Atypical Mesothelial Hyperplasia Research Articles

Investigation of HEG1, VISTA (VSIR) and PD-L1 expression levels in malignant mesothelioma by immunohistochemical methods and their relationship with histological subtypes

Malignant Mesothelioma is a primary malignant tumor of the mesothelium lining the pleura, pericardium, peritoneum and tunica vaginalis of the testis with a poor prognosis. The epithelioid subtype is graded as high and low grade in the 2021 WHO classification of thoracic tumors. Recently, promising results from clinical trials of treatment with immune checkpoint inhibitors are reported. The aim of our study was to shed light on clinical studies on potential immune checkpoint inhibitors by examining VISTA and PD-L1 expression levels as well as HEG1 in malignant mesothelioma subtypes. Our study included 69 cases diagnosed with ‘malignant mesothelioma, well-differentiated papillary mesothelial tumor, atypical mesothelial hyperplasia’ at Dicle University Faculty of Medicine Department of Pathology between 2015 and 2021. Primary antibodies against HEG1, VISTA, and PD-L1 were used in the immunohistochemical study. The results showed a significant relationship between PD-L1 expression and sarcomatoid and high-grade epithelioid malignant mesotheliomas. VISTA was detected at a high rate in epithelioid malignant mesotheliomas and was negative in non-mesothelial tumors. HEG1 was positively monitored in mesothelial-derived tumors and negatively monitored in non-mesothelial tumors. The obtained results suggest that HEG1 could be further explored as a useful marker in determining mesothelial origin and that the expression levels of VISTA and PD-L1 markers may vary in histological subtypes in the selection of drugs for the treatment of malignant mesothelioma.

HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma

Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.

About the diagnostic value of BAP-1 antibody in malignant pleural mesothelioma: a meta-analysis

ABSTRACTBackground: The positive diagnosis of MPM is based on morphologic features coupled with immunohistochemical findings. Many antibodies have been published especially in order to differentiate between malignant tumors and atypical mesothelial hyperplasia. BAP-1 is a BRCA1-binding protein whose loss of expression was frequently reported in MPM. Our aim was to assess the diagnostic value of this antibody in comparison to the most sensitive diagnostic antibody represented by the calretinin antibody.Methods: We performed a meta-analysis using the Meta-Disc software 5.1.32.Results: According to our inclusion criteria, 19 studies with 11 studies dealing with BAP1 antibody and 8 studies dealing with calretinin antibody were included. The SEN of BAP 1 and calretinin antibodies was respectively estimated to 54.6% and 86.5%. The SPE reached respectively 95.7% and 76.6%. The dOR was estimated respectively to 23.664 and 38.8. The I-square revealed a heterogeneity of the parameters studied. The metaregression analysis revealed as covariates the amplification system and the histologic subtype as causing effects of heterogeneity for BAP1 antibodies and histologic subtype and chromogene as causing effects of heterogeneity for calretinin antibody.Conclusion: This meta-analysis revealed that BAP1 antibody should be associated with more sensitive antibodies in order to assess the diagnosis.

Role of respiratory-triggered diffusion-weighted MRI in the assessment of pleural disease.

To evaluate the correlation between apparent diffusion coefficient (ADC) values and histopathological features in a cohort of patients with suspected malignant pleural disease. We evaluated 56 consecutive patients undergoing a chest MRI examination for clinical suspicion of malignant pleural disease; all patients underwent thoracoscopic biopsy for histological assessment. All MRI examinations were performed with a 1.5-T scanner using a dedicated protocol, including a respiratory-triggered diffusion-weighted sequence with three b-values (0, 100 and 750). The ADC values were calculated, and a statistical analysis was performed. The average ADC value in non-neoplastic pleural disease (NNPD) resulted in 1.84 ± 0.37 × 10-3 mm2 s-1, whereas we obtained an average value of 0.96 ± 0.19 × 10-3 mm2 s-1 in epitheliod, of 0.76 ± 0.33 × 10-3 mm2 s-1 in biphasic and of 0.67 ± 0.2 × 10-3 mm2 s-1 in sarcomatoid pleural mesotheliomas. Histology revealed the presence of malignant pleural mesothelioma (MPM) in 44 patients, chronic pleuritis in 8 patients and atypical mesothelial hyperplasia in 4 patients. Statistical analysis showed a significant difference between NNPD and MPM (p < 0.001) and between epithelioid and sarcomatoid MPM subtypes (p = 0.0004), whereas biphasic MPMs showed a wide range of overlapping with the other groups. We observed a statistically significant difference between NNPD, epitheliod and sarcomatoid subtypes of MPM regarding ADC values. Our study confirmed previous data regarding distribution of ADC values in pleural disease using a respiratory-triggered diffusion-weighted technique that allowed us to minimize motion artefacts and to reduct acquisition time.

