Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma

Our plain-English summary of Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma, by Y. Kinoshita, M. Hamasaki, M. Yoshimura, et al (Modern Pathology, 2020).

The study

• Authors: Y. Kinoshita, M. Hamasaki, M. Yoshimura, S. Matsumoto, A. Iwasaki, K. Nabeshima
• Journal: Modern Pathology
• Published: 2020;33(2):235-244
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Neurofibromatosis type 2 (NF2) gene, a tumor suppressor gene located on chromosome 22q12.2, is frequently abnormal in mesothelioma. Recent studies have revealed the effectiveness of diagnostic assays for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. These include detection of homozygous deletion of the 9p21 locus by fluorescence in situ hybridization (FISH) (9p21 FISH), loss of expression of BAP1 as detected by immunohistochemistry, and loss of expression of methylthioadenosine phosphorylase (MTAP) as detected by immunohistochemistry. However, the application of FISH detection of NF2 gene deletion (NF2 FISH) in differentiation of malignant pleural mesothelioma from reactive mesothelial hyperplasia has not been fully evaluated. In this study, we investigated whether NF2 FISH, either alone or in a combination with other diagnostic assays (9p21 FISH, MTAP immunohistochemistry, and BAP1 immunohistochemistry), is effective for distinguishing malignant pleural mesothelioma from reactive mesothelial hyperplasia. This study cohort included malignant pleural mesothelioma (n = 47) and reactive mesothelial hyperplasia cases (n = 27) from a period between 2001 and 2017. We used FISH to examine deletion status of NF2 and 9p21 and immunohistochemistry to examine expression of MTAP and BAP1 in malignant pleural mesothelioma and in reactive mesothelial hyperplasia. Hemizygous NF2 loss (chromosome 22 monosomy or hemizygous deletion) was detected in 25 of 47 (53.2%) mesothelioma cases. None of the mesothelioma cases showed homozygous NF2 deletion. Hemizygous NF2 loss showed 53.2% sensitivity and 100% specificity in differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. A combination of NF2 FISH, 9p21 FISH, and BAP1 immunohistochemistry yielded greater sensitivity (100%) than that detected for either diagnostic assay alone (53.2% for NF2 FISH, 78.7% for 9p21 FISH, 70.2% for MTAP immunohistochemistry, or 57.4% for BAP1 immunohistochemistry). Thus, NF2 FISH in combination with other diagnostic assays is effective for distinguishing malignant pleural mesothelioma from reactive mesothelial hyperplasia.

In plain English

This was a single-center, retrospective study from Fukuoka University Hospital in Japan. It asked whether a laboratory test for loss of the NF2 gene, called fluorescence in situ hybridization (FISH), helps tell malignant pleural mesothelioma apart from reactive mesothelial hyperplasia, a non-cancerous condition. The authors tested tissue from 47 mesothelioma cases and 27 reactive hyperplasia cases dated 2001 to 2017, alongside three other tests (9p21 FISH, and MTAP and BAP1 immunohistochemistry). Asbestos exposure was not studied. Cutoffs for the NF2 test were set using the reactive hyperplasia cases. Hemizygous NF2 loss (loss of one of the two copies) was found in 25 of 47 mesothelioma cases (53.2%) and in none of the reactive cases. Each test had 100% specificity. Sensitivities were 53.2% for NF2 FISH, 78.7% for 9p21 FISH, 70.2% for MTAP and 57.4% for BAP1. Combining NF2 FISH, 9p21 FISH and BAP1 detected all 47 mesothelioma cases. NF2 loss was not associated with shorter survival. The authors concluded that NF2 FISH combined with other tests was effective. They noted the small single-center sample and the old samples as limitations.

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: Single-center retrospective study of diagnostic test accuracy on archived pathology tissue
• Who was studied: 47 malignant pleural mesothelioma cases (41 males, 6 females, mean age 67.3 years; 32 epithelioid, 5 sarcomatoid, 10 biphasic) and 27 reactive mesothelial hyperplasia cases (26 males, 1 female, mean age 33.0 years), from the pleural lesion files of the Department of Pathology, Fukuoka University Hospital, Japan, 2001 to 2017
• Exposure: No asbestos or other environmental exposure was assessed. The study evaluated tissue tests: NF2 FISH and 9p21 FISH (gene deletion), and MTAP and BAP1 immunohistochemistry (protein loss)
• Main results:
  • Hemizygous NF2 loss was found in 25 of 47 mesothelioma cases (53.2%): 4.3% showed hemizygous deletion and 48.9% showed chromosome 22 monosomy. No mesothelioma case showed homozygous NF2 deletion
  • None of the 27 reactive mesothelial hyperplasia cases showed NF2 loss of either kind
  • Each single test had 100% specificity. Sensitivities for detecting mesothelioma were 53.2% for NF2 FISH, 78.7% for 9p21 FISH, 70.2% for MTAP immunohistochemistry (one case excluded) and 57.4% for BAP1 immunohistochemistry
  • Sensitivity was 93.6% for 9p21 FISH plus BAP1 and 89.4% for MTAP plus BAP1. The combination of NF2 FISH, 9p21 FISH and BAP1 detected all 47 mesothelioma cases (100% sensitivity, 100% specificity). NF2 FISH, BAP1 and MTAP together gave 97.9%
  • Among mesothelioma cases, hemizygous NF2 loss was not statistically associated with age, gender, histologic subtype, 9p21 deletion, MTAP loss or BAP1 loss
  • Hemizygous NF2 loss and BAP1 loss were not associated with shorter overall survival. 9p21 homozygous deletion and MTAP loss were associated with shorter overall survival (p less than 0.001 each)
• The authors' conclusion: The authors concluded that hemizygous loss is the most common NF2 alteration seen by FISH in malignant pleural mesothelioma, and that NF2 FISH combined with other diagnostic assays was effective for distinguishing it from reactive mesothelial hyperplasia
• Limitations the authors state:
  • Single-center retrospective design with a relatively small number of patients; the authors said validation studies are preferred
  • Some samples were old, dating back to 2001. The authors reported that internal control cells gave normal FISH signals
  • Inactivation of the remaining NF2 copy in cases with hemizygous loss could not be examined

Topics

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

Medical terms in this study, explained in our Lexicon: Fluorescence In Situ Hybridization (FISH), Pleural Mesothelioma, Tumor Suppressor Gene, Mesothelioma, Reactive Mesothelial Hyperplasia, Homozygous Deletion, BAP1, Immunohistochemistry.

Related studies

• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Fluorescence in situ hybridization detection of chromosome 22 monosomy in pleural effusion cytology for the diagnosis of mesothelioma — Y. Kinoshita, M. Hamasaki, et al. (2021)
• BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma — S.M. McGregor, J. McElherne, et al. (2017)
• MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma — D.B. Chapel, J.J. Schulte, et al. (2020)
• Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia — M. Yoshimura, Y. Kinoshita, et al. (2019)
• Utility of Methylthioadenosine Phosphorylase Compared With BAP1 Immunohistochemistry, and CDKN2A and NF2 Fluorescence In Situ Hybridization in Separating Reactive Mesothelial Proliferations From Epithelioid Malignant Mesotheliomas — K.B. Berg, S. Dacic, et al. (2018)

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