BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations

Our plain-English summary of BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations, by M. Cigognetti, S. Lonardi, S. Fisogni, et al (Modern Pathology, 2015).

The study

• Authors: M. Cigognetti, S. Lonardi, S. Fisogni, P. Balzarini, V. Pellegrini, A. Tironi, L. Bercich, M. Bugatti, G. Rossi, B. Murer, M. Barbareschi, S. Giuliani, A. Cavazza, G. Marchetti, W. Vermi, F. Facchetti
• Journal: Modern Pathology
• Published: 2015;28(8):1043-57
• Cited by: 213 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The distinction between malignant mesothelioma and reactive mesothelial proliferation can be challenging both on histology and cytology. Recently, variants of the BRCA1-associated protein 1 (BAP1) gene resulting in nuclear protein loss were reported in hereditary and sporadic mesothelioma. Using immunohistochemistry, we evaluated the utility of BAP1 expression in the differential diagnosis between mesothelioma and other mesothelial proliferations on a large series of biopsies that included 212 mesotheliomas, 12 benign mesothelial tumors, and 42 reactive mesothelial proliferations. BAP1 stain was also performed in 70 cytological samples (45 mesotheliomas and 25 reactive mesothelial proliferations). BAP1 was expressed in all benign mesothelial tumors, whereas 139/212 (66%) mesotheliomas were BAP1 negative, especially in epithelioid/biphasic compared with sarcomatoid/desmoplastic subtypes (69% vs 15%). BAP1 loss was homogeneous in neoplastic cells except for two epithelioid mesotheliomas showing tumor heterogeneity. By fluorescence in situ hybridization, BAP1 protein loss was paralleled by homozygous deletion of the BAP1 locus in the vast majority of BAP1-negative tumors (31/41, 76%), whereas 9/10 BAP1-positive mesotheliomas were normal. In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1-positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection.

In plain English

Pathologists from five Italian hospitals tested whether staining archived samples for the BAP1 protein helps tell mesothelioma from benign or reactive (non-cancerous) growth of lining cells. Samples included 212 mesothelioma biopsies, 12 benign mesothelial tumors, 42 reactive mesothelial proliferations, fluid (cytology) samples, and lung and ovarian cancers. All benign mesothelial tumors kept BAP1. BAP1 was lost in 139/212 (66%) mesotheliomas: 128/184 (70%) epithelioid, 9/15 (60%) biphasic, and 2/13 (15%) sarcomatoid or desmoplastic. Of 6 BAP1-negative reactive cases, 5 were later diagnosed with mesothelioma; the sixth patient died with abdominal metastases without a further biopsy. By comparison, 3/36 (8%) BAP1-positive reactive cases developed mesothelioma. In fluid samples, 29 of 45 mesotheliomas lacked BAP1. Only 2 of 184 lung adenocarcinomas lacked it entirely. Gene testing found homozygous BAP1 deletion in 31 of 41 BAP1-negative mesotheliomas. The authors concluded that BAP1 loss had 100% specificity for separating benign from malignant mesothelial proliferations, but lower sensitivity. Asbestos exposure was not analyzed. It appeared only as background, in some patients' histories and in descriptions of other research.

