bims-mesote Biomed News
on Mesothelioma
Issue of 2021‒11‒14
fourteen papers selected by
Laura Mannarino
Humanitas Research
  1. Malignant Pleural Mesothelioma Nodal Status: Where Are We at?
  2. ATG7 immunohistochemical expression in Malignant Pleural Mesothelioma. A preliminary report.
  3. Incidence, mortality and survival in malignant pleural mesothelioma before and after asbestos in Denmark, Finland, Norway and Sweden.
  4. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p.
  5. Extended Pleurectomy/Decortication for Malignant Pleural Mesothelioma: Humanitas's Experience.
  6. Serum Calretinin as a Biomarker in Malignant Mesothelioma.
  7. Insights into Intra-Tumoral Heterogeneity: Transcriptional Profiling of Chemoresistant MPM Cell Subpopulations Reveals Involvement of NFkB and DNA Repair Pathways and Contributes a Prognostic Signature.
  8. Malignant Pleural Effusion in Malignant Pleural Mesothelioma: An Innocent Bystander?
  9. Case of a 57-Year-Old Man With Malignant Mesothelioma Presenting With Miliary Nodules on Chest Imaging.
  10. The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target.
  11. IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma.
  12. A case of nonislet cell tumor hypoglycemia associated with malignant mesothelioma requiring a multifaceted approach for optimal glycemic control.
  13. Histology of the pleural rind at [18F]FDG PET/CT hot and cold spots in mesothelioma patients after talc pleurodesis and neoadjuvant chemotherapy.
  14. UHRF1 Immunohistochemical Staining Separates Benign Reactive Spindle Cell Mesothelial Proliferations From Sarcomatoid Mesotheliomas.
  1. J Clin Med. 2021 Nov 05. pii: 5177. [Epub ahead of print]10(21):
    Malignant Pleural Mesothelioma Nodal Status: Where Are We at?
    Sara Ricciardi, Francesco Carleo, Massimo O Jaus, Marco Di Martino, Luigi Carbone, Alberto Ricci, Giuseppe Cardillo.
      Due to the lack of both prospective trial and high-volume retrospective studies, the management of clinical N+ malignant pleural mesothelioma (MPM) patients remains highly debated. Node positive patients show poor survival compared with node-negative ones; thus, lymph node staging appears crucial in determining treatment strategy. Notwithstanding the improvement in pre-treatment staging and the update on lymph node classification in the 8th edition of TNM, several open controversies remain on N parameter. How should we stage suspected N+ patients? How should we treat node positive patients? Which is the definition of a "resectable patient"? Is the site or the number the main prognostic factor for node positive patients? The aim of our narrative review is to analyse the existing relevant literature on lymph node status in MPM.
    Keywords:  malignant pleura mesothelioma; node positive MPM; prognostic factors; staging; surgery
    DOI:  https://doi.org/10.3390/jcm10215177
  2. Histol Histopathol. 2021 Nov 11. 18396
    ATG7 immunohistochemical expression in Malignant Pleural Mesothelioma. A preliminary report.
    Venerando Rapisarda, Giuseppe Broggi, Rosario Caltabiano, Claudia Lombardo, Sergio Castorina, Angela Trovato, Caterina Ledda, Veronica Filetti, Carla Loreto.
      Literature evidence has demonstrated a high incidence of asbestos-related malignant pleural mesothelioma (MPM) in a Sicilian town (Biancavilla, Italy), where fluoro-edenite (FE) fibers were discovered some decades ago. As ATG7 immunohistochemical analysis has been ascribed as a prognostic tool of improved survival, we decided to investigate, in MPM patients, exposed and not exposed to FE fibers, the immunohistochemical expression of this autophagy-related protein named ATG7. We analyzed the correlation between ATG7 immunohistochemical level and clinicopathological parameters. Twenty MPM tissue samples, from patients with available clinical and follow-up data, were included in paraffin and processed for immunohistochemistry. The immunohistochemical results confirmed activation of the autophagic process in MPM. Densitometric and morphometric expressions of ATG7 were significantly increased in MPMs when compared to the control tissues. A significant association of a high level of ATG7 with increased survival was demonstrated, with a mean overall survival (OS) of 12.5 months for patients with high expression vs. a mean OS of 4.5 months for patients with low ATG7 expression. In addition, a significant correlation between ATG7 expression and the survival time of MPM patients was observed. This study represents a starting point to hypothesize the prognostic role of ATG7 which could be a reliable prognostic indicator in MPM.
