We analyzed the practice of mesothelioma post-mortems in the United Kingdom (UK). Between 2003 and 2004, a questionnaire was sent to all UK Consultant Histopathologists, and 12% were recruited. In general post-mortems, the Coroner approved 60% of requests for organ retention, and Pathologists failed to make such a request in 5.9% of cases. In asbestos cases, the lungs were not fixed for sampling in 54.8% of cases, owing to the Coroners’ refusal in 46.4% and the pathologists’ failure to make a request in 8.4% of cases. In epithelioid mesothelioma, mesothelial and epithelial stains were considered to be of similar importance, and calretinin was the most popular individual stain. In sarcomatoid mesothelioma, mesothelial stains were chosen by 45.9% of pathologists, cytokeratin by 18.7% and epithelial stains by 18.5%. Calretinin was the most popular stain. Accurate mesothelioma diagnosis is impeded by the lack of tissue being made available by the Coroner and failure of some pathologists to make requests. Pathologists use appropriate immunohistochemical testing in epithelioid mesothelioma. In sarcomatoid mesothelioma, epithelioid stains were popular but have limited use. The Coroner should approve more requests for organ retention, and information should be disseminated to pathologists regarding best practice in mesothelioma.

CytopathologyVolume 21, Issue 4 p. 273-275 Diagnosis of alveolar rhabdomyosarcoma in effusion cytology: a diagnostic pitfall S. A. Thiryayi, S. A. Thiryayi Manchester Cytology CentreSearch for more papers by this authorD. N. Rana, D. N. Rana Manchester Cytology CentreSearch for more papers by this authorJ. Roulson, J. Roulson Department of HistopathologySearch for more papers by this authorP. Crosbie, P. Crosbie Department of Respiratory Medicine, Manchester Royal InfirmarySearch for more papers by this authorM. Woodhead, M. Woodhead Department of Respiratory Medicine, Manchester Royal InfirmarySearch for more papers by this authorB. P. Eyden, B. P. Eyden Department of Histopathology, Christie NHS Foundation Trust, Manchester, UKSearch for more papers by this authorP. S. Hasleton, P. S. Hasleton Department of HistopathologySearch for more papers by this author S. A. Thiryayi, S. A. Thiryayi Manchester Cytology CentreSearch for more papers by this authorD. N. Rana, D. N. Rana Manchester Cytology CentreSearch for more papers by this authorJ. Roulson, J. Roulson Department of HistopathologySearch for more papers by this authorP. Crosbie, P. Crosbie Department of Respiratory Medicine, Manchester Royal InfirmarySearch for more papers by this authorM. Woodhead, M. Woodhead Department of Respiratory Medicine, Manchester Royal InfirmarySearch for more papers by this authorB. P. Eyden, B. P. Eyden Department of Histopathology, Christie NHS Foundation Trust, Manchester, UKSearch for more papers by this authorP. S. Hasleton, P. S. Hasleton Department of HistopathologySearch for more papers by this author First published: 07 July 2010 https://doi.org/10.1111/j.1365-2303.2009.00700.xCitations: 11 Sakinah A. Thiryayi, Manchester Cytology Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UKTel.: +44 161 276 5111; Fax: +44 161 276 5149;E-mail: sakinah.a.t@hotmail.co.uk Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume21, Issue4August 2010Pages 273-275 RelatedInformation

Interstitial lung diseases are heterogeneous, encompassing a variety of aetiological factors. There is considerable variability in histological appearance over time in an individual patient and across the patient population. Light and electron microscopy reveal common themes, such as injury and apoptosis of the cellular elements of the lung parenchyma, basement membrane fragmentation, alveolar collapse and hyaline membrane formation. Organising inflammation and fibrogenesis are more variable features.The different histological patterns may represent a temporal sequence of changes within the evolution of disease, with focal or diffuse alveolar damage, as seen in adult respiratory distress syndrome or acute interstitial pneumonia. Alternatively, they represent a range of possible end-points, perhaps reflecting different aetiological factors. For instance, usual interstitial pneumonia is seen as a nonimmune-mediated process. This range of outcome is also informed by genetic or other variation in expression and function of pro-fibrotic mediators. The strong clinical association between interstitial lung disease and connective tissue diseases provides a clear argument for a role for auto-immunity in the pathogenesis of some interstitial pneumonia. Clear differentiation of immune interstitial pneumonia from other types has not been achieved, due to both inherent and sampling variability.There is considerable evidence for an activation of the adaptive immune system in interstitial lung disease, and also for the generation of auto-antibodies. However, the precise role of immune dysregulation in the pathogenesis of this disease remains unknown.

