Diagnostic Usefulness of p16/CDKN2A FISH in Distinguishing Between Sarcomatoid Mesothelioma and Fibrous Pleuritis

Wu, Di; Hiroshima, Kenzo; Matsumoto, Shinji; Nabeshima, Kazuki; Yusa, Toshikazu; Ozaki, Daisuke; Fujino, Michio; Yamakawa, Hisami; Nakatani, Yukio; Tada, Yuji; Shimada, Hideaki; Tagawa, Masatoshi

doi:10.1309/ajcpt94jvwihbkrd

Cited by 107 publications

(85 citation statements)

References 34 publications

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“…Previous studies have demonstrated a strong association between sarcomatoid mesotheliomas and homozygous CDKN2A deletions. 36,37 Although a similar association was not identified herein, the presence of only two sarcomatoid mesotheliomas within our cohort may account for this discrepancy. However, as previously mentioned, the vast majority of peritoneal mesotheliomas are epithelioid in histologic subtype.…”

Section: Discussionsupporting

confidence: 57%

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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: Discussionsupporting

confidence: 57%

“…Of note, the lack of association between homozygous CDKN2A deletions and sarcomatoid mesothelioma contrasts previous studies. 36,37 However, the small sample size of sarcomatoid mesotheliomas (n = 2) within the study cohort may account for this discrepancy.…”

Section: Clinical and Pathologic Characteristicsmentioning

confidence: 96%

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

et al. 2016

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“…Similar results have been reported by others. 7,9 In this paper, we have utilized FISH for p16 (CDKN2A) to attempt to determine whether surface mesothelial proliferations ever show deletions. We purposely picked cases in which there were both a surface similar magnitude in the surface and the invasive tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that some proportion of mesotheliomas demonstrate homozygous deletion of p16 when assayed by fluorescence in situ hybridization (FISH), either using cytology preparations or tissue biopsies. [4][5][6][7][8][9] In this study we have used p16 FISH testing on a series of pleural and peritoneal mesotheliomas that, on biopsy, have a surface mesothelial proliferation as well as an invasive component to determine whether surface proliferations ever show p16 deletion and, if so, whether that finding correlates with p16 deletion in the underlying mesothelioma.…”

mentioning

confidence: 99%

p16 FISH Deletion in Surface Epithelial Mesothelial Proliferations Is Predictive of Underlying Invasive Mesothelioma

Hwang

Tse²,

Rodriguez³

et al. 2014

American Journal of Surgical Pathology

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An atypical mesothelial proliferation along the pleural or peritoneal surface without evidence of invasive tumor poses a diagnostic challenge. Homozygous deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH) has been shown to be a good marker of malignancy in mesothelial proliferations, but correlations of p16 status between atypical surface proliferations and underlying mesothelioma have not been described. We used p16 FISH to investigate 11 pleural and 7 peritoneal mesotheliomas that had both an invasive component and a separate surface mesothelial proliferation. In 5/11 pleural samples and 1/7 peritoneal samples, the invasive mesotheliomas showed homozygous deletion of p16 (all cases in excess of 90% of cells deleted); the surface proliferation in all 6 cases with deletion in the invasive tumor was also p16 deleted. Conversely, the 12 tumors that did not show p16 deletion in the invasive compartment also did not have deletion in the surface component. We conclude that (1) surface mesothelial proliferations near invasive mesotheliomas show the same pattern of p16 by FISH as the underlying tumor and may represent in situ disease or growth of the underlying mesothelioma along the serosal surface; (2) p16 deletion in mesothelial surface proliferations is strongly associated with p16 deletion in underlying mesotheliomas, and biopsies consisting of pure surface mesothelial proliferations that are p16 deleted allow a diagnosis of mesothelioma without an additional biopsy if there is clinical (thoracosopic/laparoscopic) or radiologic evidence of diffuse pleural or peritoneal tumor; (3) however, the absence of p16 deletion in surface proliferations does not rule out underlying invasive mesothelioma.

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“…Wu et al 54 examined p16 FISH to discriminate reactive from malignant mesothelium in 60 patients. Hemizygous or homozygous deletion of p16 was not seen in fibrous pleurisy (FP), but was detected in 66.7% of epithelioid MPM, 87.5% of biphasic MPM and 100% of sarcomatoid cases, highlighting potential utility in the differentiation of MPM from FP.…”

Section: Section 6: Pathological Diagnosismentioning

confidence: 99%

British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma

Woolhouse

Bishop

Darlison

et al. 2018

Thorax

177

219

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Diagnostic Usefulness of p16/CDKN2A FISH in Distinguishing Between Sarcomatoid Mesothelioma and Fibrous Pleuritis

Cited by 107 publications

References 34 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

p16 FISH Deletion in Surface Epithelial Mesothelial Proliferations Is Predictive of Underlying Invasive Mesothelioma

British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma

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