MUC4, a novel immunohistochemical marker identified by gene expression profiling, differentiates pleural sarcomatoid mesothelioma from lung sarcomatoid carcinoma

Our plain-English summary of MUC4, a novel immunohistochemical marker identified by gene expression profiling, differentiates pleural sarcomatoid mesothelioma from lung sarcomatoid carcinoma, by V.J. Amatya, K. Kushitani, A.S. Mawas, et al (Modern Pathology, 2017).

The study

• Authors: V.J. Amatya, K. Kushitani, A.S. Mawas, Y. Miyata, M. Okada, T. Kishimoto, K. Inai, Y. Takeshima
• Journal: Modern Pathology
• Published: 2017;30(5):672-681
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Sarcomatoid mesothelioma, a histological subtype of malignant pleural mesothelioma, is a very aggressive tumor with a poor prognosis. Histological diagnosis of sarcomatoid mesothelioma largely depends on the histomorphological feature of spindled tumor cells with immunohistochemical reactivity to cytokeratins. Diagnosis also requires clinico-radiological and/or macroscopic evidence of an extrapulmonary location to differentiate it from lung sarcomatoid carcinoma. Although there are promising immunohistochemical antibody panels to differentiate mesothelioma from lung carcinoma, a consensus on the immunohistochemical markers that distinguish sarcomatoid mesothelioma from lung sarcomatoid carcinoma has not been reached and requires further study. We performed whole gene expression analysis of formalin-fixed paraffin-embedded tissue from sarcomatoid mesothelioma and lung sarcomatoid carcinoma and observed significant differences in the expression of MUC4 and other genes between sarcomatoid mesothelioma and lung sarcomatoid carcinoma. Immunohistochemistry demonstrated that MUC4 was expressed in the spindled tumor cells of lung sarcomatoid carcinoma (21/29, 72%) but was not expressed in any sarcomatoid mesothelioma (0/31, 0%). To differentiate sarcomatoid mesothelioma from lung sarcomatoid carcinoma, negative MUC4 expression showed 100% sensitivity and 72% specificity and accuracy rate of 87%, which is higher than immunohistochemical markers such as calretinin, D2-40 and Claudin-4. Therefore, we recommend to include MUC4 as a novel and useful negative immunohistochemical marker for differentiating sarcomatoid mesothelioma from lung sarcomatoid carcinoma.

In plain English

This laboratory study from Hiroshima University, Japan, looked for a tissue marker to tell sarcomatoid mesothelioma of the pleura apart from lung sarcomatoid carcinoma. These are two spindle-cell tumors that look very similar under the microscope. The authors first compared gene activity in archived tissue from six cases of each tumor. They found 2099 statistically significant transcripts that differed more than two-fold between the two groups. One of them, MUC4, was more active in the lung tumors. They then stained tissue from 31 sarcomatoid mesotheliomas and 29 lung sarcomatoid carcinomas diagnosed in 2005–2014. MUC4 protein appeared in 21 of 29 lung sarcomatoid carcinomas (72%) and in none of 31 sarcomatoid mesotheliomas. Used as a test where a negative result points to mesothelioma, MUC4 showed 100% sensitivity, 72% specificity and 87% accuracy. That accuracy was higher than for the markers calretinin and D2-40. Combining negative MUC4, TTF-1 and Claudin-4 reached 95% accuracy. The authors proposed adding MUC4 as a negative marker to the panel used to separate these tumors. The study did not examine 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: Laboratory diagnostic study of archived surgical and autopsy tumor tissue. Gene expression profiling (microarray, checked by RT-PCR) was done in a subset of cases, followed by immunohistochemical staining of all cases.
• Who was studied: 31 cases of sarcomatoid mesothelioma (25 pure sarcomatoid, 6 biphasic with predominantly sarcomatoid growth) and 29 cases of lung sarcomatoid carcinoma (5 spindle cell carcinoma, 24 pleomorphic carcinoma). Cases were diagnosed after surgical resection and/or autopsy at Hiroshima University Hospital, Japan, during 2005–2014. Cases whose tumor location could not be confirmed were excluded.
• Exposure: Not studied. The study compared gene expression and tissue staining markers between two tumor types. Asbestos exposure was mentioned only in the background and was not assessed.
• Main results:
  • In the gene expression analysis (6 sarcomatoid mesotheliomas, 6 lung sarcomatoid carcinomas), 2099 statistically significant mRNA transcripts differed by more than two-fold between the two tumor types. At more than five-fold, 156 transcripts were higher in sarcomatoid mesothelioma and 46 (including MUC4 and Claudin4) were higher in lung sarcomatoid carcinoma.
  • By real-time RT-PCR, MUC4 mRNA expression was negligible in all six sarcomatoid mesotheliomas and was observed in five of the six lung sarcomatoid carcinomas.
  • By immunohistochemistry, MUC4 was expressed in spindled tumor cells of 21 of 29 lung sarcomatoid carcinomas (72%) and in 0 of 31 sarcomatoid mesotheliomas (0%).
  • Used to distinguish sarcomatoid mesothelioma from lung sarcomatoid carcinoma, negative MUC4 expression had 100% sensitivity, 72% specificity and an 87% accuracy rate, the highest of the single markers tested.
  • Positive D2-40 staining had 71% sensitivity and 69% specificity. Positive calretinin staining had 55% specificity, with a sensitivity of 74% given in Table 3.
  • The combination of negative MUC4, TTF-1 and Claudin-4 was seen in 26 of 29 lung sarcomatoid carcinomas (90% specificity) and 0 of 31 sarcomatoid mesotheliomas (100% sensitivity), with a 95% accuracy rate.
• The authors' conclusion: The authors concluded that MUC4, identified through whole gene expression analysis, differentiates sarcomatoid mesothelioma from lung sarcomatoid carcinoma, and that combining it with TTF-1/p40 and Claudin-4 improved sensitivity and specificity. They proposed including MUC4 as an additional negative marker in the immunohistochemical panel.
• Limitations the authors state:
  • The authors noted that MUC4 specificity alone was 72%, which led them to consider combinations of markers.
  • The authors used formalin-fixed paraffin-embedded tissue rather than frozen tissue, and the small amount of RNA extracted had to be amplified before analysis.
  • A gene the microarray found higher in sarcomatoid mesothelioma (IGF2) did not show significant differential expression on RT-PCR. IGF2, CLIC4 and SPARC proteins also showed no significant difference between the tumor types.

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: Sarcomatoid, Mesothelioma, Carcinoma, Histological Subtype, Pleural Mesothelioma, Prognosis, Immunohistochemistry, Calretinin.

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