The Journal of Pathology

Our medical research library holds 44 studies published in The Journal of Pathology (1971–2024). 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. 39 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 4 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: John Wiley And Sons
• Published: 1969 to the present, England
• Language: English
• ISSN: 0022-3417 (print), 1096-9896 (electronic)
• Continues: Diagnostic Histopathology
• Its record in the NLM Catalog

2020s

• Expanding the clinicopathologic spectrum and genomic landscape of tumors with SMARCA2/4::CREM fusions. J. Cyrta, J.K. Dermawan, A. Tauziède-Espariat, et al. 2024;264(3):305-317. PubMed · Publisher · Free full text

  Abstract

  CREB gene family (ATF1, CREB1, CREM) fusions with either EWSR1 or FUS gene partners drive the pathogenesis of a wide range of neoplasms, including various soft tissue tumors, intracranial myxoid mesenchymal tumors (IMMTs), hyalinizing clear cell carcinoma (HCCC), and rare mesotheliomas. Recently, a SMARCA2::CREM fusion was reported in one case each of IMMT and HCCC. In this study, we expand the clinicopathologic and molecular spectrum of these neoplasms by describing three additional cases with SMARCA2::CREM and one with a novel SMARCA4::CREM fusion, highlighting the recurrent potential of additional CREB gene fusion partners beyond FET family members. To evaluate if these fusions define a new pathologic entity, we performed a comprehensive genomic and methylation analysis and compared the results to other related tumors. Tumors occurred in children and young adults (median age 20 years) and spanned a broad anatomic distribution, including soft tissue, intracranial, head and neck, and prostatic urethra. Microscopically, the tumors shared an undifferentiated round to epithelioid cell phenotype and a hyalinized fibrous stroma. Immunohistochemically, a polyphenotypic profile was observed, with variable expression of SOX10, desmin, and/or epithelial markers. No targetable genomic alterations were found using panel-based DNA sequencing. By DNA methylation and transcriptomic analyses, tumors grouped closely to FET::CREB entities, but not with SMARCA4/SMARCB1-deficient tumors. High expression of CREM by immunohistochemistry was also documented in these tumors. Patients experienced local recurrence (n = 2), locoregional lymph node metastases (n = 2), and an isolated visceral metastasis (n = 1). Overall, our study suggests that SMARCA2/4::CREM fusions define a distinct group of neoplasms with round cell to epithelioid histology, a variable immunoprofile, and a definite risk of malignancy. Larger studies are needed to further explore the pathogenetic relationship with the FET::CREB family of tumors. © 2024 The Pathological Society of Great Britain and Ireland.

  © 2024 The Pathological Society of Great Britain and Ireland.

• Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8. C.E. de Andrea, M.C. Ochoa, M. Villalba-Esparza, et al. 2021;255(2):190-201. PubMed · Publisher

  Abstract

  Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

  © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

• Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma. A. De Rienzo, L.R. Chirieac, Y.P. Hung, et al. 2021;253(1):68-79. PubMed · Publisher · Free full text

  Abstract

  BRCA1-associated protein-1 (BAP1) expression is commonly lost in several tumors including malignant pleural mesothelioma (MPM). Presence or absence of immunohistochemical BAP1 nuclear staining in tumor cells is currently used for differential diagnosis of MPM. In this study, a large cohort of 596 MPM tumors with available clinical data was analyzed to examine associations of BAP1 staining pattern with clinical and molecular features that may reflect the impact of BAP1 mutation on MPM biology. Cases were classified according to the BAP1 staining pattern of tumor cells. Exome and RNA-sequencing data were available for subsets of cases. Levels of mRNA encoding claudin 15 (CLDN15) and vimentin (VIM) were determined using RT-qPCR on 483 cases to estimate the relative proportions of epithelial-like and mesenchymal-like components in each tumor. Four BAP1 staining patterns were observed: single-pattern nuclear staining (36%), single-pattern cytoplasmic staining (25%), single-pattern absent staining (12%), and combinations of these staining patterns (27%). This study confirmed prior reports that nuclear BAP1 is more frequently associated with wild-type BAP1 and sarcomatoid histology. However, no associations between BAP1 staining pattern(s) and mutations in specific protein domains and/or mutation type were observed. BAP1 staining patterns were significantly associated (p < 0.001) with BAP1 gene expression, MPM histologic subtypes, molecular clusters, and markers of epithelial-to-mesenchymal transition. Frequent observation of combinations of BAP1 staining patterns in MPM tumors indicated intra-tumoral heterogeneity of BAP1 status. Cytoplasmic BAP1 staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM. In conclusion, novel significant associations among different BAP1 staining patterns and subgroups of MPM tumors were observed, suggesting that the role of BAP1 in tumor progression may be more complex than its presumed tumor suppressor function. Cytoplasmic staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM, potentially addressing a critical need in clinical decision-making in this disease. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

  © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

• CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness. S. Inaguma, J. Lasota, P. Czapiewski, et al. 2020;250(2):205-216. PubMed · Publisher · Free full text

  Abstract

  Diffuse malignant mesothelioma of the pleura (MPM) is a highly aggressive tumour that typically is associated with short survival. CD70 and CD27 belong to the tumour necrosis factor (TNF) and the TNF receptor (TNFR) superfamily, respectively. Under physiological conditions, the tightly regulated interaction between CD70 and CD27 plays a co-stimulatory role in promoting T-cell expansion and differentiation through the NFκB pathway. Aberrantly high CD70 expression has been documented in haematological and solid malignancies in association with immune evasion in malignant cells. In this study, 172 well-characterised primary diffuse MPM tumours including epithelioid (n = 145), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, CD27, CD3, CD4, CD8, CD56, PDCD1 (PD-1), and FOXP3 expression. Twenty per cent (34/172) of the mesothelioma cells expressed CD70 on the cell membrane. Overall survival was significantly decreased in the cohort of patients with CD70-expressing tumour cells (p < 0.01). Patients with MPM containing a higher number of CD3+ (p < 0.01), CD4+ (p < 0.01), CD8+ (p < 0.01), or FOXP3+ (p < 0.01) tumour-infiltrating lymphoid cells (TILs) showed significantly worse clinical outcomes. As potential independent risk factors for MPM patients, multivariate Cox proportional hazards regression analysis revealed CD70 expression on mesothelioma cells [hazard ratio (HR) 2.25; p = 0.010], higher FOXP3+ TILs (HR 2.81; p = 0.004), and higher CD3+ TIL accumulation (HR 6.12; p < 0.001). In contrast, as a potential independent favourable factor, higher CD27+ TIL accumulation (HR 0.48; p = 0.037) was identified. In vitro experiments and an immunodeficient mouse model revealed that CD70 enhances the invasiveness of MPM cells through MET-ERK axis activation. Further analyses in syngeneic mouse models demonstrated possible roles for CD70 in immune evasion. Collectively, these findings suggest that the CD70-CD27 pathway enhances the malignant phenotypes of MPM and diminishes anti-tumor immune response in patients with these neoplasms. These markers might be useful in MPM for prognostic evaluations as well as targeted therapeutics. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

2010s

• Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma. V. Laszlo, M.A. Hoda, T. Garay, et al. 2015;237(2):203-14. PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM.

  Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Mesothelioma cells breaking bad: loss of integrin α7 promotes cell motility and poor clinical outcomes in patients. D.J. Burkin, T.M. Fontelonga. 2015;237(3):282-4. Comment PubMed · Publisher

  Abstract

  Mesothelioma is a disease of pleural cells lining the lungs which is often caused by exposure to asbestos. The molecular mechanism(s) that regulate the transformation of pleural mesothelioma cells to a migratory and malignant phenotype are unclear. In recent work published in this journal, Laszlo et al performed a set of elegant experiments to identify a key molecular mechanism that may explain the aggressive nature of this disease. Using patient-derived mesothelioma cells with high versus low migratory activity, the authors conducted a genome-wide expression analysis. They identified a significant reduction in ITGA7 expression only in highly migratory malignant pleural mesothelioma cells and showed that loss of ITGA7 expression was associated with methylation of the promoter. Forced expression of integrin α7 reversed the migratory phenotype of these cells. Finally, the authors identified a strong correlation between ITGA7 expression and patient survival. Together, these results identify expression of integrin α7 as a molecular mechanism for the aggressive migratory transformation of mesothelioma and identify a potentially novel diagnostic and therapeutic target.

  Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. L. Jiang, Y. Yamashita, S.H. Chew, et al. 2014;233(4):402-14. PubMed · Publisher

  Abstract

  Due to the formerly widespread use of asbestos, malignant mesothelioma (MM) is increasingly frequent worldwide. MM is classified into epithelioid (EM), sarcomatoid (SM), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM, and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM, we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor (Ctgf), whose expression was significantly increased in SM compared with EM; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM, Ctgf was a major regulator of MM proliferation and invasion through activation of the β-catenin-TCF-LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial-mesenchymal transition in MM. Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6-GSK3β-β-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target.

  Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma. S. Busacca, M. Sheaff, K. Arthur, et al. 2012;227(2):200-8. PubMed · Publisher

  Abstract

  Therapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity; however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons; however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level; (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides; (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance; and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker.

  Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Iron overload signature in chrysotile-induced malignant mesothelioma. L. Jiang, S. Akatsuka, H. Nagai, et al. 2012;228(3):366-77. PubMed · Publisher

  Abstract

  Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure.

  Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis. R. Uzhachenko, N. Issaeva, K. Boyd, et al. 2012;227(4):456-69. PubMed · Publisher

  Abstract

  Fus1, encoded by a 3p21.3 tumour suppressor gene, is down-regulated, mutated or lost in the majority of inflammatory thoracic malignancies. The mitochondrial localization of Fus1 stimulated us to investigate how Fus1 modulates inflammatory response and mitochondrial function in a mouse model of asbestos-induced peritoneal inflammation. Asbestos treatment resulted in a decreased Fus1 expression in wild-type (WT) peritoneal immune cells, suggesting that asbestos exposure may compromise the Fus1-mediated inflammatory response. Untreated Fus1(-/-) mice had an ~eight-fold higher proportion of peritoneal granulocytes than Fus1(+/+) mice, pointing at ongoing chronic inflammation. Fus1(-/-) mice exhibited a perturbed inflammatory response to asbestos, reflected in decreased immune organ weight and peritoneal fluid protein concentration, along with an increased proportion of peritoneal macrophages. Fus1(-/-) immune cells showed augmented asbestos-induced activation of key inflammatory, anti-oxidant and genotoxic stress response proteins ERK1/2, NFκB, SOD2, γH2AX, etc. Moreover, Fus1(-/-) mice demonstrated altered dynamics of pro- and anti-inflammatory cytokine expression, such as IFNγ, TNFα, IL-1A, IL-1B and IL-10. 'Late' response cytokine Ccl5 was persistently under-expressed in Fus1(-/-) immune cells at both basal and asbestos-activated states. We observed an asbestos-related difference in the size of CD3(+) CD4(-) CD8(-) DN T cell subset that was expanded four-fold in Fus1(-/-) mice. Finally, we demonstrated Fus1-dependent basal and asbestos-induced changes in major mitochondrial parameters (ROS production, mitochondrial potential and UCP2 expression) in Fus1(-/-) immune cells and in Fus1-depleted cancer cells, thus supporting our hypothesis that Fus1 establishes its immune- and tumour-suppressive activities via regulation of mitochondrial homeostasis.

  Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma. T. Li, H. Li, Y. Wang, et al. 2011;223(4):519-30. PubMed · Publisher · Free full text

  Abstract

  The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, are involved in tumour progression, metastasis, and survival. We investigated the expression of CXCR4, CXCL12, and CXCR7 in malignant pleural mesothelioma to determine if they are possible biomarkers and potential therapeutic targets. Forty-one mesothelioma tumour tissues, ten normal human pleural tissues, and two mesothelioma cell lines were stained with anti-CXCR4, anti-CXCL12, anti-CXCR7, and anti-p-Akt antibodies. RT-PCR was performed to determine the expression of CXCR4, CXCL12, and CXCR7 in six human mesothelioma cell lines (H28, 211H, H2052, ms-1, H290, and H513) and one human normal mesothelial cell line, LP9. These seven cell lines were also stained with anti-CXCR7. We found that CXCR4 and CXCL12 were expressed in 97.6% and 78.0% mesothelioma tissue samples, concurrently with strong expression of p-Akt (R(2) = 0.739 and 0.620, respectively). In addition, CXCR7 expression was weaker than CXCR4 expression in mesothelioma tissues. Furthermore, RT-PCR showed that CXCR4 and CXCL12 were overexpressed in 5/6 mesothelioma cell lines (211H, H2052, ms-1, H290, and H513), whereas CXCR7 was overexpressed in only 2/6 (H513 and H2052). Moreover, we found that the CXCR4 antagonist AMD3100 inhibited the growth of all five mesothelioma cell lines that overexpress CXCR4 and CXCL12. Our results suggest that the Akt-mTOR pathway is involved during the interruption of the CXCL12/CXCR4 axis in these five mesothelioma cell lines. In conclusion, CXCR4 and CXCL12 are highly expressed in most mesothelioma cell lines and tumour tissues, suggesting that CXCR4 and CXCL12 may be used as biomarkers for patients with mesothelioma. The CXCL12-CXCR4 interaction may be a potential therapeutic target for mesothelioma.

  Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

2000s

• Expression of glycoprotein 90K in human malignant pleural mesothelioma: correlation with patient survival. L. Strizzi, R. Muraro, G. Vianale, et al. 2002;197(2):218-23. PubMed · Publisher

  Abstract

  The expression of the tumour-associated glycoprotein 90K in patients with malignant pleural mesothelioma (MM) has not been described. This study used enzyme-linked immunoassay (ELISA) to measure 90K in pleural effusions (PEs) and sera from patients with MM (n=28), lung cancer (LC) (n=14) and benign pleural disease (BPD) (n=15). Immunohistochemistry was used to investigate 90K expression in MM and LC tissue sections. The expression of 90K was further evaluated in vitro by ELISA and western blot analysis of conditioned media and cellular extracts of MM, LC and normal human mesothelial (NHM) cell cultures. Finally, the relationships between 90K expression in MM and patient age and survival were studied. The mean 90K level was significantly higher (p<0.05) in PEs of MM patients (11.0+/-6.6 microg/ml) than in LC (6.1+/-3.2 microg/ml) or BPD (6.2+/-5.0 microg/ml) patients. Immunohistochemistry showed a positive reaction for 90K in MM biopsy sections and positive staining limited to inflammatory infiltrates in LC sections. The level of 90K was significantly higher in cell culture media of MM than of LC or NHM (p<0.001). Bands representing proteins with molecular weight of approximately 90 kDa were detected by western blot in MM cellular extracts. An inverse correlation between PE 90K levels and MM patient age (r=-0.45; p=0.017) and a positive correlation between serum 90K levels and MM patient survival (r=0.62; p=0.006) were detected by linear regression analysis. Kaplan-Meier univariate analysis showed increased survival probability for MM patients with serum 90K level >7.3 microg/ml (log rank, p<0.05). This is the first report in MM of the expression of 90K and of its potential diagnostic and prognostic application.

  Copyright 2002 John Wiley & Sons, Ltd.

• Steroid hormone receptor in pleural solitary fibrous tumours and CD34+ progenitor stromal cells. M. Bongiovanni, L. Viberti, C. Pecchioni, et al. 2002;198(2):252-7. PubMed · Publisher

  Abstract

  Solitary fibrous tumours (SFT), originally described in the pleura, were subsequently recognized in numerous extrapleural sites. This suggests that a common stem cell, present in various organs and tissues, may be at the origin of SFT and that specific factors may be involved in the proliferation of such cells. Recently it has been described that steroid hormone receptors, progesterone receptors in particular, are expressed by extrapleural SFT. In addition, progesterone may participate as growth factor in many CD34(+) stromal neoplasms, which express low levels of the hormone receptors. The present study analysed the expression of androgen (AR), oestrogen (ER) and progesterone (PR) receptors in a series of 32 pleural SFT, 10 mesotheliomas and in reactive tissue of chronic pleuritis. ER and AR were never expressed by SFT or by chronic pleuritis, whereas PR were demonstrated in 2/16 "large" (>8 cm) and in 6/16 "small" (< or =8 cm) pleural SFT (all expressing CD34, bcl-2 and CD99). PR(+) SFT had a significantly higher proliferative activity (p = 0.04) (Ki-67 mean value 6.5%) and lower p27(kip1) (mean value 51.5%) expression than the PR(-) cases (Ki-67 mean value 3.81% and p27(kip1) mean value 57.86%). One of the cases expressing a high level of PR (80%) recurred 1 year after first surgery and the recurrence was PR(+) as well, but with a lower percentage of nuclear receptor expression (12%). In addition, in chronically inflamed subserosal tissue, a subpopulation of CD34(+) endothelial and interstitial dendritic cells was identified, which also expressed PR. These findings suggest that the CD34(+) submesothelial interstitial dendritic cells, activated during reactive processes, may be the stem cells that give rise to SFT, and that progesterone might participate in the growth of SFT through modulation of its specific receptors.

  Copyright 2002 John Wiley & Sons, Ltd.

• Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. L. Strizzi, A. Catalano, G. Vianale, et al. 2001;193(4):468-75. PubMed · Publisher

  Abstract

  Vascular endothelial growth factor (VEGF), a potent mitogen for vascular endothelium, is expressed in malignant pleural mesothelioma (MM). The present report examines the effect of VEGF on MM growth. Four MM cell lines produced significantly higher VEGF levels than normal mesothelial cells (1946+/-14 pg/ml vs. 180+/-17 pg/ml; p<0.001). In addition, MM cells expressed the tyrosine kinase-related VEGF receptors Flt-1 and KDR. Recombinant human VEGF phosphorylated both Flt-1 and KDR and increased proliferation of all four MM cell lines in a dose-dependent fashion. Neutralizing antibodies against either VEGF, Flt-1 or KDR significantly reduced MM cellular proliferation. In addition, expression of VEGF, Flt-1, and KDR was observed in MM biopsies. Moreover, higher VEGF levels were found in the pleural effusions of MM patients than in the effusions of patients with non-malignant pleural disease (1885.7+/-894.9 pg/ml vs. 266.9+/-180.5 pg/ml; p<0.001). Linear regression analysis showed a significant inverse correlation between serum VEGF levels and MM patient survival (r=0.72; p<0.01). No correlation was found between tumour vessel density and either serum (r=0.26; p=0.42) or pleural effusion (r=0.35; p=0.26) VEGF levels. These results indicate that VEGF, via activation of its tyrosine kinase receptors, may be a key regulator of MM growth. In addition, VEGF production could have an impact on patient survival, not only by promoting tumour angiogenesis but also by directly stimulating tumour growth.

  Copyright 2001 John Wiley & Sons, Ltd.

1990s

• Induction of nuclear translocation of NF-kappaB in epithelial cells by respirable mineral fibres. D.M. Brown, P.H. Beswick, K. Donaldson. 1999;189(2):258-64. PubMed · Publisher

  Abstract

  A panel of mineral fibres has been studied for their ability to cause translocation of the transcription factor NF-kappaB to the nucleus in A549 lung epithelial cells. On the basis of inhalation studies, three fibres were designated as being carcinogenic-amosite asbestos, silicon carbide and refractory ceramic fibre 1 (RCF1)-or non-carcinogenic-man-made vitreous fibre (MMVF10), Code 100/475 glass fibre, and RCF4. The experiments were carried out at equal fibre number. It was hypothesized that carcinogenic fibres have greater free radical activity than non-carcinogenic fibres and that an oxidative stress produced in the lung after inhalation of fibres could cause translocation of the transcription factor NF-kappaB to the nucleus, where transcription of pro-inflammatory genes such as cytokines could occur. It was demonstrated that a simple oxidant, hydrogen peroxide, caused translocation in a time- and dose-dependent manner. The three carcinogenic fibres produced a significant dose-dependent translocation of NF-kappaB to the nucleus, whereas the non-carcinogenic fibres did not. Silicon carbide fibres were the most potent of the pathogenic fibres. MMVF10 was the most potent of the non-pathogenic fibres, causing significant nuclear translocation of NF-kappaB at high fibre number. Using three antioxidants, curcumin, pyrrolidine dithiocarbamate, and Nacystelin, translocation caused by carcinogenic fibres could be significantly reduced. The present study shows that a short-term in vitro assay can discriminate between pathogenic and non-pathogenic fibres in terms of a key pro-inflammatory event in epithelial cells. The mechanism of the activation of NF-kappaB by pathogenic fibres and its general applicability to other fibre types remain to be determined.

  Copyright 1999 John Wiley & Sons, Ltd.

