Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis

Our plain-English summary of Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis, by D. Wu, K. Hiroshima, S. Matsumoto, et al (American Journal of Clinical Pathology, 2013).

The study

• Authors: D. Wu, K. Hiroshima, S. Matsumoto, K. Nabeshima, T. Yusa, D. Ozaki, M. Fujino, H. Yamakawa, Y. Nakatani, Y. Tada, H. Shimada, M. Tagawa
• Journal: American Journal of Clinical Pathology
• Published: 2013;139(1):39-46
• Cited by: 90 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The distinction between sarcomatoid mesothelioma and fibrous pleuritis is difficult based on histology, especially when the amount of tumor tissue examined via biopsy is small and immunohistochemical examination is inconclusive. We studied the usefulness of deletion of p16 with fluorescence in situ hybridization (FISH) and p16 hypermethylation with polymerase chain reaction for the diagnosis and prognosis of malignant pleural mesothelioma (MPM). We analyzed 50 MPMs, including 22 sarcomatoid mesothelioma cases and 10 fibrous pleuritis cases. We set the cutoff value of homozygous deletion pattern as 14.4% based on FISH signaling patterns using samples of fibrous pleuritis. The percentage of homozygous deletion pattern was higher than 14.4% in 55.6% of the epithelioid mesotheliomas (10/18) and in all of the sarcomatoid mesotheliomas (22/22). Methylation of p16 was observed in 7 (20.6%) of 34 informative cases. p16 FISH analysis can be a reliable test for distinguishing between sarcomatoid mesothelioma and fibrous pleuritis and a prognostic factor for MPM.

In plain English

This Japanese study used archived tissue from 50 patients with malignant pleural mesothelioma and 10 with fibrous pleuritis, a benign condition, seen 1999 to 2012. All but one fibrous pleuritis patient had a history of asbestos exposure; the authors diagnosed these as benign asbestos pleural effusion. The authors tested whether FISH, a test for loss of both copies of the p16 gene, could tell sarcomatoid mesothelioma from fibrous pleuritis. A cutoff of 14.4% of cells was set from the fibrous pleuritis samples. FISH worked in 48 of 50 mesotheliomas. Gene loss was found in 39 of 48: 22 of 22 sarcomatoid, 7 of 8 biphasic and 10 of 18 epithelioid. For the 22 sarcomatoid mesotheliomas versus the 10 fibrous pleuritis cases, the authors reported 100% sensitivity and specificity. Methylation of p16 was found in 7 of 34 mesotheliomas and 3 of 7 fibrous pleuritis cases. Median survival was 7 months for 34 patients with loss of both p16 copies and 22 months for 7 without. The authors concluded that FISH helps make this distinction, while methylation testing may not aid diagnosis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective laboratory study of archived tissue samples, testing two genetic methods (p16 FISH and methylation-specific PCR) for diagnosis and prognosis
• Who was studied: 50 patients with malignant pleural mesothelioma and 10 patients with fibrous pleuritis, seen between December 1999 and March 2012, from pathology archives of hospitals in Chiba, Japan. A total of 43 mesothelioma patients were analyzed for survival.
• Exposure: The study examined p16 gene deletion and p16 methylation, not asbestos exposure. Asbestos exposure is mentioned only for the fibrous pleuritis group: all but 1 had a history of asbestos exposure, and these cases were diagnosed as benign asbestos pleural effusion. No fiber types or doses are given, and no exposure information is given for the mesothelioma patients.
• Main results:
  • In fibrous pleuritis samples, the homozygous deletion pattern appeared in 0 to 7.4% of nuclei (mean 3.9%, SD 2.6%). The cutoff for homozygous deletion was set at more than 14.4% of nuclei.
  • FISH analysis was successful in 48 of 50 mesothelioma cases.
  • Homozygous p16 deletion was found in 39 (81.3%) of 48 mesothelioma cases.
  • Homozygous deletion by mesothelioma subtype: 55.6% (10/18) of epithelioid, 100% (22/22) of sarcomatoid, and 87.5% (7/8) of biphasic mesotheliomas.
  • All 22 sarcomatoid mesotheliomas were above the 14.4% cutoff, and all 10 fibrous pleuritis cases were below it. For this comparison the authors reported both sensitivity and specificity of 100%. This figure does not apply to all mesotheliomas, since only 39 of 48 exceeded the cutoff.
  • When homozygous and hemizygous deletion patterns were combined, with a 42.3% cutoff, 66.7% (12/18) of epithelioid mesotheliomas could be diagnosed.
  • p16 promoter methylation was found in 20.6% (7/34) of mesotheliomas and 42.9% (3/7) of fibrous pleuritis cases. The authors reported no significant difference between the two groups.
  • No correlation was found between p16 deletion and p16 methylation in mesotheliomas.
  • Median survival by subtype was 22 months for epithelioid, 12 months for biphasic and 5 months for sarcomatoid mesothelioma (P = .0015).
  • In the survival analysis, the 34 mesothelioma patients with p16 homozygous deletion (number from Table 4) had a median survival of 7 months.
  • In the survival analysis, the 7 mesothelioma patients without p16 homozygous deletion (number from Table 4) had a median survival of 22 months (P = .0363).
  • Mesothelioma patients without p16 methylation (27 patients) survived longer than those with methylation (7 patients) (P = .0442).
• The authors' conclusion: The authors concluded that p16 deletion detected with FISH is useful for differentiating sarcomatoid mesothelioma from fibrous pleuritis, and that p16 methylation analysis may not be useful for diagnosing mesothelioma.
• Limitations the authors state:
  • FISH signal strength decreased in tissue stored for 8 years after biopsy. Two samples from 2002 and 2003 could not be analyzed because their signals were too weak.
  • FISH methods and scoring vary between laboratories, so the authors stated that each institution should set its own cutoff value.
  • Methylation results in some tumor samples may reflect contamination by non-tumor cells.
  • Further study is needed on the link between p16 methylation and tumor development.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: CDKN2A, Fluorescence In Situ Hybridization (FISH), Sarcomatoid, Mesothelioma, Histology, Biopsy, Prognosis, Pleural Mesothelioma.

Related studies

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• How useful is GLUT-1 in differentiating mesothelial hyperplasia and fibrosing pleuritis from epithelioid and sarcomatoid mesotheliomas? An international collaborative study — A.N. Husain, M.K. Mirza, et al. (2014)
• GATA3 is a useful immunohistochemical marker for distinguishing sarcomatoid malignant mesothelioma from lung sarcomatoid carcinoma and organizing pleuritis — Z.H. Piao, X.C. Zhou, et al. (2021)
• Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma — D. Wu, K. Hiroshima, et al. (2017)
• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)
• BAP1 Immunohistochemistry and p16 FISH in the Diagnosis of Sarcomatous and Desmoplastic Mesotheliomas — H.C. Hwang, S. Pyott, et al. (2016)

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