

A series of 206 necropsies in Western Australia (WA) have had routine counts made of asbestos bodies in samples of lung tissue using conventional light microscopy. Thirty-two cases had worked in the asbestos industry at Wittenoom, WA and (log) counts of asbestos bodies in their lung tissue correlated well with estimates of their (log) cumulative airborne exposure to crocidolite fibers (r = 0.60). There was no association between the number of asbestos bodies and time since exposure to asbestos ceased. In subjects without known exposure to asbestos, there was a weak but nonsignificant increase in number of asbestos bodies with increasing age, with 26% of cases having no asbestos bodies present. It is concluded that the relatively simple technique of light microscopy for counting of asbestos bodies in lung tissue provides a reliable indication of the level of past occupational exposure to crocidolite in subjects whose exposure has been only to crocidolite. This could be extremely useful in follow-up studies of cohorts that lack reliable measures of airborne exposure to crocidolite asbestos.

The concept of mesothelioma in situ: implications for diagnosis and histogenesis.

The concept of mesothelioma in situ is explored by a detailed examination of seven patients, subsequently proven to have pleural malignant mesothelioma, who initially had no evidence of gross tumor and for whom biopsy material was available at this early presentation. The tissue was assessed by routine microscopy, the immunoperoxidase technique for epithelial membrane antigen and silver staining for nucleolar organizer regions. Tiny lesions of the pleura that merged with or were adjacent to microscopically flat monolayered or folded mesothelium with cytological atypia were observed. The atypical cells reacted positively to epithelial membrane antigen, and the nucleolar organizer region counts were elevated. These observations are considered to support the possibility of the presence of mesothelioma in situ. These findings are discussed in the light of the proposed concept of mesothelioma in situ, its histogenesis, and its possible clinical relevance.

Carbamazepine hepatotoxicity: another cause of the vanishing bile duct syndrome.

Serious carbamazepine hepatotoxicity is being recognized more frequently and is usually manifest as an acute granulomatous hepatitis that is self-limiting if the drug is withdrawn. The case of a 59-year-old man who developed the vanishing bile duct syndrome after 2 months of treatment with carbamazepine for glossopharyngeal neuralgia is reported. The characteristic histological features of this syndrome may also be seen in primary biliary cirrhosis, primary sclerosing cholangitis, graft-vs.-host disease after allogeneic bone marrow transplantation, chronic liver allograft rejection, and other drug reactions. The progress of this patient to date suggests that irreversible liver injury resulting in chronic liver disease is likely, in keeping with the clinical course of the vanishing bile duct syndrome in most cases.

Miliary spread of malignant pleural mesothelioma without a clinically identifiable pleural tumour.

A 44-year-old man with past minor exposure to blue asbestos presented with supraclavicular lymphadenopathy and miliary shadowing on his chest radiograph. Cytology and electronmicroscopy on material obtained by fine needle aspiration from his cervical lymph node revealed malignant mesothelioma. Malignant mesothelioma cells were also present in bronchoalveolar lavage fluid and on transbronchial lung biopsy. At autopsy the right pleural cavity was studded with small tumour nodules. This case demonstrates that malignant mesothelioma may present as metastatic disease and without evidence on conventional investigations of a primary pleural tumour.

Diclofenac hepatitis.

We report five cases of biopsy-proven hepatitis developing between six and 20 weeks after administration of diclofenac. In one patient jaundice had previously developed following use of ibuprofen. In another the clinical, biochemical and histopathological features were those of chronic active hepatitis and treatment with corticosteroids was required. All patients recovered from their liver injury without sequelae. Resolution of symptoms occurred between three and 12 weeks following cessation of the drug, while liver function tests returned to normal between seven and 16 weeks after drug withdrawal, except in the patient with chronic active hepatitis who remained biochemically abnormal for eight months. Three of the five patients developed transient circulating autoantibodies, suggesting immune mechanisms may be important in the pathogenesis of this injury. The incidence of severe hepatic dysfunction related to the use of diclofenac appears low and is probably in the order of one case per 50-100,000 prescriptions.