Analysis of microRNA expression signatures in malignant pleural mesothelioma, pleural inflammation, and atypical mesothelial hyperplasia reveals common predictive tumorigenesis-related targets

Pleural chronic inflammation (PP) and mesothelial hyperplasia (HP) may be critical to the development of malignant pleural mesothelioma (MPM). Nonetheless, studies searching for mechanistic links involving microRNA (miRNA) regulation among these interrelated processes have not been reported. Using PCR-Array, we identified the miRNAs expressed in pleural tissues diagnosed with MPM (n=5), PP (n=4) and HP (n=5), as well as in non-cancerous/non-inflammatory tissue as the normal control (n=5). We performed bioinformatics and network analysis of differentially expressed miRNAs to identify tumorigenesis-related miRNAs and their biological networks. The targets of four down-regulated miRNAs in MPM (mir-181a-5p, miR-101-3p, miR-145-5p and miR-212-3p), one in PP (mir-101-3p) and one in HP (mir-494) were significantly enriched in “pathways in cancer”. Interactome networks revealed that >50% of down-regulated miRNAs in MPM targeted the signaling-activation molecule MAPK1, the transcription factor ETS1 and the mesenchymal transition-associated molecule FZDA, which have been associated with oncogenic function. Comparative analysis revealed that FZD4 was an overlapping gene target of down-regulated miRNAs that were associated with “pathways in cancer” in MPM, PP and HP. Moreover, MAPK1, ETS1 and Cox-2, a pro-inflammatory enzyme associated with over-expression in cancers, were among the 25 overlapping target genes in MPM and PP. This network analysis revealed a potential combinatory effect of deregulated miRNAs in MPM pathogenesis and indicated potential molecular links between pleural inflammation and hyperplasia with tumorigenesis mechanisms in pleura.

Atypical mesothelial hyperplasia mimicking mesothelioma in patient with metastatic papillary carcinoma of thyroid

Background: Atypical mesothelial hyperplasia (AMH) is characterized by rapid proliferation of mesothelial cells with cellular atypia secondary to pleural irritation. AMH is a diagnostic challenge and it is not always easy to differentiate from mesothelioma and metastatic carcinoma to pleura. Only few related case reports have been published so far. Case Presentation: Herein we present a case of an 80 year old Saudi woman, who was treated one year ago with total thyroidectomy and radioactive iodine ablation twice for metastatic papillary carcinoma of thyroid, presented with right pleural effusion which was positive for mesothelial cells and computed tomography of chest showed right pleural masses suspected for mesothelioma or metastatic papillary carcinoma, which turned out to be AMH on immunohistochemistry. Conclusion: AMH is rare benign manifestation which can be associated with underlying malignancy. Radioactive iodine therapy could be a possible cause. The radiological features of AMH resemble that of mesothelioma or metastatic carcinoma to pleura and immunohistochemistry is confirmatory.

P53 Expression in a Malignant Mesothelioma Patient during Seven-Year Follow-up.

Malignant mesothelioma (MM) is the aggressive tumor of serosal surfaces. There are crude pathogenetic results regarding the biology of MM. Coordinated upregulations of p53 gene expression are shown in malignancies. We believed that there are changes in the p53 expression with transformation from reactive hyperplasia to MM. A 65-year-old male was admitted the hospital because of left pleuritic chest pains in 2004. Chest computed tomography (CT) results showed left pleural effusions with loculation and pleural thickening. Pathologic findings revealed reactive mesothelial hyperplasia. In 2008, the patient again felt left pleuritic chest pains. Chest CT showed progressive thickening of the left pleura. Pathologic diagnosis was atypical mesothelial hyperplasia. In 2011, chest CT showed progressive thickening of his left pleura. He was diagnosed with well-differentiated papillary mesothelioma. Serial change was analyzed by immunohistochemical staining for p53 of pleural tissues. There were no remarkable changes in p53 expressions during the transformation to MM.

