Diagnostic mesothelioma biomarkers in effusion cytology

Our plain-English summary of Diagnostic mesothelioma biomarkers in effusion cytology, by A. Eccher, I. Girolami, E. Lucenteforte, et al (Cancer Cytopathology, 2021).

The study

• Authors: A. Eccher, I. Girolami, E. Lucenteforte, G. Troncone, A. Scarpa, L. Pantanowitz
• Journal: Cancer Cytopathology
• Published: 2021;129(7):506-516
• Type of article: Review
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1-associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology.

© 2021 American Cancer Society.

In plain English

This was a review of published evidence on biomarkers distinguishing malignant pleural mesothelioma from reactive, benign mesothelial cells in pleural fluid cytology samples. The authors called it a state-of-the-art review, not a formal quantitative analysis; it studied no patients or asbestos exposure. Citing earlier meta-analyses, they reported that soluble mesothelin in pleural fluid had sensitivity 0.79 (95% CI, 0.75-0.83) and specificity 0.85 (95% CI, 0.83-0.87) in one, and sensitivity 0.69 (95% CI, 0.64-0.72) and specificity 0.90 (95% CI, 0.85-0.94) in another. For BAP1 staining loss, one meta-analysis reported specificity 0.96 (95% CI, 0.89-0.99) and sensitivity 0.58 (95% CI, 0.50-0.65), with very low yield in sarcomatoid mesothelioma. p16 homozygous deletion by FISH, and loss of MTAP staining as its surrogate, were described as highly specific with variable sensitivity. Because p16 homozygous deletion also occurs in other cancers, that specificity applies only once cells are shown to be mesothelial. GLUT1 was described as informative only when positive. The authors concluded that no marker should be relied on alone and markers are best combined. They noted that systematic appraisals of these markers remain sparse, heterogeneous and mostly tissue-based.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review, which the authors call a state-of-the-art review, of published literature. It does not report new data.
• Who was studied: Published studies and earlier meta-analyses on diagnostic biomarkers for distinguishing pleural mesothelioma from reactive benign mesothelium in pleural effusion cytology specimens. The article gives no number of included studies and no search dates.
• Exposure: Not an exposure study. Asbestos is mentioned only as background on the cause of mesothelioma. The review concerns laboratory diagnostic markers: soluble mesothelin, fibulin-3, GLUT1, IMP3, BAP1, EZH2, 5-hmC, p16 FISH, MTAP and microRNAs.
• Main results:
  • Soluble mesothelin in pleural effusions, as reported by Cui et al (11 studies): pooled sensitivity 0.79 (95% CI, 0.75-0.83) and specificity 0.85 (95% CI, 0.83-0.87).
  • Soluble mesothelin, as reported in another review by Gao et al: sensitivity 0.69 (95% CI, 0.64-0.72) and specificity 0.90 (95% CI, 0.85-0.94) for malignant pleural mesothelioma.
  • Fibulin-3 in pleural effusions, as reported by Ren et al from a small number of studies: pooled sensitivity 0.73 (95% CI, 0.54-0.86) and specificity 0.80 (95% CI, 0.60-0.91).
  • GLUT1, from a meta-analysis by Zhong et al of 24 studies (969 mesothelioma patients, 1080 patients with reactive mesothelial cells): the text gives pooled sensitivity 0.73 (95% CI, 0.62-0.81) and specificity 0.95 (95% CI, 0.91-0.98). Table 1 gives different figures for the same source.
  • GLUT1 was described as informative only when it stains positive, because a negative stain does not exclude malignancy.
  • BAP1 loss, from a meta-analysis by Wang et al: pooled specificity 0.96 (95% CI, 0.89-0.99) and sensitivity 0.58 (95% CI, 0.50-0.65).
  • Studies cited for BAP1 showed 50% to 65% sensitivity in pleural mesotheliomas, with very low diagnostic yield in sarcomatoid mesothelioma.
  • CDKN2A/p16 homozygous deletion was reported in sarcomatoid (67%-100%), biphasic (69%-95%) and epithelioid (48%-70%) malignant pleural mesothelioma.
  • p16 homozygous deletion was described as highly specific, with sensitivity of 0.48-0.88 for mesothelioma overall.
  • Sensitivity of p16 homozygous deletion was slightly higher, 0.80-1.00, for sarcomatoid mesothelioma.
  • p16 homozygous deletion is also common in other cancers, so it cannot by itself separate mesothelioma from metastatic carcinoma.
  • Table 1 states that the high specificity of p16 homozygous deletion applies to a mesothelioma diagnosis only once the atypical cells have been shown to be mesothelial.
  • MTAP evaluation by immunohistochemistry, a surrogate for p16 homozygous deletion by FISH, showed high concordance with FISH, high specificity and variable sensitivity (0.45-0.65).
  • EZH2 on cell blocks, in one cited study: combining EZH2 with other markers increased sensitivity to 77.5%, and to 87.5% with 3 markers.
  • In the same cited study, EZH2 was also expressed in up to 30% of reactive (benign) cases.
• The authors' conclusion: The authors concluded that newer markers such as BAP1, p16 and MTAP are highly specific but still have unsatisfactory sensitivity, that no marker should be relied on alone, and that markers are best used in combination. They also stated that the best microRNA panel has not yet been established.
• Limitations the authors state:
  • The authors did not perform a systematic, formal quantitative analysis of each biomarker's diagnostic performance.
  • The authors described systematic appraisals of the diagnostic performance of many of these biomarkers as sparse and heterogeneous. They said these appraisals are based mostly on tissue (histological) samples and lack subgroup analysis.
  • The only systematic study of p16 diagnostic performance dates from 2012.
  • Most research on soluble markers used blood rather than pleural fluid samples.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Biomarker, Cytology, Malignant Mesothelioma, Prognosis, Pleural Biopsy, Mesothelial Cells, Pleural Effusion.

Related studies

• A combination of MTAP and BAP1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma — Y. Kinoshita, T. Hida, et al. (2018)
• Fluorescence in situ hybridization detection of chromosome 22 monosomy in pleural effusion cytology for the diagnosis of mesothelioma — Y. Kinoshita, M. Hamasaki, et al. (2021)
• Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens — H.C. Hwang, B.S. Sheffield, et al. (2016)
• Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens — K.B. Berg, A.M. Churg, et al. (2020)
• Proteome screening of pleural effusions identifies galectin 1 as a diagnostic biomarker and highlights several prognostic biomarkers for malignant mesothelioma — F. Mundt, H.J. Johansson, et al. (2014)
• Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology — J. Andrici, A. Sheen, et al. (2015)

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