• Value of morphometry, texture analysis, densitometry, and histometry in the differential diagnosis and prognosis of malignant mesothelioma. B. Weyn, G. Van De Wouwer, M. Koprowski, et al. 1999;189(4):581-9. PubMed · Publisher

  Abstract

  Malignant mesothelioma is a tumour with increasing incidence due to widespread use of its causative agent, asbestos, in the past decades. The poor survival necessitates a correct differentiation from other lesions at the same site, such as hyperplastic mesothelium and carcinomas metastatic to pleura or peritoneum. Since genetic and immunohistochemical markers are not absolutely differentiating, the diagnosis is based on the histology complemented with (immuno)histochemistry. However, as the tumour presents itself in numerous heterogeneous histological forms, visual evaluation is extremely difficult. In order to evaluate the prognostic and diagnostic performance of syntactic structure analysis (SSA), chromatin texture analysis, densitometry, and morphometry, an automated KNN-classification system has been used to compare Feulgen-stained tissue sections of hyperplastic mesothelium, malignant mesothelioma, and pulmonary adenocarcinoma. In addition, we also studied most discriminative aspects in the differentiation, typing, and prediction of survival. The results indicate that for the diagnosis of malignant mesothelioma, chromatin texture parameters outperform SSA, densitometry, and morphometry (recognition score=96.8 per cent). Most discriminative parameters highlight spatial patterns of the chromatin distribution that are hard to appraise visually and directly show the benefits of a quantitative approach. Typing of the tumour is best described by SSA parameters, relating to the spatial arrangement of the cells in the tissue (recognition score=94.9 per cent). In survival time classifications, chromatin texture yields the highest recognition score (82.9 per cent), although accurate estimations are unreliable due to a large degree of misclassification.

  Copyright 1999 John Wiley & Sons, Ltd.

• Fibroblast mitogens in bronchoalveolar lavage (BAL) fluid from asbestos-exposed subjects with and without clinical evidence of asbestosis: no evidence for the role of PDGF, TNF-alpha, IGF-1, or IL-1 beta. S.E. Mutsaers, N.K. Harrison, R.J. McAnulty, et al. 1998;185(2):199-203. PubMed · Publisher

  Abstract

  Asbestosis is a fibrotic lung disease resulting from inhalation of asbestos fibres. Its pathogenesis is poorly understood but probably involves stimulation of fibroblast proliferation and collagen production by mediators released from inflammatory and resident lung cells. In vitro studies have implicate PDGF, TNF-alpha, IGF-1, TGF-beta, and IL-1 in asbestosis, but the role of these mediators in vivo is not known. This study aimed to characterize mediators in bronchoalveolar lavage (BAL) fluid from patients exposed to asbestos with (n = 24) or without (n = 34) asbestosis, compared with ten normal subjects. Human lung fibroblasts were exposed to serial dilutions of BAL fluids and the effects on fibroblast proliferation were assessed. The median mitogenic activity of BAL fluid from asbestos-exposed (17 per cent above medium control, range 3-44 per cent) and asbestosis (14 per cent, range 2-60 per cent) groups was higher than that of BAL fluid from controls (10 per cent, range 2-20 per cent; P < 0.01 and P < 0.05, respectively), but there was no significant difference between the patient groups. The mitogenic activity of BAL fluids was not reduced by incubation with neutralizing antibodies to PDGF-AA, PDGF-AB, PDGF-BB, TNF-alpha, IGF-1, and IL-1 beta. We conclude that BAL fluids from patients exposed to asbestos contain mitogens for human lung fibroblasts, but that PDGF, TNF-alpha, IGF-1, or IL-1 beta do not contribute to this activity.

• SV40-like DNA sequences in pleural mesothelioma, bronchopulmonary carcinoma, and non-malignant pulmonary diseases. F. Galateau-Salle, P. Bidet, Y. Iwatsubo, et al. 1998;184(3):252-7. PubMed · Publisher

  Abstract

  Pleural and pulmonary malignancies are usually associated with well-known carcinogen exposure. Recently, the presence of simian virus 40 (SV40)-like DNA sequences has been detected in brain and bone-related human cancers and in pleural mesothelioma. In order to determine whether SV40-like DNA sequences are also present in bronchopulmonary carcinoma and non-malignant lung samples, 125 frozen pleural and pulmonary samples (including 21 mesotheliomas, 63 bronchopulmonary carcinomas, 8 other tumours, and 33 non-malignant samples) and 38 additional samples distant from tumours were studied for the occurrence of SV40-like DNA sequences by polymerase chain reaction (PCR) amplification followed by hybridization with specific probes. Sequences related to SV40 large T antigen (Tag) were present in 28.6 per cent of bronchopulmonary carcinomas, 47.6 per cent of mesotheliomas, and 16.0 per cent of cases with non-neoplastic pleural and pulmonary disease. No statistically significant difference in the occurrence of these DNA sequences was found between malignant mesothelioma and bronchopulmonary carcinoma, but a significantly higher number of mesothelioma cases exhibited SV40-like DNA sequences in comparison with cases of non-malignant pleural or pulmonary disease (P < 0.04). Among cases positive for SV40-like DNA sequences, a history of asbestos exposure was found in 3 out of 12 bronchopulmonary carcinomas and 8 out of 10 mesotheliomas. Immunohistochemistry using monoclonal antibodies directed against Tag did not demonstrate nuclear staining. The DNA sequences were not related to BK virus sequences, but three samples were positive with probes hybridizing with JC virus DNA sequences. In conclusion, this study demonstrates the presence of SV40-like DNA sequences in pulmonary neoplasms and in non-malignant lung tissues. It appears that the presence of SV40-like DNA is not unique to cancer.

• Cytogenetic and pathogenic effects of long and short amosite asbestos. K. Donaldson, N. Golyasnya. 1995;177(3):303-7. PubMed · Publisher

  Abstract

  This study utilized two samples of amosite asbestos which differ in their length, but not in their diameter and which have been shown previously to have very different abilities to cause pathology in rats exposed by instillation or inhalation. The activity of these amosite samples in causing chromosomal aberrations in Chinese hamster ovary cells in culture was examined, along with the effect of the glutathione (GSH) synthesis-inhibiting agent buthionine sulphoximine. The incidence of chromosomal aberrations in cells treated with the short fibre sample was similar to control levels; the long amosite sample caused significantly more chromosomal aberrations than the short fibre sample. When cells were treated with buthionine sulphoximine to decrease the levels of intracellular glutathione, the incidence of chromosomal aberrations was increased in the control cells, but also on treatment with both short and long amosite, the long sample again being considerably more active than the short. The pathogenicity of the long amosite may result from the ability of the fibres to cause chromosome damage, while the enhancement of this damage caused by decreasing intracellular glutathione suggests that the asbestos fibres may impose an oxidant stress on the cells which contributes to these aberrations.

