Pathology

Our medical research library holds 39 studies published in Pathology (1969–2024). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 26 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 3 studies PubMed has no abstract for, we give the abstract printed in the article or, where there is none, a summary we wrote from it, each labeled as such.

About the journal

• Publisher: Lippincott Williams & Wilkins
• Published: 1969 to the present, England
• Language: English
• ISSN: 0031-3025 (print), 1465-3931 (electronic)
• Its record in the NLM Catalog

2020s

• The significance of BAP1 and MTAP/CDKN2A expression in well-differentiated papillary mesothelial tumour: a series of 21 cases and a review of the literature. A. Hassan, S. Prabhakaran, E. Pulford, et al. 2024;56(5):662-670. Review PubMed · Publisher

  Abstract

  The nomenclature and diagnostic criteria of well-differentiated papillary mesothelial tumour (WDPMT) have been changed in the 2021 World Health Organization (WHO) classification of thoracic tumours, and a new entity, mesothelioma in situ (MIS), introduced. Histologically these two entities may be similar. However, MIS is regarded as a precursor to invasive mesothelioma and requires demonstration of loss of BAP1 and/or MTAP/CDKN2A for diagnosis, whereas performance of these ancillary tests is desirable but not essential for a diagnosis of WDPMT, in which the significance of BAP1 and/or MTAP/CDKN2A loss is not well understood or well defined. Against this backdrop, we undertook an investigation of 21 cases of WDPMT, identified from our case files and diagnosed according to 2021 WHO criteria, to explore the relationship between histology and BAP1 and MTAP/CDKN2A expression with clinical features including asbestos exposure, focality of tumours and clinical outcome. There were 18 women and three men, with ages ranging from 23-77 years (median 62 years), in which six had a history of asbestos exposure, two had no exposure, and in 13 exposure history was unavailable. Of 20 peritoneal tumours and one pleural tumour, 13 were detected incidentally at the time of surgery for unrelated conditions and eight peritoneal tumours were multifocal at the time of diagnosis. BAP1 immunohistochemistry (IHC) was performed in all 21 tumours, with nine tumours showing BAP1 expression loss. MTAP/CDKN2A testing was performed in 14 tumours, comprising MTAP IHC in 12 and CDKN2A fluorescence in situ hybridisation (FISH) in two, with three tumours showing MTAP/CDKN2A expression loss. Two tumours with MTAP/CDKN2A loss also showed BAP1 expression loss. Four patients progressed to invasive mesothelioma, including one male with a pleural tumour and asbestos exposure, and three females with multifocal peritoneal tumours, two with asbestos exposure and one without exposure. BAP1 expression loss was seen in all tumours from the four patients who progressed to invasive mesothelioma, whilst two of these tumours showed retained MTAP IHC and two were not tested. There was one patient with a tumour with MTAP loss and retained BAP1 who died from unrelated causes 5 months after diagnosis. Eight patients received WDPMT-specific treatment in addition to the initial excision. Survival for all patients ranged from 4-218 months, with one patient dying of mesothelioma at 49 months. Based on our results in this series of 21 patients with WDPMT diagnosed according to 2021 WHO criteria, we propose that WDPMT with BAP1 expression loss may best be regarded as papillary MIS and that a history of asbestos exposure and the presence of multifocal tumours in patients diagnosed with WDPMT should prompt ancillary testing with BAP1 IHC. Further we propose that BAP1 IHC should be essential in the diagnosis of WDPMT, with the diagnosis restricted to those tumours which show retained BAP1 expression. However more studies in larger cohorts of patients are needed to explore the relationship between BAP1 expression and MTAP loss in WDPMT, which will help to define this entity and separate it more clearly from MIS and invasive mesothelioma.

  Copyright © 2024. Published by Elsevier B.V.

• Cytological diagnosis of mesothelioma in situ versus invasive mesothelioma. A. Churg, F. Galateau-Salle, L. Tan, et al. 2022;54(1):133-136. Case report · Letter PubMed · Publisher

  Summary

  In this letter, the authors asked whether pleural effusion cytology can distinguish mesothelioma in situ from invasive mesothelioma when there is no radiological or direct visual evidence of tumour. Responding to an earlier report by Pulford et al., they described a patient they had previously reported as having mesothelioma in situ. The patient presented in 2014 at age 70 with a right pleural effusion of unknown aetiology. It was drained repeatedly over 4 years and recurred rapidly each time. Until 2018, imaging showed only an effusion, with no pleural thickening. All pleural fluid cytology specimens showed multiple balls of slightly atypical mesothelial cells. A 2015 cell block, stained retrospectively, showed loss of BAP1. Pleural biopsies in 2016 and 2017, from pleura the operator reported as visually normal, showed mesothelioma in situ with BAP1 loss. In 2018, imaging first showed pleural thickening, the effusion had become haemorrhagic, and a biopsy revealed invasive mesothelioma. The authors considered it extremely unlikely that invasive disease had been missed over 4 years. They noted an arguable subtle increase in atypia over time, but judged all samples malignant and meeting guideline criteria for mesothelioma. They concluded that when there is only an effusion and no tumour on imaging or direct inspection, a diagnosis such as 'at least mesothelioma in situ, cannot exclude invasive diffuse mesothelioma' would be appropriate, because mesothelioma in situ is in theory potentially treatable and curable.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Histopathological typing in diffuse malignant epithelioid mesothelioma: implication for prognosis and molecular basis. F. Forest, D. Laville, C. Habougit, et al. 2021;53(6):728-734. PubMed · Publisher

