Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens

Hwang, Harry C.; Sheffield, Brandon S.; Rodriguez, Stéphanie; Thompson, Kim; Tse, Christopher H.; Gown, Allen M.; Churg, Andrew

doi:10.1097/pas.0000000000000529

Cited by 147 publications

(137 citation statements)

References 19 publications

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“…8,9,[21][22][23][24][25] The aim of this study was to evaluate the utility of BAP1 IHC in the diagnosis of MM in effusions. To do this, we investigated the BAP1 protein expression on a large series of cell blocks from pleural/peritoneal effusions, with a definite diagnosis of MM or an uncertain diagnosis between MM and MH, and benign effusions.…”

mentioning

confidence: 99%

Loss of BRCA1‐associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions

Cozzi

Oprescu

Rullo

et al. 2017

Diagnostic Cytopathology

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Background: The important diagnostic challenge facing the cytopathologist is whether a mesothelial proliferation on effusions represents a malignant mesothelioma (MM) or a benign mesothelial hyperplasia (MH). Here, we evaluated the diagnostic utility of BAP1 immunohistochemistry (IHC) in distinguishing between reactive and neoplastic mesothelial cells. Methods:In pleural and peritoneal effusions from 147 patients with diagnosed MM or with a differential diagnosis of MM and MH, the expression of BAP1 was examined by IHC on paraffinembedded cell blocks (n 5 121) and biopsies (n 5 44). Included were also synchronous and methacronous cytology/biopsy pair samples. BAP1 IHC was evaluated for nuclear staining as positive or negative on target mesothelial cells, with appropriate internal control.Results: In MM cases, loss of BAP1 nuclear staining was observed in 76.5% of the cell blocks and 47.5% of the biopsies. All BAP1-negative cases with a differential diagnosis of benign and malignant mesothelial proliferations were MM at follow-up. All MH cases, the 29% of epithelial MM and the 90% of nonepithelial MM, retained BAP1 expression. Synchronous and methacronous biopsy/cytology pairs showed matching BAP1 results. Conclusion:In effusions with mesotheliomatous cells or atypical mesothelial cells of uncertain significance, negative BAP1 IHC strongly supports a diagnosis of MM. With prudence in interpreting immunostaining, BAP1 may be included in IHC panels for MM cytodiagnosis, given its high specificity and sensitivity. 1 An effusion is the only available sample in specific settings, as in the elderly or in patients with co-morbidities. Based on cytomorphology alone, the differential diagnosis between MM, mesothelial hyperplasia (MH), and metastatic carcinoma may be difficult. It is necessary to use ancillary techniques, primarily immunohistochemistry (IHC). 1 IHC markers to distinguish epithelioid MM from metastatic carcinoma are well-defined, 2,3 whereas those to distinguish epithelioid MM from MH are less definite, except for GLUT-1, IMP-3, Desmin, and EMA. Regarding the practical utility of the latter two markers, Desmin shows low sensitivity 4 and EMA shows low specificity. 5-7Recently, a new marker has been proposed to aid in distinguishing MM from MH, namely BRCA1-associated protein 1 (BAP1 The aim of this study was to evaluate the utility of BAP1 IHC in the diagnosis of MM in effusions. To do this, we investigated the BAP1 protein expression on a large series of cell blocks from pleural/peritoneal effusions, with a definite diagnosis of MM or an uncertain diagnosis between MM and MH, and benign effusions. BAP1 immunostaining was also performed on biopsy samples with the same diagnoses to evaluate the differences between effusion and tissue samples. | M A TE RI A L S A ND M E TH ODSThis study was designated as exempt by the ethics committee due to its retrospective nature; moreover, no protected health information The following formulae of BAP1 testing for the outcome MM were calculated: sensitivity, defined as ...