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: Retrospective diagnostic laboratory study of archived pathology samples using BAP1 immunohistochemistry, with BAP1 gene testing by fluorescence in situ hybridization (FISH) on a subset
• Who was studied: Archived samples from five Italian hospitals (Brescia, Modena, Reggio Emilia, Mestre, Trento). These were 212 mesothelioma biopsies from 212 patients (207 pleural, 5 peritoneal), 12 benign mesothelial tumors, and 42 reactive mesothelial proliferation biopsies from 41 patients. There were also 11 normal mesothelium controls. Cytology and cell-block samples comprised 45 mesotheliomas, 17 or 18 benign reactions, and 8 atypical indeterminate samples. Comparison tumors were 184 lung adenocarcinomas, 21 lung squamous cell carcinomas, 95 ovarian carcinomas and 8 lung epithelioid hemangioendotheliomas. Follow-up lasted up to 9 years.
• Exposure: Not an asbestos exposure study; no fiber types or doses were analyzed. The factor studied was loss of the BAP1 protein in mesothelial cells. Past asbestos exposure was noted for 15 of the pleural reactive proliferation cases.
• Main results:
  • All benign mesothelial tumors expressed BAP1
  • BAP1 was lost in 139/212 (66%) mesotheliomas
  • By subtype, BAP1 was lost in 128/184 (70%) epithelioid and 9/15 (60%) biphasic mesotheliomas
  • BAP1 loss was infrequent in sarcomatoid and desmoplastic mesotheliomas (2/13, 15%)
  • Among the 6 BAP1-negative reactive mesothelial proliferations, 5 were diagnosed with mesothelioma within 2 to 104 weeks, according to the Discussion
  • The sixth BAP1-negative reactive case was a peritoneal atypical proliferation. That patient died 4 years later with multiple abdominal metastases, and no further biopsy was done.
  • Among reactive mesothelial proliferations, 3/36 (8%) BAP1-positive cases had mesothelioma diagnosed later
  • In reactive proliferations, excluding 5 cases with pleural metastases, the authors reported that lack of BAP1 had a positive predictive value of 100% (95% CI 54 to 100%). They reported a negative predictive value of 90% (95% CI 74 to 98%) for developing mesothelioma.
  • For distinguishing benign mesothelial lesions from mesothelioma, specificity was 100% and sensitivity 66%. Sensitivity was 69% for epithelioid and biphasic subtypes only.
  • In cytology samples, 29 of 45 mesotheliomas (64%) were BAP1 negative
  • Of 8 cytology samples with atypical cells of uncertain nature, 6 were BAP1 negative, and all 6 were linked to a biopsy showing BAP1-negative mesothelioma
  • Among lung and ovarian carcinomas, only one acinar and one solid lung adenocarcinoma (of 184) were entirely BAP1 negative
  • Against lung and ovary carcinomas, BAP1 stain gave specificity and sensitivity of 99/70% and 100/70%, respectively
  • By FISH, homozygous deletion of the BAP1 gene was found in 31 of 41 BAP1-negative mesotheliomas (76%)
  • By FISH, homozygous BAP1 deletion was also found in 1 of 10 mesotheliomas that still expressed the BAP1 protein
• The authors' conclusion: The authors concluded that BAP1 loss had 100% specificity for distinguishing benign from malignant mesothelial proliferations, though with lower sensitivity. They also concluded that finding BAP1 loss in uncertain cases should prompt immediate reevaluation of the patient.
• Limitations the authors state:
  • Sensitivity of BAP1 loss for mesothelioma was lower than its specificity
  • One BAP1-negative peritoneal reactive case (patient died with multiple abdominal metastases) had no further biopsy to confirm mesothelioma
  • Follow-up of reactive proliferation cases was of variable duration

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma, Malignant Mesothelioma, Histology, Cytology, Immunohistochemistry, Differential Diagnosis, Epithelioid.

Related studies

• Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma — R. Pillappa, J.J. Maleszewski, et al. (2018)
• Diagnostic value of BRCA1-associated protein-1, glucose transporter-1 and desmin expression in the discrimination between reactive mesothelial proliferation and malignant mesothelioma in tissues and effusions — S. Önder, E. Özogul, et al. (2019)
• Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia — M. Yoshimura, Y. Kinoshita, et al. (2019)
• Differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells using the cell proliferation markers minichromosome maintenance protein 7, geminin, topoisomerase II alpha and Ki-67 — F. Kimura, I. Okayasu, et al. (2013)
• Utility of BRCA1-associated protein 1 immunoperoxidase stain to differentiate benign versus malignant mesothelial proliferations in cytologic specimens — Z. McCroskey, G. Staerkel, et al. (2017)
• Loss of BRCA1-associated protein 1 (BAP1) expression is rare in non-small cell lung cancer — D. Owen, B.S. Sheffield, et al. (2017)

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