  Abstract

  The prognostic impact of tumour grading, cytological and architectural patterns and stromal features in diffuse pleural malignant epithelioid mesothelioma (MEM) has been partly studied but not correlated to molecular features. We performed a retrospective study on 92 MEM in our department in order to assess the prognostic role of architectural and stromal patterns, especially tumour to stroma ratio. Secondly, based on The Cancer Genome Atlas (TCGA) database, we analysed the differentially expressed genes in prognostic groups of interest. Our results showed that tumour grading, tumour to stroma ratio and predominant pattern were related to overall survival, p≤0.001, p=0.01 and p=0.001, respectively. In univariate analysis, for high grade tumours hazard ratio (HR) was 4.75 (2.47-9.16), for stroma poor tumours HR=0.016, for predominant tubular or tubulopapillary pattern HR=0.044. In multivariate analysis, high grade tumours were related to overall survival [HR=3.09 (1.50-6.35), p=0.002] and predominant tubular or tubulopapillary pattern [HR=0.56 (0.32-0.99), p=0.045]. In TCGA analysis, after grading of diagnostic slides, we showed that KRTDAP and CXRCR1 expression was higher in low grade tumours, unlike PDZD7 and GPR176 expression which was higher in high grade tumours. FAM81B had a higher expression in stroma poor tumours. We did not find any differentially expressed genes in the architectural patterns group. Our work suggests that tumour grading is an important parameter in MEM with an underlying genomic basis. The role of tumour to stroma ratio needs to be investigated and might also have a genomic basis.

  Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

• Programmed cell death 1 ligand 1 (PD-L1) expression is associated with poor prognosis of malignant pleural mesothelioma patients with good performance status. E. Rrapaj, L. Giacometti, P. Spina, et al. 2021;53(4):462-469. PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM) is often associated with a poor prognosis and options for the treatment of this disease are few. To date, the important role of the immune microenvironment in modifying the disease natural history is well established. The programmed cell death pathway (PD-1/PD-L1) limits the T lymphocyte activation in peripheral tissues when an inflammatory response occurs, and controls the tumour immune escape. PD-L1 is broadly expressed in several malignant tumours and associated with poor clinical outcomes. Thus, the aim of our study is to investigate the potential role of PD-L1 expression in MPM prognosis. Biopsy samples from 198 patients diagnosed with MPM were examined by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) to evaluate PD-L1 protein and gene expression. For PD-L1 protein expression we consider at least 5% membranous staining as positive. Gene expression levels were calculated with ΔΔCt method. Positive expression of PD-L1 by IHC was correlated with worse overall survival (OS; p=0.0225) in MPM patients. PD-L1 positive status was correlated with worse OS in the subgroup of patients with ECOG score <2 (p=0.0004, n=129) and these data were confirmed by multivariate analysis. No significant correlation was found between PD-L1 gene expression and OS. Our results show that PD-L1 evaluated by IHC assay may be a prognostic biomarker for MPM patients with good performance status.

  Copyright © 2020 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

• The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis. S. Klebe, Y. Nakatani, K. Dobra, et al. 2021;53(4):446-453. PubMed · Publisher

  Abstract

  Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.

  Copyright © 2021. Published by Elsevier B.V.

• ALK positive malignant peritoneal mesothelioma mimicking inflammatory myofibroblastic tumour: a diagnostic pitfall. A. Louw, C. Wallace, S.M. Chai, et al. 2020;52(6):719-722. Case report · Letter PubMed · Publisher

• Malignant mesothelioma in situ: diagnostic and clinical considerations. E. Pulford, D.W. Henderson, S. Klebe. 2020;52(6):635-642. PubMed · Publisher

  Abstract

  In situ stages of malignancy have been characterised in various neoplasms. Mesothelioma in situ (MIS) has been a controversial diagnosis, lacking clear diagnostic criteria and understanding as to whether it is truly a premalignant lesion in the progression of malignant mesothelioma (MM). Originally understood as a concept and defined as atypical mesothelial proliferation in the presence of invasion, it has now been suggested that loss of nuclear labelling for BRCA1-associated protein-1 (BAP1) in flat, non-invasive mesothelial lesions can define MIS. This study aimed to characterise BAP1 expression in a cohort of 19 patients diagnosed with MIS (either pure MIS, n=3, or MIS-predominant invasive MM, n=16) and to compare survival between MIS, MIS-predominant MM and MM (n=114) in order to gain insight into the characteristics of MIS. We defined pure MIS as any architectural pattern of surface mesothelial cells with loss of BAP1 in the absence of invasion, but in specimens with superficial stromal invasion we also accepted the original definition of cytologically and architecturally atypical mesothelial proliferation, in the absence of inflammatory features, with or without loss of BAP1. We observed that MIS associated with minimal invasion was associated with significantly improved survival compared to MM (8 months vs 22 months). This suggests that MIS is indeed a precursor to MM and that these cases represent earlier stage disease. Loss of BAP1 was present in 60% of mesotheliomas with invasion, so not all early cases can be detected by BAP1 loss, but our study provides evidence that BAP1 loss may be an early molecular alteration in MM pathogenesis in patients that have loss of BAP1. We confirm that BAP1 loss can be useful for diagnosis of pure MIS in surgical specimens, permitting earlier diagnosis. However, identification of a predominant MIS component with minimal invasion has prognostic and conceptual implications. Whilst no approved therapy is available for MIS, close follow up of patients with BAP1 mutation in mesothelial cells and/or diagnosis of MIS is required to monitor for disease progression and potentially investigate earlier treatment interventions.

  Copyright © 2020. Published by Elsevier B.V.