Aims: Immunohistochemistry is frequently employed to aid the distinction between mesothelioma and pulmonary adenocarcinoma metastatic to the pleura, but there is uncertainty as to which antibodies are most useful. We analysed published data in order to establish sensitivity and specificity of antibodies used to distinguish between these tumours with a view to defining the most appropriate immunohistochemical panel to use when faced with this diagnostic problem.Methods and results: A systematic analysis of the results of 88 published papers comparing immunohistochemical staining of a panel of antibodies in mesothelioma with epithelioid areas, and pulmonary adenocarcinoma metastatic to the pleura. Results for a total of 15 antibodies were analysed and expressed in terms of sensitivity and specificity. The most sensitive antibodies for identifying pulmonary adenocarcinoma were MOC-31 and BG8 (both 93%), whilst the most specific were monoclonal CEA (97%) and TTF-1 (100%). The most sensitive antibodies to identify epithelioid mesothelioma were CK5/6 (83%) and HBME-1 (85%). The most specific antibodies were CK5/6 (85%) and WT1 (96%).Conclusions: No single antibody is able to differentiate reliably between these two tumours. The use of a small panel of antibodies with a high combined sensitivity and specificity is recommended.

The autopsy is in decline, despite the fact that accurate mortality statistics remain essential for public health and health service planning. The falling autopsy rate combined with the Coroners Review and Human Tissue Act have contributed to this decline, and to a falling use of autopsy histology, with potential impact on clinical audit and mortality statistics. At a time when the need for reform and improvement in the death certification process is so prominent, we felt it important to assess the value of the autopsy and autopsy histology. We carried out a meta‐analysis of discrepancies between clinical and autopsy diagnoses and the contribution of autopsy histology. There has been little improvement in the overall rate of discrepancies between the 1960s and the present. At least a third of death certificates are likely to be incorrect and 50% of autopsies produce findings unsuspected before death. In addition, the cases which give rise to discrepancies cannot be identified prior to autopsy. Over 20% of clinically unexpected autopsy findings, including 5% of major findings, can be correctly diagnosed only by histological examination. Although the autopsy and particularly autopsy histology are being undermined, they are still the most accurate method of determining the cause of death and auditing accuracy of clinical diagnosis, diagnostic tests and death certification.

Aims: Recent evidence has implicated the macrophage as an effector cell in the inflammatory processes in transplant rejection, as well as cardiac disease, including coronary atherosclerosis. Although the latter is a vascular disease, the entire myocardium is affected. We have previously demonstrated the presence and distribution of macrophages in the 'normal' human heart. In this paper the distribution of myocardial macrophages, in the various chambers of the failing human heart, from cases of coronary atheroma and cardiomyopathy undergoing heart transplantation is documented.Methods and results: Tissue blocks were removed at specific sites taken from six cases with ischaemic heart disease (IHD) (four males, two females, age range 54-62 years), and four cases with idiopathic dilated cardiomyopathy (IDCM) (three males, one female, age range 18-49 years). These were compared with hearts from five cases of sudden death, unrelated to heart disease. Sections were stained with a CD68 pan macrophage marker. Positive cells were enumerated in 20 random fields. Results were analysed using a generalized linear modelling method using a Poisson distribution. Macrophages were identified within the interstitium and often close to blood vessels in all hearts. Macrophages from IHD hearts demonstrated the most intense staining and were often larger and more elongated than those found in 'normal' control hearts. Macrophages were also often degranulated and staining was diffuse in the interstitium. Overall, there were significantly more macrophages in most areas from IHD hearts than from IDCM hearts or control hearts (P < 0.001).Conclusions: Significantly more macrophages were found in all four chambers in diseased hearts compared with controls. Macrophage numbers were higher in the atria than in ventricles in the diseased myocardium. This study suggests selective recruitment of macrophages into the atria in the disease states studied.