• Immunohistochemical staining of ras oncogene product in neoplastic and non-neoplastic mesothelial tissues: immunoreactivity for N-ras and lack of immunohistochemical staining for Ha-ras and K-ras. M. Ramael, I. Deblier, C. Eerdekens, et al. 1993;169(4):421-4. PubMed · Publisher

  Abstract

  Immunohistochemical staining of 36 malignant mesotheliomas and 45 cases of non-neoplastic mesothelium including 20 specimens with signs of hyperplasia were investigated using murine monoclonal antibodies directed against p21 ras protein, Ha-ras protein, K-ras protein, and N-ras protein. All cases of non-neoplastic mesothelium and the majority of the malignant mesotheliomas (78 per cent) showed cytoplasmic and often submembranous immunoreactivity in more than 50 per cent of the cells with both the pan-ras and N-ras antibody. No immunoreactivity was observed for Ha- and K-ras. There was no statistically significant difference with respect to immunoreactivity between neoplastic and non-neoplastic mesothelium or between the various mesothelioma subtypes.

• The diagnostic implications of variable cytokeratin expression in mesotheliomas. F.G. Mayall, H. Goddard, A.R. Gibbs. 1993;170(2):165-8. PubMed · Publisher

  Abstract

  Immunostaining for cytokeratin has a well-established diagnostic application in distinguishing sarcomatous mesotheliomas from sarcomas based on the premise that cytokeratin expression is common in mesotheliomas but very rare in sarcomas. However, the frequency of cytokeratin detection is highly dependent on the choice of antibody. The aim of this study was to examine the distribution of simple cytokeratins and stratified cytokeratins in 45 mesotheliomas of various types and to assess the diagnostic utility of a simple cytokeratin antibody, a stratified cytokeratin antibody, and a broad spectrum cytokeratin antibody with the aim of establishing the superiority of one for routine diagnostic use. Particular attention was paid to the potential utility of these antibodies in biopsy specimens. The broad spectrum cytokeratin antibody performed better than both the simple cytokeratin antibody (paired t-test: P < 0.01) and the stratified cytokeratin antibody (P < 0.01) as a diagnostic marker of mesothelioma and should be used in preference to the other two antibodies, particularly when considering small biopsy specimens.

• 'Pleural' and pulmonary carcinosarcomas. F.G. Mayall, A.R. Gibbs. 1992;167(3):305-11. PubMed · Publisher

  Abstract

  The histological distinction between carcinosarcoma and mesothelioma has received little attention. The object of this study was to describe the histology and immunohistochemistry of two carcinosarcomas presenting as pleural tumours. These were compared with 12 carcinosarcomas from sites within the lung, and with the established features of mesothelioma. Histologically and immunohistochemically, these 'pleural' carcinosarcomas are similar to conventional pulmonary carcinosarcomas but accurate recognition is hindered by their gross appearance and biphasic histology which closely mimic mesothelioma. They may exhibit features such as neutral mucin, expression of carcinoembryonic antigen, squamous differentiation, and neuroendocrine differentiation which, when present, are evidence against mesothelioma. These tumours are rare and have passed unnoticed until now.

• Asbestos-stimulated tumour necrosis factor release from alveolar macrophages depends on fibre length and opsonization. K. Donaldson, X.Y. Li, S. Dogra, et al. 1992;168(2):243-8. PubMed · Publisher

  Abstract

  Fibre length has been shown to be an important factor in the ability of respirable fibres to cause lung fibrosis and cancer. We have reported that a long sample of amosite asbestos is more carcinogenic and fibrogenic than a short sample of similar diameter. These amosite asbestos samples were studied with regard to their ability to stimulate the release of the pro-inflammatory cytokine tumour necrosis factor (TNF) from rat alveolar macrophages in vitro. The long fibre sample was found to stimulate substantially greater release of the cytokine than the short sample. Furthermore, on treatment of the fibres with rat immunoglobulin G (IgG), there was an increase in the ability of both the long and the short sample to stimulate TNF secretion, although the long sample retained by far the greatest activity. Coating of the fibres with a range of other proteins had no substantial effect on their ability to stimulate TNF secretion. Quartz and titanium dioxide (TiO2) were included as control particles and the TNF-stimulating activity of quartz was notably increased by opsonization with IgG. TiO2 showed a similar low activity to that of the short fibre sample of amosite but this again could be modestly increased by opsonization with IgG. The simulation of TNF release caused by treatment with immunoglobulin-opsonized long fibre amosite could be inhibited by treatment of the macrophages with the protein kinase C-inhibitor staurosporine. The study demonstrates a fibre length-related ability to stimulate cytokine secretion by alveolar macrophages, and its enhancement by opsonization with IgG.(ABSTRACT TRUNCATED AT 250 WORDS)

• Immunoreactivity for the beta chain of the platelet-derived growth factor receptor in malignant mesothelioma and non-neoplastic mesothelium. M. Ramael, C. Buysse, J. van den Bossche, et al. 1992;167(1):1-4. PubMed · Publisher

  Abstract

  The results of an immunohistochemical study of platelet-derived growth factor receptor (PDGF-R) beta chain in human non-neoplastic mesothelium (35 cases) and in malignant mesothelioma (33 cases) using a murine monoclonal antibody are reported. In approximately half of the malignant mesotheliomas, there was immunoreactivity in the cytoplasm of the neoplastic cells for the beta chain of the PDGF-R. In some cases, there was also membrane immunoreactivity. There were no statistically significant differences between the various mesothelioma subtypes. Immunoreactivity for PDGF-R beta chain was absent in non-neoplastic mesothelium.

• Nucleolar organizer regions in mesothelial proliferations. M. Ramael, J. Van den Bossche, C. Buysse, et al. 1992;167(4):435. Comment · Letter PubMed · Publisher

• A morphometrically-based classification rule for the diagnosis of primary mesothelial lesions. F. Robutti, P.G. Betta, A. Donna, et al. 1990;162(1):57-60. PubMed · Publisher

  Abstract

  A computer-aided morphometrical study was performed on histological specimens of reactive hyperplastic (n = 10) and malignant (n = 17) mesothelium. For each cell, seven nuclear features were measured and 13 parameters computed. Using stepwise variable selection, discriminant analysis chose the nuclear contour index, the standard deviation of the nuclear area, and the mean of the nuclear perimeter as discriminating features between hyperplastic and malignant mesothelium. The coefficients of these variables were included in a discriminant function which gave perfect discrimination between the two groups of lesions. When the function was assessed on a test set of hyperplastic (n = 10) and malignant (n = 17) mesothelial lesions treated as 'unknown', complete separation between these two diagnostic categories was achieved. This classification rule may help to increase the level of confidence with which a histological diagnosis of mesothelioma can be established.

• DNA analysis by flow cytometry in malignant pleural mesothelioma: relationship to histology and survival. H. Dazzi, N. Thatcher, P.S. Hasleton, et al. 1990;162(1):51-5. PubMed · Publisher

  Abstract

  In a retrospective study of 70 patients with malignant pleural mesothelioma, 168 formalin-fixed, paraffin-embedded tumour specimens were examined for DNA content by flow cytometry. In 20 patients where two or more blocks of the same tumour were available, there was considerable agreement between ploidy status and S-phase percentage in the different specimens. There were no significant differences for survival for patients who had been exposed to asbestos and those in whom no exposure could be elicited, nor for aneuploid and diploid tumours. The S-phase content was examined for different areas of the same tumour and the percentages were largely in agreement. However, those patients who had tumours with an S-phase percentage greater than the median (6 per cent) had a significantly shorter survival than those with tumours of lower S-phase percentage. Differences in DNA content and other cell cycle parameters were not associated with the histological subtypes.