2010s

• Nuclear grading, BAP1, mesothelin and PD-L1 expression in malignant pleural mesothelioma: prognostic implications. F. Forest, A. Patoir, P. Dal Col, et al. 2018;50(6):635-641. PubMed · Publisher

  Abstract

  For malignant pleural mesothelioma (MPM), histopathological subtype is one of the most important prognostic factors. Several immunohistochemical stains whose expressions have possible therapeutic implications have been identified in MPM such as BAP1, mesothelin and PD-L1. The aim of our work was to evaluate the clinical significance and prognostic implications of BAP1, mesothelin and PD-L1 expression in 117 patients with a diagnosis of MPM who were diagnosed in our institution between 2002 and 2017. We also correlated this immunohistochemical profile to a recently described nuclear grading and to histopathological subtype. Mesothelin expression, BAP1 loss and PD-L1 expression were associated with histopathological subtype (p < 0.0001), BAP1 loss was more frequent in epithelioid subtype whereas PD-L1 expression was more frequent in non-epithelioid subtype. For epithelioid MPM, BAP1 expression was associated with overall survival (p = 0.034), with a longer survival when BAP1 expression is lost. Necrosis and nuclear grading are associated with overall survival (p = 0.0048 and <0.0001, respectively), with longer survival when necrosis was absent and for grade I. For non-epithelioid MPM, overall survival was not related to clinical, histopathological or immunohistochemical expression of BAP1, mesothelin or PD-L1. In multivariate analysis, grade I for nuclear grading was an independent prognostic factor associated with overall survival (p < 0.0001). In epithelioid and non-epithelioid MPM, we analysed overall survival in subgroups with combined mesothelin, BAP1 and PD-L1 expression. In epithelioid MPM, BAP1 retained/mesothelin negativity/PD-L1 > 1%, and BAP1 retained/mesothelin positivity/PD-L1 > 1% profiles, are associated with shorter overall survival. In non-epithelioid MPM, BAP1 loss/mesothelin negativity/PD-L1 > 1% is associated with shorter overall survival. Our work confirms that nuclear grading in epithelioid MPM is a strong and independent prognosis factor. Moreover, this study on several promising immunohistochemical stains whose expressions have possible therapeutic implications identifies subgroups with a poor prognosis.

  Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

• Pleural malignant mesothelioma versus pleuropulmonary synovial sarcoma: a clinicopathological study of 22 cases with molecular analysis and survival data. S. Klebe, S. Prabhakaran, A. Hocking, et al. 2018;50(6):629-634. PubMed · Publisher

  Abstract

  The aim of this study was to carry out a comparative analysis by transducin-like enhancer of split 1 (TLE1) immunohistochemistry and molecular analysis of SYT-SSX, for 16 pleural predominantly sarcomatoid mesotheliomas and six cases of pleuropulmonary synovial sarcoma (five pleural in distribution only, with one case of a predominantly subpleural upper lobe synovial sarcoma), all of which were solely or predominantly monophasic. Our comparison included survival and some clinical data. We consider that the following points emerged from this study.

  Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

• Metastatic primary peritoneal malignant mesothelioma mimicking primary diffuse gastric carcinoma: a rare encounter in gastric biopsy. Y. Yang, D. Gunawardane, D. Moffat, et al. 2017;49(3):317-319. Case report · Letter PubMed · Publisher

• Calretinin but not caveolin-1 correlates with tumour histology and survival in malignant mesothelioma. B. Thapa, M. Walkiewicz, C. Murone, et al. 2016;48(7):660-665. PubMed · Publisher

  Abstract

  Malignant mesothelioma (MM) continues to be a disease with poor prognosis and limited treatment options. Calretinin and caveolin-1 expression by tumour in MM have recently been described to be associated with tumour histology, differentiation and consequently survival. In a large, well annotated cohort, we studied both of these biomarkers and explored their association with clinicopathological parameters and survival. A retrospective search of patients with MM who underwent surgery at the Austin Hospital in Melbourne, Australia, was conducted. Clinical history and outcome data were retrieved from patient records. Tissue microarrays (TMAs) were constructed and stained for calretinin and caveolin-1. 'H scores' were derived, taking intensity and distribution of staining, and the cohort was dichotomised using median values for both markers. In the 329 patients evaluated, median age was 67 years. Males outnumbered females by 5:1. Epithelioid histology 202/319 (62.9%) was the most common, followed by biphasic 72/319 (21.8%) and sarcomatoid 45/319 (13.6%); histology could not be confirmed in 10 patients. Calretinin expression was detected in 246 of the 324 (76%) evaluable patients and high expression was associated with epithelioid histology (p < 0.0001). Caveolin-1 was expressed in 298 (94%) of 317 evaluable patients which was much higher compared to its expression in a cohort of lung adenocarcinomas (8/58, 13.7%). However, no association with histology was found (p = 0.409). When taken as a continuous variable, calretinin expression was found to be an independent predictor of survival, alongside histology, neutrophil-lymphocyte ratio, weight loss and stage. No prognostic value was demonstrable for caveolin-1 expression and calretinin/caveolin-1 ratio. There was no relationship between calretinin and caveolin-1 expression. In MM, increased calretinin expression is associated with epithelioid histology and better survival. Caveolin-1 is a sensitive MM marker and is expressed in a high proportion of cases but lacks association with histology and survival.

  Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

• Loss of expression of BAP1 is very rare in non-small cell lung carcinoma. J. Andrici, T.R. Parkhill, J. Jung, et al. 2016;48(4):336-40. PubMed · Publisher

  Abstract

  Germline mutations of the BAP1 gene have been implicated in a cancer predisposition syndrome which includes mesothelioma, uveal melanoma, cutaneous melanocytic lesions, renal cell carcinoma, and possibly other malignancies. Double hit inactivation of BAP1 with subsequent loss of expression of the BAP1 protein also occurs in approximately 50% of mesotheliomas. The link between BAP1 mutation and lung cancer is yet to be fully explored. We sought to assess BAP1 expression in a large cohort of lung cancers undergoing surgery with curative intent. We searched the Anatomical Pathology database of our institution for lung cancer patients undergoing surgery with curative intent between 2000 and 2010. Immunohistochemistry for BAP1 was then performed in tissue microarray format. Our cohort included 257 lung cancer patients, of which 155 (60%) were adenocarcinomas and 72 (28%) were squamous cell carcinomas, with no other subtype comprising more than 3%. BAP1 loss of expression was found in only one lung cancer. We conclude that BAP1 mutation occurs very infrequently (0.4%) in non-small cell lung cancer. Given that the pathological differential diagnosis between lung carcinoma and mesothelioma may sometimes be difficult, this finding increases the specificity of loss of expression for BAP1 for the diagnosis of mesothelioma.

  Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

• Vasculogenic mimicry in malignant mesothelioma: an experimental and immunohistochemical analysis. E. Pulford, A. Hocking, K. Griggs, et al. 2016;48(7):650-659. PubMed · Publisher

  Abstract

  Vasculogenic mimicry, the process in which cancer cells form angiomatoid structures independent of or in addition to host angiogenesis has been recorded in several otherwise non-endothelial malignant neoplasms. This study describes evidence of routine vascular mimicry by human mesothelioma cell lines in vitro, when the cell lines are cultured alone or co-cultured with human umbilical vascular endothelial cells, with the formation of angiomatoid tubular networks. Vasculogenic mimicry is also supported by immunohistochemical demonstration of human-specific anti-mitochondria antibody labelling of tumour-associated vasculature of human mesothelioma cells xenotransplanted into nude mice, and by evidence of vascular mimicry in some biopsy samples of human malignant mesotheliomas. These studies show mosaic interlacing of cells that co-label or label individually for immunohistochemical markers of endothelial and mesothelial differentiation. If vascular mimicry in mesothelioma can be characterised more fully, this may facilitate identification of more specific and targeted therapeutic approaches such as anti-angiogenesis in combination with chemotherapy and immunotherapy or other therapeutic approaches.

  Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

• Loss of expression of BAP1 predicts longer survival in mesothelioma. M. Farzin, C.W. Toon, A. Clarkson, et al. 2015;47(4):302-7. PubMed · Publisher

  Abstract

  BRCA1-associated protein 1 (BAP1) is a tumour suppressor gene frequently inactivated in mesothelioma, rarely also in association with germline mutation. BAP1 mutations have been associated with improved prognosis and distinct clinicopathological features. We sought to determine the clinicopathological significance of BAP1 immunohistochemistry (IHC) in mesothelioma.We performed IHC on a tissue microarray (TMA) cohort comprising all available thoracic mesotheliomas encountered during the period 1991-2014 at our institution (n = 229). All cases were independently reviewed to confirm the diagnosis and subclassify as epithelioid, sarcomatoid or biphasic. The median age at diagnosis was 72 years; 188 (82.1%) were male; 120 (52.4%) were epithelioid (median survival 13.0 months), 67 (29.3%) sarcomatoid (median survival 5.6 months) and 42 (18.3%) biphasic (median survival 10.6 months). Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in non-neoplastic cells) occurred in 106 (46.3%) mesotheliomas. There was complete interobserver concordance for BAP1 IHC status. BAP1 loss was strongly associated with younger age at onset (p < 0.01) and epithelioid differentiation (p < 0.01). BAP1 loss predicted an improved median survival of 16.11 months (95% CI 12.16-20.06) versus 6.34 months (95% CI 5.34-7.34), p < 0.01. In a multivariate model including age, gender and histological type, BAP1 loss, younger age and epithelioid differentiation remained protective (all p < 0.01).If our results are confirmed by others, BAP1 IHC may have a role to predict prolonged survival or triage formal genetic testing for germline BAP1 mutation in patients presenting with mesothelioma.

• Diffuse mesothelioma of the peritoneum: correlation between histological and clinical parameters and survival in 73 patients. S. Liu, P. Staats, M. Lee, et al. 2014;46(7):604-9. PubMed · Publisher

  Abstract

  There are few studies addressing survival of diffuse peritoneal mesotheliomas (DPM).In this study, survival data were obtained retrospectively from 73 patients treated with intended cytoreductive surgery for DPM, with a mean follow-up of 42 months. Mesotheliomas were classified as well differentiated papillary (WDPM, n = 2), multicystic (MCM, n = 4), and epithelioid mesotheliomas were subclassified as tubulopapillary (TPM, n = 27), solid/deciduoid (S/DM, n = 34), and or biphasic mesothelioma (BPM, n = 6). Invasion was characterised as absent (grade 0), into stroma (grade 1), into fat (grade 2), and into adjacent structures (grade 3). Peritoneal cancer index (PCI) and completeness of cytoreduction (CCR) were assessed surgically.There were no deaths in the WDPM, MCM, and epithelioid DPM with ≤ grade 1 invasion. There was a stepwise decrease in overall survival from invasive TPM, S/DM, and BPM (p < 0.0001). By univariate analysis, advanced age (p = 0.01), incomplete CCR (p < 0.001), PCI (p = 0.004), mitotic count (p < 0.001), nuclear grade (p < 0.0001), stromal inflammation (p = 0.013), depth of invasion (p < 0.0001), necrosis (p = 0.002), and sarcomatoid growth (p < 0.0001) were associated with decreased overall survival. By multivariate analysis, only sarcomatoid growth (p = 0.0006), depth of invasion (p = 0.02), elevated CCR (CCR 2-3) (p = 0.02), and presence of inflammatory stroma (p = 0.04) were significant variables associated with decreased overall survival.DPM form a spectrum of indolent to highly aggressive tumours. Solid epithelioid/deciduoid tumours have a prognosis intermediate between biphasic mesotheliomas and invasive TPM. The presence and degree of invasion, sarcomatoid features, and inflammatory stroma are poor prognostic indicators.

• A diagnosis of malignant pleural mesothelioma can be made by effusion cytology: results of a 20 year audit. A. Segal, G.F. Sterrett, F.A. Frost, et al. 2013;45(1):44-8. PubMed · Publisher

  Abstract

  Aims: Cytological diagnosis of malignant pleural mesothelioma (MPM) is controversial, but has been used in our institution for over 30 years. To assess the role of effusion cytology in mesothelioma diagnosis we conducted an audit of pleural fluid cytology results over a 20 year period (1988-2007).

  Methods: Pleural samples were received from 6285 patients; data linkage with Western Australian Cancer and Mesothelioma Registries demonstrated that 815 of these patients had a diagnosis of MPM. Cytological examination of a pleural effusion specimen had been performed in 517 (63%) of these 815 patients.

