The diagnostic value of immunohistochemically detected methylthioadenosine phosphorylase deficiency in malignant pleural mesotheliomas

Our plain-English summary of The diagnostic value of immunohistochemically detected methylthioadenosine phosphorylase deficiency in malignant pleural mesotheliomas, by Z.G. Zimling, A. Jørgensen, E. Santoni-Rugiu (Histopathology, 2012).

The study

• Authors: Z.G. Zimling, A. Jørgensen, E. Santoni-Rugiu
• Journal: Histopathology
• Published: 2012;60(6B):E96-105
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aims: Malignant pleural mesothelioma (MPM) often causes diagnostic difficulties for pathologists. We assessed whether loss of methylthioadenosine phosphorylase (MTAP), a key enzyme in the intracellular recycling of adenosine triphosphate (ATP) often deleted in MPM, could be detected with immunohistochemistry (IHC) and used as a diagnostic marker for MPM.

Methods And Results: We used IHC to detect MTAP in a cohort of 99 MPMs and 39 reactive mesothelial proliferations (RP) (reactive mesothelial hyperplasia n = 33, reactive pleural fibrosis n = 6). MTAP staining was assessed by an H score. The median H score of the RP cohort was set as a reference point. Cases with H scores below this reference point were considered to have decreased MTAP expression. We found that 64 of 99 (65%) of the investigated MPMs had decreased MTAP expression, while this was only true for nine of 39 (23%) of the RPs (P = 0.001). We further evaluated MTAP expression in a cohort of coagulated pleural effusions from 14 patients with MPM and 20 patients with RP by using a double-staining technique with Wilms tumour 1 (WT1) as a mesothelial marker. In these samples, decreased MTAP expression diagnosed MPM with a sensitivity of 71% and a specificity of 90%.

Conclusions: Decreased MTAP expression could potentially be useful in combination with other markers in the diagnosis of MPM.

© 2012 Blackwell Publishing Ltd.

In plain English

The authors tested whether loss of the enzyme MTAP on tissue staining could help pathologists distinguish malignant pleural mesothelioma from benign reactive changes of the pleura. They studied biopsies from 99 patients with mesothelioma and 39 benign reactive samples. They also studied pleural fluid from 14 mesothelioma patients and 20 comparison patients with reactive mesothelial cells, four with fluid linked to other cancers (lung, breast). All patients were diagnosed in Copenhagen, 1999–2008.

Decreased MTAP staining was found in 64 of 99 mesotheliomas (65%) and in 9 of 39 benign samples (23%). It was more common in sarcomatoid (92%) and biphasic (69%) than epithelioid tumours (57%). Only 19 of 99 tumours lost staining completely.

In pleural fluid, using combined staining with the marker WT1, decreased MTAP was found in 10 of 14 mesothelioma samples and 2 of 20 comparison samples, one from a lung cancer patient (sensitivity 71%, specificity 90%).

The authors concluded that decreased MTAP could potentially help alongside other markers, but not as a single marker on tissue sections. They noted that some groups were small. The article did not address asbestos exposure.

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: Diagnostic accuracy study of immunohistochemical staining for MTAP on archived tissue biopsies and pleural fluid samples
• Who was studied: Patients diagnosed at Rigshospitalet, Copenhagen, Denmark, during 1999–2008. The tissue samples were biopsies from 99 patients with malignant pleural mesothelioma (58 epithelioid, 29 biphasic, 12 sarcomatoid) and 39 surgical specimens from patients with non-neoplastic thoracic disease (33 reactive mesothelial hyperplasia, 6 reactive pleural fibrosis). The pleural fluid samples were 34 coagulated pleural effusions. Fourteen came from patients later diagnosed with mesothelioma. The other 20 came from patients with reactive mesothelial proliferations: 13 infectious effusions, four non-mesothelial malignant effusions (NSCLC, breast cancer) and three with other causes (cardiac insufficiency, chylothorax).
• Main results:
  • With single MTAP staining of biopsies, 64 of 99 (65%) mesotheliomas had decreased MTAP expression, compared with 9 of 39 (23%) benign reactive proliferations (P = 0.001).
  • Only 19 of 99 tumours showed complete absence of MTAP staining. 45 of 99 showed a mixed staining pattern.
  • Decreased MTAP expression was found in 92% of sarcomatoid, 69% of biphasic and 57% of epithelioid mesotheliomas.
  • On biopsies, distinguishing reactive mesothelial hyperplasia from epithelioid mesothelioma gave a sensitivity of 57%, a specificity of 79% and a likelihood ratio of 2.5.
  • On biopsies, distinguishing reactive pleural fibrosis from sarcomatoid mesothelioma gave a sensitivity of 92%, a specificity of 67% and a likelihood ratio of 2.8.
  • With WT1/MTAP double staining of biopsies, decreased MTAP was seen in 41 of 82 evaluable tumours and in 3 of 35 benign reactive samples. 11 tumours could not be evaluated because they did not express WT1.
  • In pleural fluid samples, decreased MTAP was found in 10 of 14 samples from patients with epithelioid or biphasic mesothelioma. It was also found in 2 of 20 comparison samples with reactive mesothelial proliferations: one from a patient with cardiac insufficiency and one from a patient with squamous NSCLC. This gave a sensitivity of 71%, a specificity of 90% and a likelihood ratio of 7.
  • The authors stated that none of the biopsy results justified recommending MTAP as a single marker for distinguishing mesothelioma from benign reactive proliferations on tissue sections.
• The authors' conclusion: The authors concluded that decreased MTAP expression could potentially be useful in combination with other markers in diagnosing malignant pleural mesothelioma.
• Limitations the authors state:
  • The mesothelioma samples were studied as tissue microarrays (small cores), which may not represent the whole biopsy.
  • The comparison of sarcomatoid mesothelioma with reactive pleural fibrosis rested on only 12 and 6 cases and should be interpreted with caution.
  • WT1 is not a perfect marker of mesothelial origin, and some tumours could not be evaluated because they did not express it.
  • Most samples showed reduced rather than completely absent MTAP staining, which might make the test difficult to interpret.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, MTAP, Immunohistochemistry, Reactive Mesothelial Hyperplasia, Fibrosis, Pleural Effusion.

Related studies

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• Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens — K.B. Berg, A.M. Churg, et al. (2020)
• 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)
• Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: a case report — K. Minami, N. Jimbo, et al. (2020)
• 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)
• Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma — Y. Kinoshita, M. Hamasaki, et al. (2020)

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