BACKGROUND:Angiogenesis has been implicated in the pathogenesis of idiopathic interstitial pneumonia (IIP). The aim of this study was to examine the relationship between plasma concentrations of the angiogenic cytokines interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) and clinical parameters of disease progression over a 6 month period to identify potential aetiological mediators and prognostic markers of disease activity in patients with IIP. METHODS:Forty nine patients with IIP (40 men) were recruited to the study. Plasma cytokine measurements, pulmonary function tests, and high resolution computed tomography (HRCT) scans were performed on recruitment and after 6 months. Plasma cytokine measurements were also performed in 15 healthy volunteers for control purposes. RESULTS:Patients with IIP had significantly higher median (IQR) baseline concentrations of IL-8 and ET-1 than controls (155 (77-303) pg/ml v 31 (0-100) pg/ml, p<0.001) and (1.21 (0.91-1.88) pg/ml v 0.84 (0.67-1.13) pg/ml, p<0.01), respectively. Baseline concentrations of IL-8, ET-1, and VEGF were significantly related to the baseline HRCT fibrosis score (r = 0.42, p<0.005; r = 0.39, p<0.01; and r = 0.42, p<0.005, respectively). Patients with IIP who developed progressive disease had significantly higher baseline levels of IL-8 (345 (270-497) pg/ml v 121 (73-266) pg/ml, p = 0.001) and VEGF (1048 (666-2149) pg/ml v 658 (438-837) pg/ml, p = 0.019). Over 6 months the change in VEGF was significantly related to the change in HRCT fibrosis score (r = 0.565, p = 0.035) and negatively related to the change in forced vital capacity (r = -0.353, p = 0.035).

BACKGROUND:There have been few inter-observer studies of diffuse parenchymal lung disease (DPLD), but the recent ATS/ERS consensus classification provides a basis for such a study.METHODS:A method for categorising numerically the percentage likelihood of these differential diagnoses was developed, and the diagnostic confidence of pathologists using this classification and the reproducibility of their diagnoses were assessed.RESULTS:The overall kappa coefficient of agreement for the first choice diagnosis was 0.38 (n = 133 biopsies), increasing to 0.43 for patients (n = 83) with multiple biopsies. Weighted kappa coefficients of agreement, quantifying the level of probability of individual diagnoses, were moderate to good (mean 0.58, range 0.40-0.75). However, in 18% of biopsy specimens the diagnosis was given with low confidence. Over 50% of inter-observer variation related to the diagnosis of non-specific interstitial pneumonia and, in particular, its distinction from usual interstitial pneumonia.CONCLUSION:These results show that the ATS/ERS classification can be applied reproducibly by pathologists who evaluate DPLD routinely, and support the practice of taking multiple biopsy specimens.

Heath, D., Smith, P., and Hasleton, P. S. (1973). Thorax, 28, 551-558. Effects of chlorphentermine on the rat lung. Chlorphentermine hydrochloride ('Lucofen') is a sympathomimetic agent which is used in the treatment of obesity at a dosage of 25 mg thrice daily. When this drug, which is available on the British market, was administered intraperitoneally to rats in a dosage of 50 mg per kg body weight for 50 days, they all developed striking pathological changes in the lungs. Numerous large cells with foamy cytoplasm appeared in the alveolar spaces. Groups of them clumped together and disintegrated to pack the alveoli with granular eosinophilic material. The identification of these cells proved to be difficult even by electron microscopy, and this ultrastructural study is described separately in the following paper. During our acute experiments the rats did not develop right ventricular hypertrophy or hypertensive pulmonary vascular disease.