  Results: Definitive cytological diagnosis of MPM was made in 377/517 cases, resulting in an 'absolute' sensitivity of 73%. An additional 66 patients were diagnosed as atypical/suspicious, resulting in a 'complete' sensitivity of 86%. If only biopsy/necropsy proven cases are considered, the absolute sensitivity is 68% and the complete sensitivity is 82%. There were no false positive diagnoses of malignancy; two patients with metastatic adenocarcinoma were initially diagnosed as MPM, prior to the availability of specific mesothelial markers, resulting in a positive predictive value of 99%.

  Conclusions: Effusion cytology is an inexpensive, minimally invasive procedure which should be included in the diagnostic work-up of cases of suspected MPM.

• Diffuse mesothelioma of the peritoneum: a pathological study of 64 tumours treated with cytoreductive therapy. M. Lee, H.R. Alexander, A. Burke. 2013;45(5):464-73. PubMed · Publisher

  Abstract

  Background: Diffuse peritoneal mesothelioma (DPM) forms a spectrum of indolent surface tumours to malignant invasive cancers. There are few pathological series that span well and poorly differentiated lesions that show diffuse peritoneal spread.

  Methods: Sixty-four DPM treated by initial cytoreductive therapy were retrospectively reviewed. Tumours were classified by surface and invasive growth pattern and correlated with risk factors, peritoneal cancer index (PCI) and completeness of cytoreduction (CCR). Degree of invasion was quantitated as absent (0), into stroma (I), into fat (II), and into adjacent structures (III) and was correlated with cytological features. Selected immunohistochemical stains were performed.

  Results: There were three well differentiated papillary mesotheliomas (WDPM; type A), four multicystic mesothelioma (type B), 22 tubulopapillary epithelioid mesotheliomas (type C), and 35 poorly differentiated epithelioid mesotheliomas with solid or sarcomatoid growth (Type D). Seven type D tumours had prominent sarcomatoid areas, 12 deciduoid areas, and four lymphohistiocytoid features. Risk factors were present in all groups except type A, and included prior abdominal surgery (n=24), asbestos exposure (n=5) and radiation (n=2). Extra-pleural mesothelioma was present in all groups except type B (total n=7, 11%). Two type A and eight type C tumours lacked invasion; only type D showed level III invasion. The invasive portion of one type A tumour and two type B tumours showed adenomatoid features. PCI and CCR were greater in type D compared to the other groups (p=0.02), as well as mitotic rate, degree of necrosis, and nuclear pleomorphism (p<0.001). Degree of invasion was strongly correlated with CCR (p=0.007), necrosis (p<0.0001), nuclear grade (p<0.0001), and mitotic rate (p=0.001), but not PCI (p=0.1). Immunohistochemical results were similar across groups, with frequent positivity for CA125 (94%), EGFR (94%) and calretinin (93%), followed by p16 (85%), cytokeratin 5,6 (76%), D2-40 (71%) and WT-1 (47%). PAX-8 was negative in all tumours, except one type A tumour that showed diffuse nuclear positivity.

  Conclusions: Diffuse peritoneal mesotheliomas can be classified into four groups that reflect invasive potential, degree of adverse histological features, and amenability for CCR. Non-invasive tumours include both type A and type C tumours.

• Facts and fiction: premalignant lesions of lung tissues. S. Klebe, D.W. Henderson. 2013;45(3):305-15. Review PubMed · Publisher

  Abstract

  Lung cancer is now the leading cause of death from cancer in Australia. Most patients are diagnosed with late-stage disease. Although diagnosis at pre-invasive stages could theoretically improve outcomes, mooted precursor lesions are often asymptomatic and often undetectable by non-invasive investigations. Nonetheless, they merit study to identify early and essential molecular steps involved in lung carcinoma pathogenesis, with the aim of developing therapies targeted against one or more such steps. Some lung cancers appear to develop via a series of progressive morphological changes with correlating molecular alterations, but others seem to arise in histologically normal epithelium, and these differences may reflect anatomically and functionally distinct epithelial compartments of the respiratory tract. Pre-invasive precursor lesions recognised by the World Health Organization (WHO) include squamous metaplasia with dysplasia and carcinoma in situ, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Other lesions that likely represent pre-invasive lesions, but which are not currently WHO-listed, include human papillomavirus (HPV)-related respiratory papillomatosis and mesothelioma in situ. No single cancer stem cell marker has been identified. Field cancerisation plays an important role in lung cancer development, and includes the spread of pre-invasive clones along the respiratory epithelium or the occurrence of multiple separate foci of pre-invasive abnormalities such as squamous dysplasia and carcinoma in situ.In addition to well-characterised step-wise progression in squamous cell carcinomas and some adenocarcinomas, alternative pathways exist, and are currently being investigated. In addition, molecular techniques, including miRNA screening on blood samples or cytology samples--such as sputum samples--may become clinically relevant and more accurate in predicting lung cancer progression.

• Obtaining expert opinions in diagnostically difficult cases. C. Hemmings. 2013;45(1):80. Letter · Comment PubMed · Publisher

• The usefulness of expert opinion in medicolegal referrals of malignant mesothelioma. D.L. Dixon, K.M. Griggs, M. Ely, et al. 2013;45(5):523-5. Letter PubMed · Publisher

• Tumours associated with BAP1 mutations. R. Murali, T. Wiesner, R.A. Scolyer. 2013;45(2):116-26. Review PubMed · Publisher

  Abstract

  BAP1 (BRCA1-Associated Protein 1) was initially identified as a protein that binds to BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway. Germline mutations of BAP1 confer increased susceptibility for the development of several tumours, including uveal melanoma, epithelioid atypical Spitz tumours, cutaneous melanoma, and mesothelioma. However, the complete tumour spectrum associated with germline BAP1 mutations is not yet known. Somatic BAP1 mutations are seen in cutaneous melanocytic tumours (epithelioid atypical Spitz tumours and melanoma), uveal melanoma, mesothelioma, clear cell renal cell carcinoma, and other tumours. Here, we review the current state of knowledge about the functional roles of BAP1, and summarise data on tumours associated with BAP1 mutations. Awareness of these tumours will help pathologists and clinicians to identify patients with a high likelihood of harbouring germline or somatic BAP1 mutations. We recommend that pathologists consider testing for BAP1 mutations in epithelioid atypical Spitz tumours and uveal melanomas, or when other BAP1-associated tumours occur in individual patients. Tumour tissues may be screened for BAP1 mutations/loss/inactivation by immunohistochemistry (IHC) (demonstrated by loss of nuclear staining in tumour cells). Confirmatory sequencing may be considered in tumours that exhibit BAP1 loss by IHC and in those with equivocal IHC results. If a BAP1 mutation is confirmed in a tumour, the patient's treating physician should be informed of the possibility of a BAP1 germline mutation, so they can consider whether genetic counselling and further testing of the patient and investigation of their family is appropriate. Recognition and evaluation of larger numbers of BAP1-associated tumours will also be necessary to facilitate identification of additional distinct clinico-pathological characteristics or other genotype-phenotype correlations that may have prognostic and management implications.