    DOI:  https://doi.org/10.14670/HH-18-396
  3. BMC Cancer. 2021 Nov 08. 21(1): 1189
    Incidence, mortality and survival in malignant pleural mesothelioma before and after asbestos in Denmark, Finland, Norway and Sweden.
    Kari Hemminki, Asta Försti, Tianhui Chen, Akseli Hemminki.
      BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but fatal cancer, which is largely caused by exposure to asbestos. Reliable information about the incidence of MPM prior the influence of asbestos is lacking. The nationwide regional incidence trends for MPM remain poorly characterized. We use nationwide MPM data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to assess incidence, mortality and survival trends for MPM in these countries.METHODS: We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1958 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization.
    RESULTS: The lowest incidence that we recorded for MPM was 0.02/100,000 for NO women and 0.05/100,000 for FI men in 1953-57, marking the incidence before the influence of asbestos. The highest rate of 1.9/100,000 was recorded for DK in 1997. Female incidence was much lower than male incidence. In each country, the male incidence trend for MPM culminated, first in SE around 1990. The regional incidence trends matched with earlier asbestos-related industrial activity, shipbuilding in FI and SE, cement manufacturing and shipbuilding in DK and seafaring in NO. Relative 1-year survival increased from about 20 to 50% but 5-year survival remained at or below 10%.
    CONCLUSION: In the Nordic countries, the male incidence trends for MPM climaxed and started to decrease, indicating that the prevention of exposure was beneficial. Survival in MPM has improved for both sexes but long-term survival remains dismal.
    Keywords:  Age-specific incidence; Birth cohort analysis; Incidence trends; Regional incidence; Relative survival; Risk factors
    DOI:  https://doi.org/10.1186/s12885-021-08913-2
  4. Open Med (Wars). 2021 ;16(1): 1653-1667
    MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p.
    Pei Wang, Cuiwei Bai, Shasha Shen, Chang Jiang, Jie Deng, Dan Han.
      The aim of this study was to clarify the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in proliferation, migration, and invasion of malignant pleural mesothelioma (MPM) cells. The quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect the expression of MALAT1 in MPM cell lines. The effects of MALAT1 and miR-141-3p on the proliferation, migration, and invasion of MPM cells were studied through a series of in vitro cellular experiments. The flow cytometry was utilized to detect the cell apoptosis. The dual-luciferase reporter assay was employed to explore the binding relationship among MALAT1, miR-141-3p, and YES-associated protein 1 (YAP1). MALAT1 was overexpressed in MPM cell lines, while its knockdown significantly inhibited the cell proliferation, migration, and invasion, and increased the number of MPM cells in the G0/G1 phase. In addition, MALAT1 could directly bind to miR-141-3p and inhibit its expression. YAP1 has been identified as a downstream target of miR-141-3p, and its expression level was inhibited by miR-141-3p. MALAT1 can be used as a competitive endogenous RNA (ceRNA) to regulate the YAP1-Hippo signaling pathway through miR-141-3p, promote the proliferation, migration, and invasion of MPM cells, and provide a new target for the therapy of MPM.
    Keywords:  YAP1-Hippo; lncRNA MALAT1; malignant pleural mesothelioma; miR-141-3p; signaling pathway
    DOI:  https://doi.org/10.1515/med-2021-0383
  5. J Clin Med. 2021 Oct 26. pii: 4968. [Epub ahead of print]10(21):
    Extended Pleurectomy/Decortication for Malignant Pleural Mesothelioma: Humanitas's Experience.
    Giuseppe Mangiameli, Edoardo Bottoni, Emanuele Voulaz, Umberto Cariboni, Alberto Testori, Alessandro Crepaldi, Veronica Maria Giudici, Emanuela Morenghi, Marco Alloisio.
