BAP1 protein loss by immunohistochemistry: A potentially useful tool for prognostic prediction in patients with uveal melanoma

Shah, Akeesha A.; Bourne, T. David; Murali, Rajmohan

doi:10.1097/pat.0000000000000002

Cited by 71 publications

(64 citation statements)

References 20 publications

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“…28 Regarding the site of MM, peritoneal tumors showed a lower percentage of BAP1 negativity compared to pleural tumors (66% vs 71%, respectively), at variance with previous studies 16 ; however, this difference is not relevant. The finding of a positive BAP1 IHC result does not exclude a MM diagnosis, given that not all MMs harbor alterations of the BAP1 gene; moreover, it does not distinguish between MM and MH.…”

Section: Discussioncontrasting

confidence: 55%

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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Section: Discussioncontrasting

confidence: 55%

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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“…The association between RNA and immunohistochemistry suggests that a cut-off value of the BAP1 gene expression, for example, measured with a quantitative PCR, could be made to predict loss of BAP1 immunoreaction. Shah et al 45 and members of our group 32 have shown that immunohistochemistry for BAP1 protein expression might be an easy way to discriminate between long and short survival, and may even replace mutation analysis of BAP1 in uveal melanoma patients. In large uveal melanoma, loss of one copy of chromosome 3, together with gain of chromosome 8q, clearly leads to this specific gene expression profile known as class 2, which is associated with loss of BAP1 gene expression, and with metastases formation.…”

Section: Discussionmentioning

confidence: 99%

Prognostic parameters in uveal melanoma and their association with BAP1 expression

et al. 2014

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Aim To determine whether BAP1 gene and protein expression associates with different prognostic parameters in uveal melanoma and whether BAP1 expression correctly identifies patients as being at risk for metastases, following enucleation of the primary tumour. Methods Thirty cases of uveal melanoma obtained by enucleation between 1999 and 2004 were analysed for a variety of prognostic markers, including histological characteristics, chromosome aberrations obtained by fluorescence in situ hybridisation (FISH) and single nucleotide polymorphism (SNP) analysis and gene expression profiling. These parameters were compared with BAP1 gene expression and BAP1 immunostaining. Results The presence of monosomy of chromosome 3 as identified by the different chromosome 3 tests showed significantly increased HRs (FISH on isolated nuclei cut-off 30%: HR 11.6, p=0.002; SNP analysis: HR 20.3, p=0.004) for death due to metastasis. The gene expression profile class 2, based on the 15-gene expression profile, similarly provided a significantly increased HR for a poor outcome (HR 8.5, p=0.005). Lower BAP1 gene expression and negative BAP1 immunostaining (50% of 28 tumours were immunonegative) were both associated with these markers for prognostication: FISH cut-off 30% monosomy 3 (BAP1 gene expression: p=0.037; BAP1 immunostaining: p=0.001), SNP-monosomy 3 (BAP1 gene expression: p=0.008; BAP1 immunostaining: p=0.002) and class 2 profile (BAP1 gene expression: p<0.001; BAP1 immunostaining: p=0.001) and were themselves associated with an increased risk of death due to metastasis (BAP1 gene expression dichotomised: HR 8.7, p=0.006; BAP1 immunostaining: HR 4.0, p=0.010). Conclusions Loss of BAP1 expression associated well with all of the methods currently used for prognostication and was itself predictive of death due to metastasis in uveal melanoma after enucleation, thereby emphasising the importance of further research on the role of BAP1 in uveal melanoma.

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“…A second limitation was that tumor DNA adequate for sequencing all coding regions of the entire BAP1 gene (which was not required for the other 4 genes) was available in only 64 of 81 (79%) participants. However, most other studies have relied on immunohistochemistry for the presence of the BAP1 protein as a surrogate marker for BAP1 mutations, 22 which is associated with considerable false-positive and false-negative results, so our study provides important new insights based on validated mutations. A third limitation was that we performed targeted sequencing of only the 5 commonly mutated genes.…”

Section: Discussionmentioning

confidence: 99%

Driver Mutations in Uveal Melanoma

et al. 2016

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BAP1 protein loss by immunohistochemistry: A potentially useful tool for prognostic prediction in patients with uveal melanoma

Cited by 71 publications

References 20 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

Prognostic parameters in uveal melanoma and their association with BAP1 expression

Driver Mutations in Uveal Melanoma

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