The Separation of Benign and Malignant Mesothelial Proliferations

The separation of benign from malignant mesothelial proliferations is crucial to patient management but is often a difficult problem for the pathologist. To review the pathologic features that allow separation of benign from malignant mesothelioma proliferations, with an emphasis on new findings. Literature review and experience of the authors. Invasion is still the most reliable indicator of malignancy. The distribution and amount of proliferating mesothelial cells are important in separating benignity from malignancy, and keratin stains can be valuable because they highlight the distribution of mesothelial cells. Hematoxylin-eosin examination remains the gold standard, and the role of immunochemistry is extremely controversial; we believe that at present there is no reliable immunohistochemical marker of malignancy in this setting. Mesothelioma in situ is a diagnosis that currently cannot be accurately made by any type of histologic examination. Desmoplastic mesotheliomas are characterized by downward growth of keratin-positive spindled cells between S100-positive fat cells; some cases of organizing pleuritis can mimic involvement of fat, but these fat-like spaces are really S100-negative artifacts aligned parallel to the pleural surface. Fluorescence in situ hybridization on tissue sections to look for homozygous p16 gene deletions is occasionally useful, but many mesotheliomas do not show homozygous p16 deletions. Equivocal biopsy specimens should be diagnosed as atypical mesothelial hyperplasia and another biopsy requested if the clinicians believe the process is malignant.

Dose‐dependent mesothelioma induction by intraperitoneal administration of multi‐wall carbon nanotubes in p53 heterozygous mice

Among various types of multi-wall carbon nanotubes (mwcnt) are those containing fibrous particles longer than 5 μm with an aspect ratio of more than three (i.e. dimensions similar to mesotheliomagenic asbestos). A previous study showed that micrometer-sized mwcnt (μm-mwcnt) administered intraperitoneally at a dose of 3000 μg/mouse corresponding to 1 × 109 fibers per mouse induced mesotheliomas in p53 heterozygous mice. Here, we report a dose-response study; three groups of p53 heterozygous mice (n = 20) were given a single intraperitoneal injection of 300 μg/mouse of μm-mwcnt (corresponding to 1 × 108 fibers), 30 μg/mouse (1 × 107) or 3 μg/mouse (1 × 106), respectively, and observed for up to 1 year. The cumulative incidence of mesotheliomas was 19/20, 17/20 and 5/20, respectively. The severity of peritoneal adhesion and granuloma formation were dose-dependent and minimal in the lowest dose group. However, the time of tumor onset was apparently independent of the dose. All mice in the lowest dose group that survived until the terminal kill had microscopic atypical mesothelial hyperplasia considered as a precursor lesion of mesothelioma. Right beneath was a mononuclear cell accumulation consisting of cd45- or cd3-positive lymphocytes and cd45/cd3-negative f4/80 faintly positive macrophages; some of the macrophages contained singular mwcnt in their cytoplasm. The lesions were devoid of epithelioid cell granuloma and fibrosis. These findings were in favor of the widely proposed mode of action of fiber carcinogenesis, that is, frustrated phagocytosis where the mesotheliomagenic microenvironment on the peritoneal surface is neither qualitatively altered by the density of the fibers per area nor by the formation of granulomas against agglomerates. (Cancer Sci 2012; 103: 1440–1444)

Metastatic Appendiceal Mucinous Adenocarcinoma to Well-Differentiated Diffuse Mesothelioma of the Peritoneal Cavity: A Mimicker of Florid Mesothelial Hyperplasia in Association With Neoplasms