      BACKGROUND: We analysed a series of malignant pleural mesothelioma (MPM) patients who consecutively underwent extended Pleurectomy/Decortication (eP/D) in a centre with a high level of thoracic surgery experience (IRCCS Humanitas Research Hospital) to explore postoperative morbidity and mortality, pattern of recurrence and survival.METHODS: A retrospective analysis was performed on MPM patients underwent eP/D in our centre from 2010 to 2021. All patients were identified from our departmental database. Postoperative complications were scored according to Clavien-Dindo criteria. Survival analysis was performed by the Kaplan-Meier methods and Cox multivariable analysis.
    RESULTS: Eighty-five patients underwent extended pleurectomy decortication (eP/D) during study period. Macroscopical residual disease (R2) was reported in one case. A neoadjuvant chemotherapy regiment was administrated in 88% of the surgical cohort. A complete trimodality treatment including induction with platinum agents and pemetrexed, radical cytoreductive surgery and volumetric modulated arc therapy technology (VMAT) could be administered in 63 patients (74%). Postoperative morbidity rate was 54.11%, major complications (defined as Clavien-Dindo ≥ 3) were reported in 11 patients (12.9%). Thirty-day mortality and 90-day mortality were, respectively, 2.35% and 3.53%. Median disease-free and overall survival were, respectively, 13.7 and 25.5 months. The occurrence of major complications (Clavien-Dindo ≥ 3), operative time, pT3-T4, pathological node involvement (pN+) were prognostic factors associated with worse survival.
    CONCLUSIONS: In our experience, eP/D is a well-tolerated procedure with acceptable mortality and morbidity, allowing for the administration of trimodality regimens in most patients. eP/D offered in a multimodality treatment setting have satisfactory long term oncological results. To obtain best oncological results the goal of surgery should be macroscopic complete resection in carefully selected patients (clinical N0).
    Keywords:  extended pleurectomy/decortication (eP/D); malignant pleural mesothelioma; trimodality treatment
    DOI:  https://doi.org/10.3390/jcm10214968
  6. J Clin Med. 2021 Oct 22. pii: 4875. [Epub ahead of print]10(21):
    Serum Calretinin as a Biomarker in Malignant Mesothelioma.
    Cita Zupanc, Alenka Franko, Danijela Štrbac, Metoda Dodič Fikfak, Viljem Kovač, Vita Dolžan, Katja Goričar.
      The early diagnosis of malignant mesothelioma (MM) could improve the prognosis of MM patients. To confirm an MM diagnosis, an immunohistochemical analysis of several tumor tissue markers, including calretinin, is currently required. Our aim is to evaluate serum calretinin as a potential biomarker in asbestos-related diseases, especially in MM. Our study includes 549 subjects: 164 MM patients, 117 subjects with asbestosis, 195 subjects with pleural plaques and 73 occupationally asbestos-exposed subjects without asbestos-related diseases. The serum calretinin concentration was determined with a commercially available enzyme immunoassay. Data on the soluble mesothelin-related peptides (SMRP) concentration are available from previous studies. MM patients had a significantly higher calretinin concentration than subjects without disease, subjects with pleural plaques or subjects with asbestosis (all p < 0.001). The histological type was significantly associated with serum calretinin: patients with sarcomatoid MM had lower calretinin than patients with the epithelioid type (p = 0.001). In a ROC curve analysis, the area under the curve for calretinin concentration predicting MM was 0.826 (95% CI = 0.782-0.869; p < 0.001). At the cutoff value of 0.32 ng/mL, sensitivity was 0.683, while specificity was 0.886. The combination of calretinin and SMRP had the highest predictive value. Calretinin is a useful biomarker that can distinguish MM from other asbestos-related diseases and could, therefore, contribute to an earlier non-invasive diagnosis of MM.
    Keywords:  asbestos-related disease; biomarker; calretinin; malignant mesothelioma
    DOI:  https://doi.org/10.3390/jcm10214875
  7. Int J Mol Sci. 2021 Nov 08. pii: 12071. [Epub ahead of print]22(21):
    Insights into Intra-Tumoral Heterogeneity: Transcriptional Profiling of Chemoresistant MPM Cell Subpopulations Reveals Involvement of NFkB and DNA Repair Pathways and Contributes a Prognostic Signature.
