Cytoplasmic MTAP expression loss detected by immunohistochemistry correlates with 9p21 homozygous deletion detected by FISH in pleural effusion cytology of mesothelioma

Hamasaki, Makoto; Kinoshita, Yoshiaki; Yoshimura, Masayo; Matsumoto, Shinji; Kamei, Toshiaki; Hiroshima, Kenzo; Sato, Ayuko; Tsujimura, Tohru; Kawahara, Katsunobu; Nabeshima, Kazuki

doi:10.1111/his.13872

Cited by 34 publications

(35 citation statements)

References 5 publications

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“…They also defined loss as nuclear and cytoplasmic staining of less intensity than the internal positive control of inflammatory cells . In our experience, this approach may be problematic because cytoplasmic staining is consistently present (in intact cases) but nuclear staining is very variable, and in fact in a subsequent letter the same group suggested that cytoplasmic loss correlates best with CDKN2A homozygous deletion …”

Section: Discussionmentioning

confidence: 98%

Usefulness of methylthioadenosine phosphorylase and BRCA‐associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens

Berg

Churg

Cheung

et al. 2019

Cancer Cytopathology

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BACKGROUND:The separation of benign from malignant mesothelial proliferations on effusion cytology can be difficult.Loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry is an established marker of malignancy in mesothelial proliferations, but to the authors' knowledge largely has been applied only to biopsies. The current study was conducted to determine the usefulness of MTAP immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens. METHODS: A total of 21 effusion cytology cases of malignant mesothelioma were stained for MTAP and BRCA-associated protein 1 (BAP1), with 15 reactive mesothelial cytology cases used as a control. Fourteen cases had a paired surgical specimen for comparison, and 7 cases were run for CDKN2A deletion by fluorescence in situ hybridization. RESULTS: Complete loss of MTAP cytoplasmic staining was noted in 7 of 21 effusion samples (33%), and no loss was observed in 11 effusion samples (52%); 11 of these cases had a matching surgical specimen and all 11 specimens demonstrated the same MTAP pattern. Partial loss was observed in 3 effusion specimens (80%, 40%, and 40% intact staining, respectively), but in all 3 the surgical specimen demonstrated 100% staining. None of the 15 reactive mesothelial cytology specimens demonstrated MTAP cytoplasmic loss. CDKN2A FISH demonstrated concordance in 5 of 7 cases (71%). MTAP immunohistochemistry had a sensitivity of 33% and a specificity of 100% for this differential diagnosis. CONCLUSIONS: MTAP staining demonstrated generally good concordance between the cytologic and surgical specimens and appears to be useful in the diagnosis of mesothelioma on effusion specimens. Complete loss of MTAP is a reliable marker of malignancy, but the significance of partial loss of MTAP staining is unclear. Cancer Cytopathol 2020;128:126-132.

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Section: Discussionmentioning

confidence: 98%

Usefulness of methylthioadenosine phosphorylase and BRCA‐associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens

Berg

Churg

Cheung

et al. 2019

Cancer Cytopathology

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“…Immunostaining was performed with either the anti-MTAP mouse monoclonal antibody (clone 2G4; Abnova, Taipei, Taiwan; 1:100 dilution; room temperature (RT) 30 min) or antihuman BAP1 mouse monoclonal antibody (clone C4, 1:50 dilution; RT 45 min; Santa Cruz Biotechnology, Santa Cruz, CA, USA) using previously described methods. 27,28,32,35,45,46 BAP1 IHC/ICC was performed on both cell blocks and smear preparations. Meanwhile, MTAP IHC was limited only to cell blocks because MTAP ICC does not perform well in smear preparations in our experience (unpublished data).…”

Section: Ihc Assaymentioning

confidence: 99%

“…MTAP IHC revealed cytoplasmic as well as nuclear staining, and MTAP loss as detected by IHC was defined as cytoplasmic staining at an intensity lower than the internal positive control. 27,28,32,45,46 We evaluated the reactivity in at least 100 mesothelial cells per sample. We have previously observed a bimodal distribution in the proportion of mesothelioma cells positive for BAP1 or MTAP IHC; 27,28 stain-positive cases exhibit a high proportion of positivity (>70%), and stain-negative cases exhibit a low proportion of positivity (<30%).…”

Section: Ihc Assaymentioning

confidence: 99%

Genomic‐based ancillary assays offer improved diagnostic yield of effusion cytology with potential challenges in malignant pleural mesothelioma