• Is there a need for expert opinion for biopsy diagnosis of difficult cases of malignant mesothelioma?. S. Klebe, K.M. Griggs, M. Ely, et al. 2012;44(6):562-3. Letter PubMed · Publisher

  Summary

  This letter reported a study of how often an 'expert' pathology opinion differed from the original biopsy diagnosis in difficult cases of possible malignant mesothelioma. The authors noted that this tumour is caused by inhalation of asbestos fibres and that the diagnosis often carries compensation implications. They retrieved 275 referral cases from the files of the Department of Anatomical Pathology at Flinders Medical Centre, Adelaide, for 2005–2010. The referring laboratories' original diagnosis was available for 262 of them. Of 136 cases referred as mesothelioma, the expert agreed in 117, gave a benign diagnosis in nine and diagnosed other tumours in two. Of 39 cases referred as benign mesothelial proliferation, 26 were confirmed and 11 (28%) were diagnosed as mesothelioma. Of 73 cases with no preferred diagnosis, 51 (70%) were reported as definite mesothelioma. Overall agreement was fair (kappa 0.3155), with 57% of cases in the same category. In 9.5% of cases there was a significant change, such as from benign to malignant or the reverse, or from another tumour type to mesothelioma. Agreement did not depend on the referring laboratory's state. Sarcomatoid mesothelioma was more problematic to diagnose than other subtypes (p = 0.016). The authors concluded that expert opinion can differ significantly from the referring diagnosis. Assuming the expert's opinion is more likely to be validated by follow-up, they concluded that the potential benefits of such a referral service justify its additional cost.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Molecular biomarkers in malignant mesothelioma: state of the art. S.C. Kao, G. Reid, N. van Zandwijk, et al. 2011;43(3):201-12. Review PubMed · Publisher

  Abstract

  Malignant mesothelioma (MM) is an aggressive tumour affecting the mesothelial surfaces of the pleural and peritoneal cavities and, rarely, the pericardium and the tunica vaginalis testis. Despite a ban of asbestos in many industrialised nations, the present high incidence of MM is expected to continue, due to the long latency period between first asbestos exposure and occurrence of disease, making it an important health issue for the future. The diagnosis of MM can be difficult, both from a clinical and pathological perspective. It is not unusual for patients to undergo several medical investigations without definitive diagnosis early in their course of illness. Understandably, there is intense interest in the discovery of markers that can be assessed in pleural effusions, histological specimens, and serum to assist with the difficult early diagnosis of MM. Considering the primary aetiological role of asbestos, there is theoretically an easily identifiable target population for screening with a biomarker with adequate sensitivity and specificity or with a combination of biomarkers. In this review we focus on biomarkers that have been examined in the setting of either early diagnosis of MM in symptomatic patients or screening of asbestos-exposed individuals.

• Validation of a minimal panel of antibodies for the diagnosis of malignant pleural mesothelioma. S.C. Kao, K. Griggs, K. Lee, et al. 2011;43(4):313-7. PubMed · Publisher

  Abstract

  Aims: We previously established the use of a minimal panel of antibodies as sufficient to diagnose most epithelial malignant mesothelioma (MPM). We aimed to validate this approach and investigate the utility of a D2-40 antibody.

  Methods: A series of 80 MPM patients selected for surgery and 21 consecutive patients with pleural metastatic carcinoma were included. A minimal panel of antibodies, consisting of calretinin, BG8 and CD15, and D2-40 was investigated.

  Results: There were 61 epithelial and 19 biphasic MPM as well as 12 metastatic lung, six breast (5 ductal adenocarcinomas, 1 mixed ductal/lobular adenocarcinoma), two serous papillary ovarian carcinomas and one moderately differentiated colorectal adenocarcinoma. The sensitivity of positive calretinin labelling to confirm the diagnosis of MPM was 97.5%, while the 'diagnostic sensitivities' of lack of labelling for BG8 and CD15 were 91.3% and 97.5%, respectively. The use of calretinin, BG8 and CD15 resulted in correct classification in 97.5% of all MPMs. All MPM cases investigated showed at least focal positive D2-40 labelling.

  Conclusions: We have validated the usefulness of a minimal panel of antibodies with calretinin, BG8 and CD15 as the initial step to the diagnosis of MPM. D2-40 emerged as a helpful diagnostic tool for cases where our initial approach failed to conclusively diagnose MPM.

• Validation of tissue microarray technology in malignant pleural mesothelioma. S.C. Kao, K. Lee, N.J. Armstrong, et al. 2011;43(2):128-32. PubMed · Publisher

  Abstract

  Aims: Tissue microarray (TMA) technology has been utilised for assessment of cancers including malignant pleural mesothelioma (MPM). Given the intralesional heterogeneity of MPM, it is questionable if TMAs can adequately represent MPMs. We here investigate the validity of TMAs for MPM.

  Methods: TMAs were constructed from at least five cores for each of 80 archival tumours processed by two centres between 1994 and 2009. The percentage of cases correctly subtyped on TMAs compared with whole sections, in relation to the number of cores analysed, was calculated. Immunohistochemical labelling for calretinin and D2-40 was performed on TMAs and whole sections. To evaluate the validity of quantitative immunohistochemistry, percentages of positive cells were recorded and two-way analysis of variance (ANOVA) performed.