Histological and immunohistochemical study of the gall bladder lesion in primary sclerosing cholangitis.

The histological features and type of mononuclear cell infiltrate in gall bladders from six patients with primary sclerosing cholangitis were studied using routine staining techniques and immunohistochemistry. Control studies were performed using the gall bladders from six patients (age and sex matched) with chronic cholecystitis and four with primary biliary cirrhosis. A range of histological abnormalities was present in gall bladders from patients with primary sclerosing cholangitis including a mild to moderate degree of epithelial hyperplasia, pseudogland formation, and mononuclear cell infiltrate of the epithelium; moderate to severe chronic inflammatory cell infiltrate and fibrosis affecting the superficial and deep layers of the gall bladder wall; and minimal smooth muscle hypertrophy. These abnormalities were non-specific and were also present in gall bladders from patients with chronic cholecystitis and primary biliary cirrhosis. Vasculitis and granulomas were not present in the patients with primary sclerosing cholangitis. Immunohistochemistry showed that the superficial and deep mononuclear cell infiltrate in primary sclerosing cholangitis gall bladders was composed predominantly of lymphocytes, in contrast to chronic cholecystitis where macrophages were found in similar or greater numbers. Moreover, T lymphocytes (activated and resting) were present throughout the lymphocytic infiltrate and were apposed to the base and interdigitated between the biliary epithelial cells in significantly greater numbers than in chronic cholecystitis gall bladders. B lymphocytes were present only in lymphoid follicles. Comparative studies using liver biopsy specimens from three of the primary sclerosing cholangitis patients showed a similar T lymphocyte portal tract infiltrate. We conclude that a number of non-specific chronic inflammatory histological abnormalities were present in primary sclerosing cholangitis gall bladders. Immunohistochemistry found other features that were present in this disease - a predominantly lymphocytic mononuclear cell infiltrate of the superficial and deep layers of the gall bladder wall and the presence of T lymphocytes that infiltrated the biliary epithelial cells. These findings support the hypothesis that aberrant cell mediated immune mechanisms may play a role in the pathogenesis of both the intrahepatic and extrahepatic lesions in primary sclerosing cholangitis.

Nodular regenerative hyperplasia of the liver: the importance of combined macroscopic and microscopic findings.

A 40-year-old man with rheumatoid arthritis, splenomegaly and mild thrombocytopenia presented with gross ascites and a history of excess alcohol consumption. Oesophageal varices were documented endoscopically. Alcoholic cirrhosis was suspected and laparoscopy revealed a macronodular liver surface. Liver biopsy disclosed subtle microscopic structural variations which together with the laparoscopic findings were consistent with the diagnosis of nodular regenerative hyperplasia. The importance in diagnosis of macroscopic appearance combined with histological findings is emphasised. Clinically significant portal hypertension may be present at a histologically early stage of this condition.

Confirmation of the efficacy of hepatic tissue iron index in differentiating genetic haemochromatosis from alcoholic liver disease complicated by alcoholic haemosiderosis.

The hepatic tissue iron index proposed by Bassett et al was evaluated in 35 patients with homozygous genetic haemochromatosis, 67 patients with alcoholic liver disease, and 18 patients with other forms of chronic liver disease with and without cirrhosis. In patients with cirrhosis hepatic tissue iron concentration reliably differentiated alcoholic liver disease from genetic haemochromatosis. Although mean iron concentration was greater in patients with prefibrotic haemochromatosis than in those with prefibrotic alcoholic liver disease, some overlap occurred and complete differentiation of the two conditions was not possible. This overlap was particularly evident in some young patients with haemochromatosis in whom the tissue iron concentration grade fell in the range commonly seen in alcoholic haemosiderosis. Inability to differentiate early genetic haemochromatosis from alcoholic liver disease complicated by haemosiderosis was also a problem with standard Perls's staining. When the hepatic tissue iron index was calculated (hepatic tissue iron concentration/patient's age in years), clear differentiation of genetic haemochromatosis from both alcoholic liver disease and other forms of chronic liver disease was obtained in both cirrhotic and precirrhotic patients. This study confirms that the hepatic tissue iron index is a useful means of differentiating patients with genetic haemochromatosis from those with alcoholic liver disease. We suggest that biochemical estimation of tissue iron concentration and calculation of the tissue iron index in all patients in whom genetic haemochromatosis is a possible diagnosis will reduce the likelihood of misdiagnosing this as alcoholic liver disease.