• Impaired chemotactic responses of bronchoalveolar leukocytes in experimental pneumoconiosis. K. Donaldson, G.M. Brown, D.M. Brown, et al. 1990;160(1):63-9. PubMed · Publisher

  Abstract

  Rats were exposed to clouds of the following pneumoconiotic dusts: quartz, coal-mine dust, and chrysotile asbestos at 10 or 50 mg/m3 for 8, 32, and 75 days; for comparison, rats were also exposed to the non-pathogenic dust titanium dioxide (TiO2). The bronchoalveolar leukocytes (macrophages and neutrophils) from dust-exposed and control rats were obtained by lavage and tested for their ability to migrate toward zymosan-activated serum. Varying amounts of neutrophils were present depending on the ability of the dust to cause inflammation and the length of exposure. There was a marked loss of chemotactic ability in leukocytes from rats inhaling the pneumoconiotic dusts compared with controls; TiO2-exposed leukocytes had some impairment of chemotaxis, but this was substantially less than that found with the pneumoconiotic dusts. The loss of chemotactic activity did not correlate with the percentage of neutrophils in the lavage cells except when there were very high levels of neutrophils, and there was substantial impairment of chemotaxis with negligible numbers of neutrophils, showing that macrophage chemotaxis was impaired. A phagocytic burden within the leucocytes was not sufficient alone to inhibit chemotaxis, nor was the loss of chemotactic activity due to occupied receptors, since incubation failed to restore chemotaxis. Loss to chemotactic activity by leukocytes from pneumoconiotic dust-exposed lung could be an important factor in the development of pneumoconiosis.

• The malignancy grading method is not a reliable assessment of malignancy in mesothelioma. G. Tierney, M.J. Wilkinson, J.S. Jones. 1990;160(3):209-11. PubMed · Publisher

  Abstract

  The ploidy of a series of pleural lesions--reactive proliferations, malignant mesotheliomas and metastatic tumours--was measured on a Leitz Miamed DNA image analyser using Feulgen-stained slides. The technique successfully recognized all the metastatic tumours as malignant; this corresponds to previous work. However, it was not successful in classifying mesothelial lesions as benign or malignant, resulting in a very high false-negative rate and a moderately high false-positive rate. Mesothelial lesions appear to have a wide range of ploidy values irrespective of their biological behaviour. Thus, for primary mesothelial tumours, the ploidy value cannot be used as a reliable diagnostic index.

1980s

• Response of mouse lung to crocidolite asbestos. 1. Minimal fibrotic reaction to short fibres. I.Y. Adamson, D.H. Bowden. 1987;152(2):99-107. PubMed · Publisher

  Abstract

  To determine the relationship between the development of pulmonary fibrosis and the size of deposited asbestos, we prepared a pure sample of short crocidolite fibres and instilled 0.5 mg of 0.1 mg to the lungs of mice. Animals were killed up to 20 weeks later with 3H thymidine injected 1 h before death. By bronchoalveolar lavage, there was a rapid transient increase in polymorph neutrophils (PMN) and in glucosaminidase levels; alveolar macrophage (AM) numbers were elevated in the 0.5 mg group for eight weeks. Most fibres were phagocytized by AM, many of which were heavily laden and cleared from the lung over the 20 week period. Some fibres were seen in type 1 epithelial cells, frequently associated with cell injury. From cell kinetic studies, a very brief proliferative response was seen in bronchiolar epithelial and Type 2 alveolar epithelial cells. A greater response was seen in interstitial fibroblasts which showed increased labelling up to two weeks after 0.5 mg asbestos. However no granulomas were seen and very little fibrosis was found by morphology or by biochemistry at any time after 0.5 mg; no fibrosis was seen after instilling 0.1 mg. The results show that a high dose of exclusively short asbestos fibres produces minimal lung injury and fibrosis in spite of long standing macrophage-fibre interaction in the alveoli.

• Response of mouse lung to crocidolite asbestos. 2. Pulmonary fibrosis after long fibres. I.Y. Adamson, D.H. Bowden. 1987;152(2):109-17. PubMed · Publisher

  Abstract

  To determine the cellular and fibrogenic responses of the lung to long asbestos fibres, mice were instilled intratracheally with 0.1 mg of a sample of long crocidolite fibres. Animals were killed at intervals to 20 weeks with 3H thymidine injected one h before death. Following bronchoalveolar lavage, an increase in polymorph neutrophils (PMN) and alveolar macrophages (AM) was found during the first week, accompanied by elevated glucosaminidase and alveolar protein levels. Although the PMN number dropped, some were always recovered by lavage to 20 weeks. Early multifocal necrosis of bronchiolar epithelium was followed by a large increase in labelling of epithelial cells and underlying fibroblasts. Epithelial overgrowth of luminal long fibres and inflammatory exudates was followed by giant cell and granuloma formation in the interstitium. After four weeks collagen levels were significantly increased and fibrosis was seen in these peribronchiolar locations. A few small fibres were observed in AM but no evidence of fibrosis was seen in alveolar walls. These findings suggest that injury to bronchial and bronchiolar epithelium allows long fibres to reach the interstitium where subsequent macrophage-fibroblast interactions result in a severe fibrotic reaction that resembles the bronchiolar component of human asbestosis.

• Adenomatoid tumours: an immunohistochemical and ultrastructural appraisal of their histogenesis. T.J. Stephenson, P.M. Mills. 1986;148(4):327-35. PubMed · Publisher

  Abstract

  The histogenesis of adenomatoid tumour has continued to provoke debate since Golden and Ash suggested the term in 1945 for a characteristic benign neoplasm typically found in the uterus, fallopian tube or epididymis. Endothelial, epithelial, mesonephric, müllerian and mesothelial histogenesis have been suggested. The balance of evidence suggests mesothelial derivation, but two recent studies point to endothelial origin for at least some of these tumours. Twenty-two histologically typical adenomatoid tumours were studied by electron microscopy, mucin histochemistry and immunohistochemistry. Ultrastructurally, all cases showed vacuolated cells bearing long bushy microvilli and the features were not those of endothelial cells. Glandular spaces contained acid mucopolysaccharide consistent with hyaluronic acid. Immunohistochemical double labelling techniques showed the cells lining such spaces to contain cytokeratin in the absence of factor VIII related antigen and receptors for Ulex europaeus I lectin which were expressed in the endothelium of tumour blood vessels. The evidence points to mesothelial histogenesis in all cases examined.