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mentioning

confidence: 99%

Loss of BRCA1‐associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions

Cozzi

Oprescu

Rullo

et al. 2017

Diagnostic Cytopathology

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“…BAP1 and p16 markers appeared to be exclusively unexpressed or deleted in MPM, and their application in clinical practice is strongly suggested (3). However, BAP1 and p16 are not deleted or lost in all MPM tumors, and even when used together, negative results cannot confirm the benign nature of the lesions (31,36).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, they have 100% specificity for MPM; however, their sensitivity ranges between 43-93% and 61-67% for p16 and BAP1, respectively (33)(34)(35). Combination of the two assays has been reported to increase sensitivity for MPM diagnosis up to 90% in some studies; however, specificity is always 100% (29,33,36). Moreover, BAP1 and p16 have been specifically investigated for the discernment between sarcomatous and desmoplastic mesotheliomas from benign organizing pleuritis.…”

Section: Diagnostic Markers By Ihc or Fishmentioning

confidence: 99%

“…In the first part of our study, we analyzed mRNA from FFPE tissues of 36 (57). In the second part of our study, we utilized classification models to determine the diagnostic category of 14 pleural tissues (test samples) blindly analyzed, and all samples were correctly attributed to their diagnostic category (9 epithelioid MPM and 5 MH).…”

Section: New Diagnostic Toolsmentioning

confidence: 99%

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Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review

Bruno¹,

Alì²,

Fontanini³

2018

J. Thorac. Dis.

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Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with asbestos exposure. Histopathological analysis of pleural tissues is the gold standard for diagnosis; however, it can be difficult to differentiate malignant from benign pleural lesions. The purpose of this review is to describe the most important biomarkers and new diagnostic tools suggested for this differential diagnosis. There are many studies concerning the separation between MPM and benign pleural proliferations from both pleural tissues or effusions; most of them are based on the evaluation of one or few biomarkers by immunohistochemistry (IHC) or enzyme-linked immunosorbent assays (ELISAs), whereas others focused on the identification of MPM signatures given by microRNA (miRNA) or gene expression profiles as well as on the combination of molecular data and classification algorithms. None of the reported biomarkers showed adequate diagnostic accuracy, except for p16 [evaluated by fluorescent in situ hybridization (FISH)] and BAP1 (evaluated by IHC), both biomarkers are recommended by the International Mesothelioma Interest Group guidelines for histological and cytological diagnosis. BAP1 and p16 showed a specificity of 100% in discerning malignant from benign lesions because they are exclusively unexpressed or deleted in MPM. However, their sensitivity, even when used together, is not completely sufficient, and absence of their alterations cannot confirm the benign nature of the lesion. Recently, the availability of new techniques and increasing knowledge regarding MPM genetics led to the definition of some molecular panels, including genes or miRNAs specifically deregulated in MPM, that are extremely valuable for differential diagnosis. Moreover, the development of classification algorithms is facilitating the application of molecular data for clinical practice. Data regarding new diagnostic tools and MPM signatures are absolutely promising; however, before their application in clinical practice, a prospective validation is necessary, as these approaches could surely improve the differential diagnosis between malignant and benign pleural lesions.

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“…Interestingly, molecular analysis of p16 by FISH could be particularly advantageous in the differential diagnosis of desmoplastic mesothelioma due to the high frequency of p16 homozygous deletion reported in the literature in this variant of MPM. On the other hand, immunohistochemical BAP1 loss is rarely present in sarcomatous and desmoplastic mesothelioma, demonstrating its limited value in this setting (51).…”

Section: Fibrous Organizing Pleuritis Versus Desmoplastic Mpmmentioning

confidence: 99%

The pathological and molecular diagnosis of malignant pleural mesothelioma: a literature review

Alì¹,

Bruno²,

Fontanini³

2018

J. Thorac. Dis.

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on the application of a panel including positive (mesothelial-related) and negative markers with greater than 80% sensitivity and specificity, which need to be selected based on morphology and clinical information.Moreover, in challenging cases, fluorescent in situ hybridization (FISH) testing for the p16 deletion and IHC to evaluate the loss of BRCA1-associated protein 1 (BAP1) expression could be useful in distinguishing benign from malignant pleural proliferations.

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Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens

Cited by 147 publications

References 19 publications

Loss of BRCA1‐associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions

Loss of BRCA1‐associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions

Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review

The pathological and molecular diagnosis of malignant pleural mesothelioma: a literature review

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