Atypical/florid mesothelial hyperplasia associated with another neoplastic process is not an infrequent phenomenon and has been reported in a variety of tumors. In those instances, the mesothelial proliferation might create a misdiagnosis of metastatic carcinoma but seldom raises the possibility of a well-differentiated mesothelioma seeded by metastatic neoplastic cells. Herein, we report the case of a 40-year-old woman originally diagnosed with exuberant atypical mesothelial hyperplasia after an diagnostic laparoscopy. The subsequent operation, however, demonstrated a mucinous neoplasm of the appendix with involvement of the peritoneal cavity in the form of peritoneal mucinous carcinomatosis as well as metastases to the uterine serosa and adnexal surfaces. Microscopic analysis revealed an appendiceal adenocarcinoma with signet-ring-cell features that has metastasized to a diffuse well-differentiated mesothelioma of the peritoneal cavity. In many areas, the atypical mesothelial proliferation is indistinguishable from florid mesothelial hyperplasia. The true nature of the mesothelial proliferation was only confirmed after extensive additional sampling, which showed unequivocal stromal invasion. To the best of our knowledge, this is the first report of a metastatic appendiceal mucinous adenocarcinoma to a well-differentiated diffuse mesothelioma of the peritoneal cavity. Although commonly associated with atypical/ florid mesothelial hyperplasia, a carcinoma can rarely metastasize to a well-differentiated mesothelioma, which can pose significant diagnostic difficulties because it can mimic a reactive process. This unusual case report expands the spectrum of mesothelial proliferation in conjunction with a malignant neoplasm and serves to remind pathologists that such a concomitant occurrence exists.

Well-differentiated papillary mesothelioma occurring in the tunica vaginalis of the testis with contralateral atypical mesothelial hyperplasia

Well-differentiated papillary mesothelioma (WDPM) occurs rarely in the paratesticular region, with only a handful of published case reports. Often presenting with recurrent hydrocele, WDPM is a multifocal mesothelial proliferation with a predominantly indolent clinical course. Accordingly, pathologic distinction of this lesion from true malignant mesothelioma is crucial, although it may be difficult because of the variability of associated histologic features. In addition, rare cases of WDPM have progressed to malignant mesothelioma, leading to its classification as a tumor of low malignant potential. Here, we report a case of multifocal WDPM occurring in the tunica vaginalis and tunica albuginea, with contralateral atypical mesothelial hyperplasia, a potentially premalignant lesion.

Malignant mesothelioma eight years after a diagnosis of atypical mesothelial hyperplasia.

The separation of mesothelial hyperplasia from early malignant mesothelioma remains one of the most difficult problems in histopathology. Inconclusive cases are termed "atypical mesothelial hyperplasia" and treated expectantly. A 49...

Atypical mesothelial hyperplasia associated with bronchogenic carcinoma

Atypical mesothelial hyperplasia encountered in pleural fluid or in a pleural biopsy specimen raises the suspicion that one may be dealing with a diffuse malignant mesothelioma of the pleura. We studied eight cases with cytologic or histologic changes of mesothelial atypia thought to be suspicious for diffuse malignant mesothelioma. In each case, the hyperplasia was associated with a bronchogenic carcinoma in the lung subjacent to the mesothelial hyperplasia. Bronchogenic carcinoma should be added to the list of causes of atypical mesothelial hyperplasia. This combination of reactive and malignant processes should be appreciated, since pleural carcinomatosis and diffuse malignant mesothelioma must be separated for clinical and epidemiologic reasons.

Value of immunocytochemistry in the study of malignant effusions.

Recognition of malignant effusion relies heavily on cytologic examination despite the difficulty of distinguishing atypical mesothelial hyperplasia from metastatic carcinoma. The combination of CEA, EMA, vimentin, keratin, high-molecular-weight cytokeratin (HMWK), low-molecular-weight cytokeratin (LMWK), and Alcian blue was tested in 51 cytologic specimens of pleural, peritoneal, and pericardial effusions. These showed metastatic carcinoma in 38 cases (ovary, 14; lung, 8; breast, 7; GI, 4; endometrium, 4; bladder, 1) and mesothelial processes in 13 (hyperplasia, 9; mesothelioma, 4). Strong positivity for EMA (92%), CEA (90%), and Alcian blue (71%) was noted in metastatic carcinoma but not in the mesothelial processes. Keratin was positive in all cases of mesothelioma but occurred also in mesothelial hyperplasias (44%) and metastatic carcinomas (47%). In mesothelial cells, HMWK was consistently stronger than LMWK, whereas in adenocarcinoma the reverse was true. There was no difference in the degree or distribution of positivity of any of the markers among the various primary sites of the neoplasms. Our findings are consistent with the view that immunocytochemistry with a battery of antibodies is useful in the recognition of malignant effusions but cannot, as yet, determine the site of origin of metastatic neoplasms.