• Evaluation of PAS-diastase and carcinoembryonic antigen staining in the differential diagnosis of malignant mesothelioma and papillary serous carcinoma of the ovary. P.B. Silcocks, A. Herbert, D.H. Wright. 1986;149(2):133-41. PubMed · Publisher

  Abstract

  A series of malignant mesotheliomas and papillary serous carcinomas of the ovary were stained using the periodic acid Schiff reaction with diastase digestion (PAS-D) and an immunoperoxidase technique for carcinoembryonic antigen (CEA). The methods were evaluated in terms of repeatability and validity. Staining reactions were classed as positive or negative by three 'blinded' observers. Within-observer repeatability was greater for PAS-D than for CEA but there was no statistically significant difference for between-observer repeatability. The validity of the methods clearly differed, however, since the sensitivity and specificity of CEA were consistently less than that of PAS-D. Our most consistent estimates of sensitivity and specificity were compared with those of other studies and the reasons for this difference were analysed. Positive PAS-D and CEA staining were uncorrelated but a combination of the two did not appear significantly superior to PAS-D alone. We believe that PAS-D remains the method of choice for differentiating peritoneal mesotheliomas and disseminated papillary serous carcinoma of the ovary in the absence of reliable evidence of an ovarian primary because the significance of CEA positivity in occasional mesothelial tumours remains to be determined.

• Bronchiolar and alveolar lesions in the pathogenesis of crocidolite-induced pulmonary fibrosis in mice. D.H. Bowden, I.Y. Adamson. 1985;147(4):257-67. PubMed · Publisher

  Abstract

  Asbestosis is generally considered to result in restrictive pulmonary disease associated with interstitial fibrosis. Recently, however, attention has focused upon bronchiolar lesions and concomitant obstruction to air flow. The responses of conducting airways and alveoli were studied over a 20 week period following instillation of crocidolite to mice. The location of the lesions and the sequential inflammatory changes were studied by bronchoalveolar lavage, light and electron microscopy; regenerative activity was monitored by autoradiographs. Within 48 h there was multifocal necrosis of bronchiolar epithelium, maximal at bifurcations where longer fibres tend to adhere. Subsequently, intralumenal exudates were overgrown by epithelium and incorporated into the bronchiolar connective tissue where active peribronchiolar granulomas persisted until 20 weeks. Alveolar lesions were located predominantly in peribronchiolar air sacs and at the junctions of bronchioles and alveolar ducts. Focal acute injury of type 1 cells and transepithelial passage facilitated transport of short asbestos fibres to the interstitium where they were phagocytozed by macrophages. Regenerative activity was prompt with active division of type 2 epithelial cells. Biochemically, collagen increased after 4 weeks, when fibrosis was predominantly located in the bronchiolar lumens and in peribronchiolar connective tissue with lesser amounts in the centrilobular alveolar interstitium. The results suggest that the longer fibres induce bronchiolar injury and a more severe fibrotic pattern similar to the recently described changes seen in human asbestosis.

• Fine structural changes in cryptogenic fibrosing alveolitis and asbestosis. B. Corrin, A. Dewar, R. Rodriguez-Roisin, et al. 1985;147(2):107-19. PubMed · Publisher

  Abstract

  Lung biopsies from 17 patients with cryptogenic fibrosing alveolitis of a cellular rather than fibrotic pattern were examined by transmission electron microscopy in the hope that such cases would show features of pathogenetic significance. Further selection was made by choosing minimally affected areas. There was no ultrastructural evidence of immune complex deposition but alveolar epithelial and capillary damage was frequently found (17 and 14 of the 17 cases respectively). Alveolar epithelial injury consisted of patchy necrosis and regenerative hyperplasia. Alveolar capillary injury consisted of cytoplasmic swelling and basement membrane thickening and reduplication. Many of these features have not been emphasized in previous reports and their prominence in early stages of the disease suggest that they may have pathogenetic significance, possible mechanisms of which are discussed. Similar findings identified during the course of this study in 8 asbestos workers suggest that similar pathogenetic mechanisms may operate in asbestosis.

• Diagnosis of pleural malignant mesothelioma in life--a practical approach. D. Whitaker, K.B. Shilkin. 1984;143(3):147-75. Review PubMed · Publisher

  Abstract

  This review documents a practical approach to the pathological diagnosis of pleural malignant mesothelioma based on the closed needle biopsy and effusion cytology, thus avoiding the need to resort to open surgery. Tissue diagnosis is often difficult, and the pathologist's opinion may be influenced by a consideration of three factors: the clinical setting; the adequacy and availability of specimens; and the criteria for assessment and interpretation of these. The level of confidence with which a tissue diagnosis of mesothelioma can be established using limited material depends on there being an appropriate clinical background including a history of asbestos exposure. Without this, the diagnosis should be a qualified or tentative one. For an adequate tissue sample to be obtained, the closed needle biopsy procedure is best performed by an experienced operator. All aspirated pleural effusions should be forwarded for cytological evaluation. In addition to conventional morphological studies, adequate samples permit ancillary tests to be carried out. A combined interpretive approach utilizing both histopathology and cytology is recommended in order to increase the accuracy of the diagnosis.

• Transport of inhaled dust to extrapulmonary sites. P.F. Holt. 1981;133(2):123-9. PubMed · Publisher

  Abstract

  A histological study of the lungs of guinea-pigs that inhaled carbon, chrysotile asbestos or crocidolite asbestos dust indicated that dust particles in macrophages move through alveolar walls towards the pleura. After some weeks accumulations of dust-filled macrophages were found near to pulmonary blood vessels. Macrophages that ingested carbon appeared to be much less mobile than those that ingested carbon appeared to be such less mobile than those that ingested asbestos. In sections from the animals that inhaled asbestos, macrophages were found that were penetrating the wall of blood vessels, dust is transferred to extrapulmonary sites by macrophages in the blood

1970s

• Corpora amylacea in mesothelioma of the atrioventricular node. R. David, Y. Hiss. 1978;124(2):111-6. Case report PubMed · Publisher

  Abstract

  Rounded or polyhedral, acellular, dense lamellated structures were seen within gland-like spaces in a case of atrioventricular mesothelioma. These structures exhibited many of the histochemical characteristics of amyloid, viz., pink colour with green birefringence and bright red fluorescence with alkaline Congo red; ortochromasia and red birefringence with standardised toluidine blue; positive DMAB-nitrite and diazotisation coupling reactions and spontaneous autofluorescence. It is suggested that these bodies are derived from spontaneous assembly or polymerisation of microfibrils of desquamated cells lining the cystic spaces of the tumour as occurs in prostatic corpora amylacea. The peculiar intramyofibre proliferation of tumour cells in the peripheral part of the tumour suggests that viable tumour cells can penetrate, survive and proliferate within atrial or nodal myofibres leaving an intact sarcolemmal sheath. The slow tumour cell growth and the successive degeneration of central tumour cells may explain the tubular and/or glandular pattern constantly seen in this tumour.