    Mario Cioce, Andrea Sacconi, Harvey I Pass, Claudia Canino, Sabrina Strano, Giovanni Blandino, Vito Michele Fazio.
      Chemoresistance is a hallmark of malignant pleural mesothelioma (MPM) management and the expression of ALDH1A3 is responsible for the survival and activity of MPM chemoresistant cell subpopulations (ALDHbright cells). We enriched mesothelioma ALDHbright cells to near homogeneity by FACS sorting and an Aldefluor assay and performed unbiased Affymetrix gene expression profiling. Viability and ELISA assays were used to rule out significant apoptosis in the sorted cell subpopulations and to assess target engagement by butein. Statistical analysis of the results, pathway enrichment and promoter enrichment were employed for the generation of the data. Q-RTPCR was used to validate a subset of the identified, modulated mRNAs In this work, we started from the observation that the mRNA levels of the ALDH1A3 isoform could prognostically stratify MPM patients. Thus, we purified MPM ALDHbright cells from NCI-H2595 cells and interrogated their gene expression (GES) profile. We analyzed the GES of the purified cells at both a steady state and upon treatment with butein (a multifunctional tetrahydroxy-chalcone), which abates the ALDHbright cell number, thereby exerting chemo-sensitizing effects in vitro and in vivo. We identified 924 genes modulated in a statistically significant manner as a function of ALDH status and of the response to the inhibitor. Pathway and promoter enrichment identified the molecular determinant of high ALDH status and how butein treatment altered the molecular portrait of those chemoresistant cell subpopulations. Further, we unraveled an eighteen-gene signature with high prognostic significance for MPM patients, and showed that most of the identified prognostic contributors escaped the analysis of unfractionated samples. This work proves that digging into the unexplored field of intra-tumor heterogeneity (ITH) by working at the cell subpopulation level may provide findings of prognostic relevance, in addition to mechanistic insights into tumor resistance to therapy.
    Keywords:  ALDH; Cancer Stem Cell (CSC); DNA repair; NFkB; butein; chemoresistance; gene expression; intra-tumoral heterogeneity (ITH); mesothelioma
    DOI:  https://doi.org/10.3390/ijms222112071
  8. Chest. 2021 Nov;pii: S0012-3692(21)01343-X. [Epub ahead of print]160(5): 1602-1603
    Malignant Pleural Effusion in Malignant Pleural Mesothelioma: An Innocent Bystander?
    Sanjeevan Muruganandan, Victor Duong.
      
    DOI:  https://doi.org/10.1016/j.chest.2021.06.074
  9. Chest. 2021 Nov;pii: S0012-3692(21)03612-6. [Epub ahead of print]160(5): e523-e526
    Case of a 57-Year-Old Man With Malignant Mesothelioma Presenting With Miliary Nodules on Chest Imaging.
    Stephanie Baltaji, Erica Rabold, Lamé Balikani, Timothy Mickus, Sohini Ghosh.
      CASE PRESENTATION: A 57-year-old man with history of stage IIIB right-sided malignant pleural mesothelioma was admitted from his oncologist's office for progressive dyspnea of two weeks duration. He had associated dyspnea at rest and a new dry cough. He denied sputum production, hemoptysis, or fevers, but he did endorse chills, fatigue, and weight loss. The patient was a veteran of the Navy and had extensive international travel in his 20s. He had never been incarcerated and denied any sick contacts or recent travels. He had received a diagnosis of mesothelioma 11 months earlier after presenting to his physician's office with complaints of shortness of breath on exertion. Initial imaging revealed a large right-sided pleural effusion with irregular pleural thickening. He underwent right-sided thoracoscopy, and the pleural biopsy result was consistent with epithelioid mesothelioma. Because of invasion of his seventh rib, he was not a candidate for surgery and underwent palliative radiation and chemotherapy with cisplatin, pemetrexed, and bevacizumab. He was undergoing his eighth cycle of chemotherapy at the time of presentation.
    DOI:  https://doi.org/10.1016/j.chest.2021.07.2161
  10. Int J Mol Sci. 2021 Oct 23. pii: 11452. [Epub ahead of print]22(21):
    The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target.