Primary biliary cirrhosis: clinicopathological characteristics and outcome.

Thirty-five patients with primary biliary cirrhosis were seen between 1974 and 1989. The median mean age at presentation was 53 years (range: 30-77) and the female to male ratio was 7.8:1. Thirteen (37%) were asymptomatic and nine (26%) had associated auto-immune disorders. Pruritus and hepatomegaly were present in half of the patients. Advanced histological stages of disease (Stages 3 and 4) were present in 57% of patients. The median period of follow-up was 5 years (range: 0.1-20). Twelve patients died, nine from hepatic causes and three from non-hepatic causes. One has undergone liver transplantation. A Kaplan-Meier curve estimated the median survival to be 11 years. Asymptomatic patients developed progressive disease and survival was similar to that of symptomatic patients. Using Cox's proportional hazards model, age, serum bilirubin and serum albumin were found to be independent prognostic variables correlating with reduced survival.

Autoantibodies to isolated human hepatocyte plasma membranes in chronic active hepatitis. II. Specificity of antibodies.

The fine specificity of autoantibodies to human hepatocyte plasma membranes in autoimmune chronic active hepatitis was determined by one-dimensional immunoblotting. Sera from 12 patients with "classical" autoimmune chronic active hepatitis contained autoantibodies recognizing many human hepatocyte plasma membrane polypeptides in the 15 to 220 kD range. Many of these autoantibodies titrated beyond 1:80,000 and some may be potentially "pathological." In particular, one band with an apparent molecular weight of 60 kD was a dominant and consistent finding in all patients with autoimmune chronic active hepatitis by immunoblotting. Serum absorption studies showed this band to be predominantly liver-specific. Control sera from patients with chronic persistent hepatitis, nonhepatic autoimmune disease and normal healthy subjects possessed low titer reactivity that most likely represented "natural" autoantibodies. Anti-human hepatocyte plasma membranes in autoimmune chronic active hepatitis consisted of all three immunoglobulin isotypes (G,M and A) and their presence was not caused by nonspecific reactions as a consequence of hypergammaglobulinemia. Autoantibodies were shown to be specific by virtue of their absorption and exhaustion on titration. Many were directed at species nonspecific determinants, however, some autoantibodies recognized human-specific polypeptides. The majority of anti-human hepatocyte plasma membranes appeared to be organ-specific as sera from patients with autoimmune chronic active hepatitis reacted only weakly with polypeptides of kidney plasma membranes. Of the activity detected, few bands corresponded with those obtained using polypeptides of human hepatocyte plasma membranes. Our results show that patients with autoimmune chronic active hepatitis possess an array of liver-specific autoantibodies to polypeptide subunits of human hepatocyte plasma membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary sclerosing cholangitis: clinical and immunopathological review of 21 cases.

Twenty-one patients with primary sclerosing cholangitis were seen during 1979-87. The mean age at onset of disease was 51.7 years (range: 13-78 years) with a male: female ratio of 2.5:1. Six (29%) were asymptomatic at the time of diagnosis. Eleven patients (52%) had ulcerative colitis. Cholangiography demonstrated abnormalities limited to the intrahepatic ducts in 10 cases, with both intrahepatic and extrahepatic involvement in 11. Histological features on liver biopsy included: portal tract inflammation and cholestasis in all; paucity of bile ducts in 56%; piecemeal necrosis in 19% and cirrhosis in 6%. Circulating autoantibodies and elevated serum immunoglobulins were found in half of the patients and HLA-B8 was detected in 53%. A deficiency of circulating CD3 and CD8 cells was not found in the 12 patients tested. The mean follow-up was 51 months (range: 3-180 months). Three patients died from non-hepatic causes and another has received liver transplantation. A Kaplan-Meier curve predicted 70% survival at 72 months.