• Ultrastructure of the lung in the rat following exposure to crocidolite asbestos and quartz. K. Miller, I. Webster, R.I. Handfield, et al. 1978;124(1):39-44. PubMed · Publisher

  Abstract

  Lung tissue from rats that had inhaled U.I.C.C. crocidolite asbestos or quartz particles showed thickening of the interstitial tissue and the presence of collagen fibres. Aggregates of macrophages in the alveolar spaces were a dominant feature of all the sections examined from asbestos exposed rats. According to the ultrastructural studies described here, all the macrophages were mature cells, indicating that the ingested crocidolite asbestos was non-toxic. Lung sections of rats exposed to quartz particles were significantly different. Single cells were found in the alveolar spaces and many macrophages showed a characteristic pattern of vacuole formation. Other cells contained intracellular membranous lamellated bodies, similar to those found in Type II pneumocytes. Cells containing lamellated bodies were also found in the interstitial tissue. These findings suggest that the two mineral dusts have quite different biological effects on the macrophage and that the development of pulmonary fibrosis may, to some extent, be caused by a different mechanism in each instance.

• Primary epithelial tumour in the right atrium of the heart and inferior vena cava in NZR/gd inbred rats; pathology of 18 cases. C.M. Goodall, G.S. Christie, J.V. Hurley. 1975;116(4):239-51. PubMed · Publisher

  Abstract

  In NZR/Gd inbred albino rats, tumours occurred in the right atrium or inferior vena cava of approximately 20 per cent. of untreated animals, of both sexes, over the age of 1 yr. The tumours were centred in the wall of the right atrium in 15 cases, and in the inferior vena cava in another three cases; they appeared to be primary in these sites. The tumours were slowly growing, but eventually malignant. Light- and electron-microscopic study showed the tumours were composed of epithelial alveoli imbedded in a collagenous connective tissue containing spindle cells and thin-walled blood capillaries. The epithelium varied from flat to low columnar, and often secreted mucoid material into the lumina, or sometimes into surrounding tissue. This tumour, for which the name atrio-caval epithelial mesothelioma is suggested, very closely resembles a rare epithelial tumour of the right atrium previously described in humans under a variety of names. An underlying embryological anomaly had been postulated in these tumours in humans, and the occurrence of pathologically similar lesions in high incidence in hearts of NZR/Gd inbred rats should help test the hypothesis of genetic and developmental causes in the genesis of this rare cardiac neoplasm.

• Asbestos-body formation in the lungs of rats and guinea-pigs after inhalation of anthophyllite. S.K. Botham, P.F. Holt. 1972;107(4):245-52. PubMed · Publisher

  Abstract

  Within a month after inhalation of anthophyllite some anthophyllite asbestos fibres develop into asbestos bodies in the lungs of guinea-pigs, but asbestos bodies are rarely found in rats similarly exposed even allowing a development time of 18 mth. In both species diapedesis of erythrocytes through pulmonary capillary walls occurs soon after the anthophyllite is inhaled and Perls-positive granules result. From this ferruginous material the asbestos-body coating is produced.

  In both species, fibres and ferruginous material are cleared from the lungs by individual macrophages. In the guinea-pig, but seldom in the rat, some macrophages fuse in the alveolar regions to produce giant cells. The giant cells are removed less efficiently than macrophages; some block alveoli or bronchioles, others remain in the interalveolar septa. Thus the asbestos fibres and the ferruginous material required for the production of asbestos bodies are cleared more readily from the rat lung.

  Ferruginous material is normally deposited on only one asbestos fibre when several are present in a cell. The fusion of several cells to form a giant cell means that more ferruginous material is available for asbestos-body formation.

  PubMed has no abstract for this study. This is the authors' abstract, copied from the article.

• Development of asbestos bodies on amosite, chrysotile and crocidolite fibres in guinea-pig lungs. S.K. Botham, P.F. Holt. 1971;105(3):159-67. PubMed · Publisher

  Abstract

  When amosite, chrysotile and crocidolite asbestos fibres were inhaled by guinea-pigs, the fibres were distributed throughout the lungs. Some fibres were ingested by macrophages, and Perls-positive material, apparently derived from red cells, was deposited on them. Other intracellular fibres remained uncoated during the year after dusting, but after a further 6 mth uncoated chrysotile fibres were not found; there were a few anthophyllite fibres but rather more crocidolite, whilst amosite fibres were still common. Both crocidolite and amosite fibres showing early stages in coating were common 18 mth after the dusts were inhaled.

  The morphological development of asbestos body coating followed the sequence : smooth, corrugated, partially beaded, and fully beaded. Occasionally the asbestos body, if more than 20 µm in length, fragmented before being entirely beaded and the fragments were ingested by surrounding macrophages. These changes were similar to those previously seen following the inhalation of anthophyllite asbestos, but the rates of development differed, the changes being more rapid with chrysotile, slower with crocidolite and slower still with amosite, as determined by changes with time in the percentages of the various stages in the sequence of asbestos body development. There was no apparent morphological difference between asbestos bodies at the same stage of development although formed on different types of asbestos fibres.

  PubMed has no abstract for this study. This is the authors' abstract, copied from the article.

• The association of phagocytosed asbestos dust with lysosome enzymes. B.A. Smith, J.M. Davis. 1971;105(3):153-7. PubMed · Publisher

  Abstract

  The occurrence of acid phosphatase in guinea-pig granulomas produced by the intrapleural injection of asbestos dust was investigated by histochemical staining combined with electron microscopy. It was found that the acid phosphatase reaction was confined to the lysosome series of organelles, but that not all of these structures gave a positive reaction. In dust-containing macrophages and giant cells, often fewer than 50 per cent of primary lysosomes and as few as 10 per cent. of dust-containing phagosomes showed evidence of acid phosphatase. There was no increase in enzyme activity between 2 and 4 wk. When fibroblasts were present in the granulomas these usually contained small amounts of chrysotile dust. In these cells, however, both primary lysosomes and dust-containing phagosomes were positive for acid phosphatase in the majority of cases. The implication of these findings on the toxicity of chrysotile asbestos dust is discussed.

  PubMed has no abstract for this study. This is the authors' abstract, copied from the article.

• The development of glass-fibre bodies in the lungs of guinea-pigs. S.K. Botham, P.F. Holt. 1971;103(3):149-56. PubMed · Publisher

  Abstract

  Guinea-pigs were kept in an atmosphere that contained glass-fibre particles of submicron diameter. Much of the dust retained in the lung was later cleared in the bronchiolar debris as both extra- and intra-cellular fibres. Some fibres were uncoated 18 mth after inhalation.

  The dust caused leakage of red cells from alveolar capillaries. Haemolysis of these cells was followed by the appearance of iron-containing material in alveolar macrophages.

  Deposition of iron-containing material on intracellular glass fibres produced structures morphologically identical with asbestos bodies. These glass-fibre bodies also showed similar stages in their development, the original smooth coating becoming successively corrugated and beaded and finally separating into beads, so exposing the fibre which then fragmented.

  The main difference lay in the timing of these changes, since coating of a glass fibre, its subsequent beading and fragmentation, were more rapid than with anthophyllite asbestos.

  PubMed has no abstract for this study. This is the authors' abstract, copied from the article.

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