    Pınar Çakılkaya, Rikke Raagaard Sørensen, Henrik Jessen Jürgensen, Oliver Krigslund, Henrik Gårdsvoll, Christoffer F Nielsen, Eric Santoni-Rugiu, Niels Behrendt, Lars H Engelholm.
      Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients' asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.
    Keywords:  ADC; CD280; Endo180; MRC2; antibody-drug conjugate; extracellular matrix; immunohistochemistry; mesothelioma; tumor microenvironment; uPARAP
    DOI:  https://doi.org/10.3390/ijms222111452
  11. J Clin Med. 2021 Nov 07. pii: 5196. [Epub ahead of print]10(21):
    IRF3 Knockout Results in Partial or Complete Rejection of Murine Mesothelioma.
    Masaya Aoki, Licun Wu, Junichi Murakami, Yidan Zhao, Hana Yun, Marc de Perrot.
      BACKGROUND: Malignant pleural mesothelioma (MESO) has a poor prognosis despite aggressive treatment with surgery, radiation and chemotherapy, and novel therapeutic approaches are needed. IRF3 is a downstream molecule of the cGAS/STING signaling pathway, but its roles have not been investigated in MESO.METHODS: Various murine mesothelioma cell lines were inoculated into wild type (WT) and IRF3 knockout (IRF3KO) mice to compare tumor growth. AE17-bearing mice were treated with local radiotherapy (LRT) to evaluate the effect on tumor growth, and immune cell infiltration was analyzed by flow cytometry 20 days after tumor inoculation. TCGA data were used to examine the relationship between mRNA expression of IRF3 and genes of the cGAS/STING signaling cascade on prognosis in MESO. Correlations between gene expression of IRF3, cGAS/STING signaling pathway, and immune checkpoints were analyzed in TCGA MESO and our scRNA-Seq data from MESO patients.
    RESULTS: In mouse mesothelioma models, AK7, RN5 and ZiP3 were completely rejected in IRF3KO mice 20 days after the tumor challenge. AE17tumor volume was slightly larger than WT mice around day 10 before shrinking and becoming significantly smaller than WT mice on day 20. LRT accelerated tumor shrinkage of AE17 tumors in IRF3KO mice. Compared with WT mice, the number of macrophages infiltrating the tumor of IRF3KO mice was significantly reduced, and CD4+ T cells and CD8+IFNγ+ T cells were significantly increased. TCGA data showed that IRF3 expression was an unfavorable prognostic factor in MESO patients. IRF3 expression, the cGAS/STING signaling pathway, and immune checkpoints were positively correlated.
    CONCLUSION: IRF3 could play a critical role in the tumor immune microenvironment of MESO.
    Keywords:  IRF3 knockout (IRF3KO); cGAS/STING signaling pathway; immune checkpoints; interferon regulatory factor 3 (IRF3); malignant pleural mesothelioma (MESO)
    DOI:  https://doi.org/10.3390/jcm10215196
  12. Clin Case Rep. 2021 Oct;9(10): e05028
    A case of nonislet cell tumor hypoglycemia associated with malignant mesothelioma requiring a multifaceted approach for optimal glycemic control.
    Mariko Ono, Yuki Maeda, Nobuyuki Koyama, Terumasa Nagase, Yoshiya Katsura, Hiroyuki Nakamura, Kazutetsu Aoshiba.
      Nonislet tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome characterized by refractory hypoglycemia, which often requires multifaceted therapy. We reported a case of a patient with pleural malignant mesothelioma and developed NICTH, for which chemotherapy, glucocorticoids, and nutrition were given to achieve optimal glycemic control.
    Keywords:  hypoglycemia; insulin‐like growth factor II; mesothelioma
    DOI:  https://doi.org/10.1002/ccr3.5028
  13. Pathol Res Pract. 2021 Oct 19. pii: S0344-0338(21)00321-6. [Epub ahead of print]228 153660
    Histology of the pleural rind at [18F]FDG PET/CT hot and cold spots in mesothelioma patients after talc pleurodesis and neoadjuvant chemotherapy.