With their postal questionnaire, Dr Williams and colleagues found that just 4% of consultant histopathologists were actively involved in consenting for autopsy and only 20% expressed a willingness to be involved (November 2002, JRSM1). Most histopathologists (89%) felt that the clinician involved in the patient's care should be responsible for obtaining consent. Clinicians have the advantage of knowing the clinical history and indication for post mortem and may have developed a rapport with the relatives. However, clinicians often have a limited understanding of the process of post mortems and the issues surrounding the retention and disposal of organs and tissues. The pathologist performing the post mortem cannot be sure that consent obtained by a clinician is truly informed. We are conducting research into sudden unexplained death in young adults, aged 16 to 39. Our study involves obtaining informed consent from bereaved families to retain tissues and blood from post mortem for research purposes. To provide a recently bereaved relative with the information required for fully informed consent to a post mortem and the retention of organs or tissues is difficult and time-consuming, taking up to 3 hours. This is logistically impossible for both pathologist and clinicians. The public outcry after the Alder Hey and Bristol enquiries has placed informed consent for autopsy and retention of organs and tissue as a major priority. We feel that each trust should have a dedicated trained bereavement adviser, who would be responsible for obtaining informed consent for autopsy and retention of organs/tissues for diagnostic, research or donation purposes. The bereavement adviser would receive training in bereavement counselling, obtaining informed consent, the process of autopsy and issues surrounding retention and disposal of organs/tissues. They would be an important point of contact for bereaved relatives and would liaise closely with clinicians, pathologists, the coroner and primary care services (e.g. general practitioners and counsellors). A bereavement adviser seems the sensible way to provide a comprehensive service to bereaved relatives. This can only be achieved if the Department of Health supports trusts with extra funding which is ring-fenced for such a bereavement service.

Studies of human tissue have suggested an association between productive Epstein Barr virus and idiopathic pulmonary fibrosis (IPF). However, a pathogenic role for the virus has not been established. This study was undertaken to develop an animal model, which would explore the association between viral infection and pulmonary fibrosis. BALB/c mice (n=30), resistant to bleomycin, were primed with murine gammaherpesvirus 68 and then given intraperitoneal bleomycin. The mice were sacrificed at 28 days after bleomycin and their lungs assessed histologically and biochemically. Lung pathology was scored 0-3 for fibrotic and inflammatory change. BALB/c mice given virus and bleomycin showed more lung fibrosis (median score 2.2) compared to those given bleomycin alone (median 0), virus alone (median 0.2) or phosphate-buffered saline (PBS) control (median 0). Similarly mice given both virus and bleomycin showed more lung inflammation (median score 1.9) compared to those given bleomycin (median 0.5), virus (median 0.8), or PBS control (median 0.2). There was a significant difference in collagen content between the bleomycin and virus group (mean 1.86 mg) compared to the belomycin alone group (mean 1.52 mg). These results suggest that virus alone does not result in pulmonary fibrosis but that replicating virus in the presence of an exogenous injury may promote the development of pulmonary fibrosis.

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease. In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg x kg(-1) x day(-1)) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline. In animals given bleomycin and drug vehicle, total lung collagen was increased by 182+/-11% (mean+/-SEM) compared with saline controls at 14 days (p<0.001). The increase in lung-collagen accumulation was reduced by 75+/-12% (p<0.01) in animals given SDZ RAD and was accompanied by a concomitant 56+/-6% (p<0.001) reduction in lung weight. SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.

An association between idiopathic pulmonary fibrosis (IPF) and productive Epstein-Barr virus (EBV) infection has been found previously. Productive EBV replication can be associated with a rearrangement in EBV genomes termed WZhet. We hypothesized that WZhet genomes might be present in patients with IPF. Thirty-nine patients with IPF, 26 lung transplant recipients, and 24 normal subjects were studied. When EBV DNA-positive lung tissue biopsies from IPF patients were analyzed, 11 of 18 (61%) were positive for WZhet. Buffy coat DNA analysis showed that 75-85% were EBV DNA-positive in both IPF and control groups. Buffy coat analysis for WZhet was positive in 16 of 27 (59%) IPF patients, compared with none of 32 lung transplant recipients and 1 of 24 (4%) normal blood donors (p < or = 0.001). There was thus a good correlation between the presence of WZhet in lung tissue and peripheral blood. However, there was no significant association between the presence of WZhet and immunosuppressive therapy. These data further confirm the association between active EBV infection and IPF and provide a potential marker in the peripheral blood for the tracking of EBV in this disease.