Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas

Chiosea, Simion I.; Krasinskas, Alyssa M.; Cagle, Philip T.; Mitchell, Kisha A.; Zander, Dani S.; Đačić, Sanja

doi:10.1038/modpathol.2008.45

Cited by 192 publications

(176 citation statements)

References 26 publications

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“…However, the prevalence of homozygous CDKN2A deletions and hemizygous NF2 loss in peritoneal mesotheliomas is less than those reported for pleural mesotheliomas. 16,[21][22][23]26,32 In addition, the most frequent abnormality in peritoneal mesotheliomas was the loss of BAP1 protein expression rather than homozygous CDKN2A deletions. An explanation for the disparities between peritoneal and pleural mesotheliomas remains elusive, but not surprising as both entities are clinically and pathologically distinct.…”

Section: Discussionmentioning

confidence: 99%

“…22,23,32 CDKN2A was assessed using a Spectrum-Orange labeled, locus-specific probe (Abbott Molecular, Des Plains, IL, USA) with a Spectrum Green-labeled chromosome 9 centromeric (CEP9) probe. 22 Probes for NF2 assessment included a FITC-labeled chromosome 22 centromeric (CEP22q) probe and a Texas Red-labeled, locusspecific NF2 probe (Abnova, Walnut, CA, USA).…”

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

“…Staining of tissue microarrays and whole sections were performed as previously described using 4-μm unstained paraffin sections. 22,23 Each core on the tissue microarrays was identified and only individual and well-delineated cells were scored; overlapping cells were excluded from the analysis. For both tissue microarrays and whole sections, at least 60 cells were scored for each case and control.…”

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

“…Each tumor was assessed by the average and the maximum numbers of copies of the either CDKN2A or NF2 per cell and the average ratio of the gene to CEP9 and CEP22q copy numbers, respectively. 22,23,35 Immunohistochemistry Immunohistochemical labeling was performed on 4-μm unstained paraffin sections for both the tissue microarrays and whole sections. Slides were deparaffinized with serial xylene treatments and subjected to antigen retrieval using heated citrate solution (pH 9.0) at 100 o C for 10 min.…”

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

“…Homozygous deletions in CDKN2A are the most frequent genetic alteration in pleural mesothelioma with a reported deletion rate ranging from 60 to 74% by fluorescence in situ hybridization. [21][22][23] In addition, homozygous CDKN2A deletions are a poor prognostic indicator for patients with pleural mesothelioma. 22,24,25 NF2, located on chromosome 22q12, is mutated in 50% of pleural mesotheliomas with corresponding loss of the wild-type allele by deletion of either 22q or all of chromosome 22.…”

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confidence: 99%

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The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

et al. 2016

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Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n = 25, 29%), hemizygous NF2 loss (n = 30, 35%), and/or loss of BAP1 protein expression (n = 49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progressionfree survival (Po 0.02) and poor overall survival (Po 0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (Po 0.01) and overall survival rate of 18% with a median of 8 months (Po 0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

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Section: Discussionmentioning

confidence: 99%

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

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confidence: 99%

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The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

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Utility of BerEp4/calretinin and desmin/epithelial membrane antigen (EMA) dual immunocytochemical staining in effusion cytology

et al. 2022

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Background: Pleural mesothelioma (PM) is typically diagnosed late during the disease. Earlier detection can increase the chance of effective therapy.Recurrent pleural effusions are the earliest symptoms displaying an array of cytomorphological changes from reactive atypia to malignancy. Diagnosis is possible on effusion cytology by applying molecular and immunocytochemical markers, the main difficulty being when to suspect PM and to differentiate PM from metastatic adenocarcinoma and reactive mesothelial proliferations. Methods: We evaluated the diagnostic performance of two immunocytochemical dual stains (BerEp4/Calretinin and Desmin/Epithelial Membrane Antigen (EMA)) on 149 ethanol-fixed cytospin preparation as an initial step to solve the mentioned diagnostic difficulty. The immunocytochemical reactivity pattern was evaluated by two independent investigators. The final diagnosis corresponded to PM (n = 20), metastatic adenocarcinoma (n = 83), and mesotheliosis (n = 46) in these cases.Results: Calretinin had 99% specificity and 98% sensitivity for indicating a mesothelial phenotype, while BerEp4 distinguished the adenocarcinoma cases with 98% specificity and 99% sensitivity. EMA displayed 96% specificity and 99% sensitivity in malignant cases, while Desmin without EMA present showed 99% specificity and 96% sensitivity for indicating benign mesothelial proliferation.Conclusions: Interpretation of the four immunoreactions is improved when performed as dual stains. The dual staining is a useful tool in the initial handling of atypical effusions and guides the subsequent choice of antibody panels for more detailed subclassification of malignant effusions.

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Cytogenetics and fluorescence in situ hybridization as adjuncts to cytology in the diagnosis of malignant mesothelioma

Factor

Cin

Fletcher

et al. 2009

Cancer Cytopathology

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BACKGROUND: Virtually all malignant mesotheliomas (MMs) exhibit clonal chromosomal aberrations. Although the chromosome regions affected by these aberration(s) may vary from 1 tumor to another, certain regions are commonly disrupted. These aberrations are absent in benign mesothelial cells, and therefore their presence can be used to confirm a diagnosis of MM. In the current study, the authors investigated the value of karyotyping and fluorescence in situ hybridization (FISH) as adjuncts to conventional cytologic examination in patients with MM. METHODS: A retrospective analysis of 48 pleural or peritoneal fluids from patients with histologically confirmed MM was performed. Karyotypic analyses were attempted in all cases. In 27 cases, FISH for deletions of 9p21 (CDKN2A gene) and 22q was also performed because the karyotype was normal or unsuccessful. RESULTS: Karyotypes were obtained in 35 (73%) of the specimens. Of these, 15 (43%) were abnormal and 20 (57%) were normal. Thirteen additional abnormal results were detected by FISH in cases for which the karyotypes were normal or unsuccessful. A total of 24 cases (50%) had an associated cytologic interpretation. Karyotyping or FISH was abnormal in 8 cases that were interpreted cytologically as either negative or suspicious. CONCLUSIONS: The combination of FISH and karyotyping was found to improve on the diagnostic sensitivity of karyotyping alone in detecting MM in effusions. The authors concluded that karyotyping and FISH together were a more useful adjunct to cytology than FISH or karyotyping alone. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.

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Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas

Cited by 192 publications

References 26 publications

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

Utility of BerEp4/calretinin and desmin/epithelial membrane antigen (EMA) dual immunocytochemical staining in effusion cytology

Cytogenetics and fluorescence in situ hybridization as adjuncts to cytology in the diagnosis of malignant mesothelioma

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