    Alex Soltermann, Isabelle Opitz, Irene A Burger.
      The role of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in evaluating induction chemotherapy in pleural mesothelioma (PM) patients is debated. We compared histology at tumor sites with high versus low [18F]FDG uptake in order to define a morphologic correlate for persistent metabolic activity. Twenty PM patients with talc pleurodesis and induction chemotherapy followed by extrapleural pleuro-pneumonectomy (EPP, n = 17) or tumor debulking (n = 3) were included. All patients received a PET/CT scan prior to surgery. Orthogonal tissue sections of pleural rind (n total=86) were taken at areas of maximum standardized uptake value (SUVmax, n = 53) and of low [18F]FDG uptake (n = 33) and scored on hematoxylin-eosin and immunohistochemical stainings. Total metabolic activity was scored semiquantitatively. Mean SUVmax of hot and cold spots correlated with total metabolic activity per patient, but no correlation was found with ypT and tumor cells were present in both hot and cold areas. SUVmax of only hot spots and cold versus hot spots as well as cold versus hot patients correlated with increased thickness of total pleural rind and fibrosis reaction, but not thickness of vital tumor cells or giant cell reaction. They further correlated with increased expression of glucose transporter 1 (GLUT1) in giant cells but not mesothelioma amount, density, vitality or vascularization. Biphasic histology was associated with SUVmax in only hot spots and higher total metabolic activity (all p-values <0.05). Interpretation of [18F]FDG PET/CT in PM patients is difficult after talc pleurodesis and induction chemotherapy. High glucose turnover is mostly related to fibro-inflammatory remodeling of the pleural rind and GLUT1 transporter expression in giant cells. Response assessment using this technology should only be done to assess extra-thoracic lesions.
    Keywords:  Induction chemotherapy; Pleural mesothelioma; Positron emission tomography; Tumor regression
    DOI:  https://doi.org/10.1016/j.prp.2021.153660
  14. Am J Surg Pathol. 2021 Nov 15.
    UHRF1 Immunohistochemical Staining Separates Benign Reactive Spindle Cell Mesothelial Proliferations From Sarcomatoid Mesotheliomas.
    Hang Yang, Simon Cheung, Andrew Churg.
      The separation of benign from malignant mesothelial proliferations is often a difficult pathologic problem. UHRF1 (ubiquitin-like with plant homeodomain and ring finger domains-1) is a regulator of DNA methylation and an epigenetic driver of various human cancers. It has recently been reported that UHRF1 is overexpressed in mesotheliomas. We asked whether UHRF1 immunohistochemistry could be used to separate benign from malignant mesothelial proliferations. Initial studies showed that UHRF1 stained mesothelial cells but also endothelial and other non-neoplastic cells, so that accurate counting of positive mesothelial cells was difficult. Therefore, we ran dual UHRF1-AE1/AE3 stains on 2 tissue microarrays containing 40 reactive mesothelial proliferations and 61 mesotheliomas and only counted UHRF1 staining in keratin-positive cells. On average 10.3±8.6% (mean±SD; range: 0% to 36, median: 6.8%) of epithelioid mesothelioma cells stained compared with 5.3±4.8% (range: 0% to 15%, median: 4.1%) of reactive epithelial mesothelial cells. This difference was statistically significant but there was too much overlap to use diagnostically. In contrast, 37±26% (range: 2.5% to 95%, median: 31%) of cells in sarcomatoid mesotheliomas compared with 1.2±1.2% (range: 0% to 3.0%, median: 1.0%) of cells in reactive spindle cell mesothelial proliferations stained. To confirm this difference we stained whole sections of 21 sarcomatoid mesotheliomas and 19 cases of organizing pleuritis. Staining of mesothelial cells was seen in 2.1±2.4% (range: 0% to 6.8%, median: 1.0%) of organizing pleuritis cases and 44±22% (range: 14% to 90%, median: 41%) of sarcomatoid mesotheliomas. We conclude that dual UHRF1-AE1/AE3 immunohistochemistry is very useful for separating benign spindle cell mesothelial proliferations from sarcomatoid mesotheliomas.
    DOI:  https://doi.org/10.1097/PAS.0000000000001840
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