Kinoshita

Hamasaki

Matsumoto

et al. 2020

Pathology International

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BRCA1‐associated protein 1 (BAP1) or methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) or 9p21 fluorescence in situ hybridization (FISH) are useful for the diagnosis of malignant pleural mesothelioma (MPM). However, the effect of these assays on the diagnostic yield of effusion cytology in MPM cases with suspicious cytomorphology or the diagnostic challenges in BAP1 or MTAP IHC have not been fully elucidated. Two cohorts of cytologic preparations obtained from pleural effusions were examined: MPM cases in cohort 1 were used to evaluate whether BAP1 or MTAP IHC or 9p21 FISH increase the diagnostic yield of effusion cytology; cohort 2 included cases suspicious for MPM, to which BAP1 or MTAP IHC was applied to clarify the challenges in the clinical assessment of these assays. In cohort 1 (n = 28), either assay elevated 62.5% of class II or III cases to class V. In cohort 2 (n = 139), 21.7% of BAP1 immunocytochemistry in smears and 10.6% of BAP1 IHC and 9.4% of MTAP IHC in cell blocks, were identified to be challenging. The application of genomic‐based assays increased the diagnostic yield of effusion cytology in the diagnosis of MPM. However, diagnostic challenges limit the application of these assays in some cases.

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“…Recent studies have suggested that immunohistochemistry for MTAP can be used as a surrogate marker for CDKN2A/p16 deletion. [34][35][36][37][38] The rationale for this observation is that the MTAP gene is frequently codeleted with the CDKN2A/p16 gene. 28,39,40 Our study also confirms that mesotheliomas can be difficult to diagnose in fluid cytology due to significant morphologic overlap between benign, reactive, and malignant mesothelial proliferations.…”

Section: Discussionmentioning

confidence: 99%

Testing for BAP1 loss and CDKN2A/p16 homozygous deletion improves the accurate diagnosis of mesothelial proliferations in effusion cytology

Chevrier

Jerome

Galateau-Sallé

et al. 2020

Cancer Cytopathology

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BACKGROUND: A number of ancillary tests have been developed that aid in the diagnosis of mesothelioma in cytology specimens. The aim of this retrospective study was to determine whether testing for BAP1 and CDKN2A/p16 status in effusion specimens preceding the tissue diagnosis of mesothelioma would improve diagnostic accuracy and allow an earlier diagnosis of malignancy. METHODS: The study cohort included 99 matched cytology fluid specimens from 74 patients with a surgical specimen diagnosis of malignant mesothelioma (67 epithelioid, 7 biphasic, 55 pleural, and 19 peritoneal). BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) were performed retrospectively. RESULTS: BAP1 or p16 FISH testing revealed a loss in 7 of 18 (39%) samples originally categorized as benign/reactive, 20 of 33 (61%) interpretable samples categorized as atypical, and 10 of 14 (71%) cases suspicious for mesothelioma. In some cases, the diagnosis of mesothelioma could have been made up to 9 months before biopsy. Similarly, loss of BAP1 or p16 was found in 28 of 30 (93%) samples categorized as malignant, with some cases diagnosable up to 6 months before biopsy. Overall, loss of BAP1 and/or CDKN2A/p16 homozygous deletion would change the diagnostic interpretation in 37 of 60 (62%) (P = .07) effusion specimens, particularly in pleural effusions (32 of 48 samples) (P = .002). The sensitivity of morphologic interpretation alone was 30.3%; however, adding testing for BAP1 and p16 resulted in an increase in sensitivity to 68.7%. (P < .0001). CONCLUSION: These findings suggest that routine use of BAP1 immunochemistry and p16 FISH as adjunctive tests improves the diagnostic accuracy of cytology specimens and potentially allows an earlier diagnosis of malignant mesothelioma. Cancer Cytopathol

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Cytoplasmic MTAP expression loss detected by immunohistochemistry correlates with 9p21 homozygous deletion detected by FISH in pleural effusion cytology of mesothelioma

Cited by 34 publications

References 5 publications

Usefulness of methylthioadenosine phosphorylase and BRCA‐associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens

Usefulness of methylthioadenosine phosphorylase and BRCA‐associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens

Genomic‐based ancillary assays offer improved diagnostic yield of effusion cytology with potential challenges in malignant pleural mesothelioma

Testing for BAP1 loss and CDKN2A/p16 homozygous deletion improves the accurate diagnosis of mesothelial proliferations in effusion cytology

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