  Results: Five cores were assessable for 91% of patients. Four cores were sufficient to reach concordance with the whole-section result in 98% of cases for calretinin and 99% for D2-40. The correlation of the quantitative scores between the whole section and TMA cores was statistically significant (D2-40, rho = 0.84, p < 2.2e-16; calretinin, rho = 0.65, p = 7.9e-11). Neither the origin nor age of the blocks affected the results.

  Conclusion: If a minimum of four cores is used, TMA is an appropriate method for immunohistochemistry in MPM.

• Sarcomatoid localised mesothelioma mimicking intrapulmonary synovial sarcoma: a case report and review of the literature. A. Teo, C. Hemmings, R. Miller. 2010;42(2):182-4. Case report · Letter PubMed · Publisher

2000s

• Choroid plexus metastases from pleural sarcomatoid mesothelioma. A. Muljono, T. Ng, J. McMaster, et al. 2008;40(5):530-2. Case report · Letter PubMed · Publisher

• Role of fragile histidine triad protein expression in pathogenesis of malignant pleural mesothelioma. E. Tutar, H. Kiyici. 2008;40(1):42-5. PubMed · Publisher

  Abstract

  Aim: To investigate the relationship of fragile histidine triad (FHIT) and Ki-67 expression with clinicopathological variables of patients with malignant pleural mesothelioma (MPM).

  Methods: Formalin-fixed, paraffin-embedded tissue sections of 30 asbestos induced MPM (epithelial and biphasic) patients were examined for FHIT and Ki-67 expression using immunohistochemical techniques and results were compared with clinicopathological variables.

  Results: Immunohistochemical study results were as follows: 12 (40%) cases showed low FHIT expression and 18 (60%) showed high expression. There was no significant relationship between FHIT and age, gender or histological subtypes (p > 0.05). Ki-67 expression was 'low' in 13 (43.3%) cases and 'high' in 17 (56.7%) cases. No correlation could be demonstrated between Ki-67 expression and age, gender or histological subtypes (p > 0.05). No significant association was observed between FHIT and Ki-67 expression in MPM.

  Conclusion: The results support the role of FHIT as a tumour suppressor gene in asbestos induced MPM. There is no significant correlation between FHIT and cell proliferation marker expressions in malignant pleural mesothelioma. Therefore, it can be concluded that loss of FHIT does not interfere with tumour proliferation. This can be accepted as evidence for an early role of FHIT loss in carcinogenesis; however, it needs to be strengthened by further studies.

• After Helsinki: a multidisciplinary review of the relationship between asbestos exposure and lung cancer, with emphasis on studies published during 1997-2004. D.W. Henderson, K. Rödelsperger, H.J. Woitowitz, et al. 2004;36(6):517-50. Review PubMed · Publisher

  Abstract

  Despite an extensive literature, the relationship between asbestos exposure and lung cancer remains the subject of controversy, related to the fact that most asbestos-associated lung cancers occur in those who are also cigarette smokers: because smoking represents the strongest identifiable lung cancer risk factor among many others, and lung cancer is not uncommon across industrialised societies, analysis of the combined (synergistic) effects of smoking and asbestos on lung cancer risk is a more complex exercise than the relationship between asbestos inhalation and mesothelioma. As a follow-on from previous reviews of prevailing evidence, this review critically evaluates more recent studies on this relationship--concentrating on those published between 1997 and 2004--including lung cancer to mesothelioma ratios, the interactive effects of cigarette smoke and asbestos in combination, and the cumulative exposure model for lung cancer induction as set forth in The Helsinki Criteria and The AWARD Criteria (as opposed to the asbestosis-->cancer model), together with discussion of differential genetic susceptibility/resistance factors for lung carcinogenesis by both cigarette smoke and asbestos. The authors conclude that: (i) the prevailing evidence strongly supports the cumulative exposure model; (ii) the criteria for probabilistic attribution of lung cancer to mixed asbestos exposures as a consequence of the production and end-use of asbestos-containing products such as insulation and asbestos-cement building materials--as embodied in The Helsinki and AWARD Criteria--conform to, and are further consolidated by, the new evidence discussed in this review; (iii) different attribution criteria (e.g., greater cumulative exposures) are appropriate for chrysotile mining/milling and perhaps for other chrysotile-only exposures, such as friction products manufacture, than for amphibole-only exposures or mixed asbestos exposures; and (iv) emerging evidence on genetic susceptibility/resistance factors for lung cancer risk as a consequence of cigarette smoking, and potentially also asbestos exposure, suggests that genotypic variation may represent an additional confounding factor potentially affecting the strength of association and hence the probability of causal contribution in the individual subject, but at present there is insufficient evidence to draw any meaningful conclusions concerning variation in asbestos-mediated lung cancer risk relative to such resistance/susceptibility factors.

• Asbestos exposure and lung cancer. C.S. Lee, W.A. Cooper. 2004;36(6):513-4. Comment · Editorial PubMed · Publisher

1990s

• Primary malignant mesothelioma of the tunica vaginalis of the testis. Immunohistochemistry and electron microscopy. E. Berti, E. Schiaffino, M.S. Minervini, et al. 1997;29(1):96-9. Case report · Review PubMed · Publisher

  Abstract

  A case of primary malignant mesothelioma of the tunica vaginalis of the testis in a 75 year old man is here presented. Anamnesis for asbestos exposure was negative. Recurrent left hydrocele was the main symptom. Echography revealed a nodular mass in the caudal aspect of the epididymis and papillary projection on the surface of the tunica vaginalis of the testis. An inguinal left orchiectomy was performed. The tumor both in the solid area and in the papillary projections was identified as a malignant mesothelioma of epithelial type. The role of immunohistochemistry and ultrastructure for a correct definition of the tumor is underlined.

