MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma

Chapel, David; Schulte, Jefree J.; Berg, Kyra B.; Churg, Andrew; Đačić, Sanja; Fitzpatrick, Carrie; Galateau-Salle, Françoise; Hiroshima, Kenzo; Krausz, Thomas; Stang, Nolwenn Le; McGregor, Stephanie M.; Nabeshima, Kazuki; Husain, Aliya N.

doi:10.1038/s41379-019-0310-0

Cited by 123 publications

(117 citation statements)

References 28 publications

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“…40,47 In histologic specimens or cytologic preparations, the sensitivity of the differentiation has been reported to be 45-85% for 9p21 FISH, 14,[22][23][24][25]27,30 56-81% for BAP1 IHC 25,30,34 and 45-78% for MTAP IHC. 27,28,30,48 9p21 FISH, BAP1 IHC and MTAP IHC have 100% specificity for differentiating MPM from RMH/RMC. 18,[27][28][29][30]32,49 Therefore, the application of these genomic-based assays in effusion cytology is recommended to confirm the diagnosis of MPM.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…A total of 24 cases of malignant pleural mesothelioma effusion cytology with cell blocks were identified: 11 cases were from the University of Pittsburgh Medical Center and 13 cases were from Vancouver General Hospital in Vancouver, British Columbia, Canada. None of the surgical cases overlapped with cases from our prior publications . Cases either had a corresponding surgical biopsy (14 cases) or a purely cytologic diagnosis and clinical/radiologic data completely consistent with a malignant mesothelioma (10 cases).…”

Section: Methodsmentioning

confidence: 97%

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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“…Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and various other molecular markers (including epigenetic markers) have sufficient evidence behind their use however, some are still in their research stages, or yet to be used widely in clinical diagnosis. Recent studies showing homozygous loss of p16 (CDKN2A) by FISH, losses of BRCA-1 associated protein-1 (BAP1) and methylthioadenosine phosphorylase (MTAP) by IHC as being very specific for MPM (6)(7)(8)(9)(10)(11)(12)(13)(14). MTAP gene loss is usually co-deleted with p16 gene (8), and MTAP IHC loss is a good surrogate for p16 gene deletion, which is an additional useful option in current histopathological diagnosis (12).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies showing homozygous loss of p16 (CDKN2A) by FISH, losses of BRCA-1 associated protein-1 (BAP1) and methylthioadenosine phosphorylase (MTAP) by IHC as being very specific for MPM (6)(7)(8)(9)(10)(11)(12)(13)(14). MTAP gene loss is usually co-deleted with p16 gene (8), and MTAP IHC loss is a good surrogate for p16 gene deletion, which is an additional useful option in current histopathological diagnosis (12). Conversely, epigenetic markers such as DNA methylation profiles and micro RNA and circular RNA dysregulation, although supported by promising literature, are not used in clinical practice currently (2,6).…”

Section: Introductionmentioning

confidence: 99%

The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review

et al. 2020

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Malignant pleural mesothelioma (MPM) is an aggressive asbestos related disease that is generally considered to be difficult to diagnose, stage and treat. The diagnostic process is continuing to evolve and requires highly skilled pathology input, and generally an extensive list of biomarkers for definitive diagnosis. Diagnosis of MPM requires histological evidence of invasion by malignant mesothelial cells often confirmed by various immunohistochemical biomarkers in order to separate it from pleural metastatic carcinoma. Often when invasion of neoplastic mesothelial cells into adjacent tissue is not apparent, further immunohistochemical testing-namely BAP1 and MTAP, as well as FISH testing for loss of p16 (CDKN2A) are used to separate reactive mesothelial proliferation due to benign processes, from MPM. Various combinations of these markers, such as BAP1 and/or MTAP immunohistochemistry alongside FISH testing for loss of p16, have shown excellent sensitivity and specificity in the diagnosis of MPM. Additionally, over the recent years, research into epigenetic marker use in the diagnosis of MPM has gained momentum. Although still in their research stages, various markers in DNA methylation, long non-coding RNA, micro RNA, circular RNA, and histone modifications have all been found to support diagnosis of MPM with generally good sensitivity and specificity. Many of these studies are however, limited by small sample sizes or other study limitations and further research into the area would be beneficial. Epigenetic markers show promise for use in the future to facilitate the diagnosis of MPM.

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MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma

Cited by 123 publications

References 28 publications

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

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

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

The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review

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