1980s

• Modified alkali digestion method for pulmonary asbestos fibre counts. P.C. Zhang, W.B. Chung, K.W. Chan, et al. 1987;19(2):159-61. PubMed · Publisher

  Abstract

  In using the standard alkali digestion method for pulmonary asbestos fibre count, it was found that carbonaceous particles often obscured the presence of asbestos bodies (coated fibres) rendering their quantification inaccurate, particularly in lungs with a high soot particle content and a low fibre count. We applied the chloroform-ethanol separation technique from the bleaching agent digestion method to the alkali digestion method to remove the carbonaceous particles. It was found that coated fibres are much easier to visualize and count. The uncoated fibre count was nevertheless more accurate with the original method. The coated and uncoated fibre counts from 21 lung specimens were compared using both methods. The total fibre count was considered better derived from using both techniques.

• Test and teach. Number Fifty-six. Diagnosis: benign cystic peritoneal mesothelioma. J.P. McArdle. 1987;19(3):239, 315-6. Case report PubMed · Publisher

• Asbestos related interstitial pneumonitis associated with glomerulonephritis and lymphomatoid granulomatosis. C.T. Cooke, L.R. Matz, J.A. Armstrong, et al. 1986;18(3):352-6. Case report PubMed · Publisher

  Abstract

  We report a case of pulmonary asbestosis in a patient who also developed glomerulonephritis and lymphomatoid granulomatosis. The pulmonary reaction was unusual, characterized clinically by an acute onset of symptoms after a prolonged latent period and morphologically by an interstitial pneumonitis with prominent desquamative features and a paucity of fibrosis. The association of pulmonary asbestosis with glomerulonephritis and lymphomatoid granulomatosis has been hitherto unreported.

• Pleural fluid CEA levels in the diagnosis of malignant mesothelioma. D. Whitaker, K.B. Shilkin, M. Stuckey, et al. 1986;18(3):328-9. PubMed · Publisher

  Abstract

  A study was undertaken to investigate whether the levels of carcino-embryonic antigen (CEA) in serous effusions helped distinguish between primary mesothelioma and metastatic adenocarcinoma in a body cavity. The investigation was designed to assess the role of the assay only when cytological analysis of the fluid had already shown the presence of malignant cells. No case of mesothelioma studied had levels of CEA above 2.9 ng/ml, whereas 67% of the adenocarcinomas tested were above 15 ng/ml. The test is helpful, therefore, in differentiating between these two types of malignant effusions.

• Asbestos-related pleuropulmonary diseases: asbestosis, mesothelioma and lung cancer. D.W. Henderson. 1982;14(3):239-43. PubMed · Publisher

  Summary

  This editorial review by a pathologist at Flinders Medical Centre, Adelaide, considered recent developments in the pathology of asbestosis, pleural mesothelioma and asbestos-associated lung cancer, after a brief history of asbestos use. Asbestosis was described as interstitial fibrosis concentrated around the bronchioles and mainly in the lower lobes. The author advised that lung tissue from all cases of usual and desquamative interstitial pneumonia, and from resected tumours, be examined for asbestos bodies. He distinguished true asbestos bodies from ferruginous bodies with carbon or sheet-silicate cores. He cited a study of 600 asbestos bodies from 82 people who were not asbestos workers, in which 98% had amphibole cores and 2% chrysotile cores. The review also covered pulmonary cytoplasmic hyalin and proposed cellular and immune mechanisms of fibrosis. For mesothelioma, it outlined a two-step biopsy diagnosis and the use of mucin histochemistry, electron microscopy and carcinoembryonic antigen staining to tell it apart from adenocarcinoma. The author noted that most asbestos-associated mesotheliomas had resulted from crocidolite, with tremolite and erionite implicated in Turkey. Smoking did not affect mesothelioma risk. Asbestos exposure alone increased lung cancer risk about 5-fold. Cited age-standardized lung cancer death rates per 100,000 man-years were 11.3 for people with neither smoking nor asbestos exposure, 58.4 for non-smoking asbestos workers, 122.6 for smokers and 601.6 for asbestos workers who smoked. Asbestos bodies were found in 96% of an urban population, but there was no persuasive evidence that such low-level exposure caused disease. The author called for further study and stressed that avoiding cigarette smoking was the most important preventive measure for people already exposed.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Test and teach. Number twenty-seven. Diagnosis: malignant pleural mesothelioma. H.M. Chambers, D.W. Henderson. 1981;13(1):8-9, 159-61. PubMed · Publisher

• Malignant mesothelioma: a review of 35 cases with diagnosis and prognosis. M.H. Griffiths, R.J. Riddell, J.M. Xipell. 1980;12(4):591-603. PubMed · Publisher

  Abstract

  Twenty-five men and 10 women with malignant mesothelioma seen at the Austin Hospital between 1965 and 1978 were reviewed. The patients ranged in age from 34 to 79 yr. Prognosis was poor but was somewhat better for patients with epithelioid tumours than for patients with fibrous mesotheliomas and biphasic tumours. A history of occupational exposure to asbestos was obtained in the majority of patients, the latent period being from 18 to 52 yr. Ten patients had no history of asbestos exposure. The pathological diagnosis was established on tissue obtained at open biopsy in 22 cases and at post mortem in 11. Needle biopsy provided a diagnosis in only 2 cases. Cytology suggested a diagnosis of mesothelioma in 1 case. Gross pathology in general conformed with a diffuse confluent-nodular serosal tumor. A right sided preponderance was found in pleural tumours, and metastases were found rather more frequently than is usually reported. Histological features were distinctive in the majority of cases provided that sufficient material was examined. Recognition of coexisting patterns was often more helpful in making the diagnosis than any one single feature. Histochemical reactions are useful in distinguishing mesothelioma from mucin-secreting adenocarcinoma. In a majority of cases the histology and histochemistry were not characteristic and the diagnosis depended on the clinical features and the absence of another primary source of tumour.

1960s

• Asbestos bodies in lungs: an Australian report. J.M. Xipell, P.S. Bhathal. 1969;1(4):327-30. PubMed · Publisher

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