Pleural Mesothelioma With Unusual Squamous Differentiation: A Clinicopathological Case Report With Molecular Insights From Whole-Exome Sequencing

Our plain-English summary of Pleural Mesothelioma With Unusual Squamous Differentiation: A Clinicopathological Case Report With Molecular Insights From Whole-Exome Sequencing, by J. Bodemeyer, M.E. Mierzwa, J. Seraphin, et al (Pathology International, 2026).

The study

• Authors: J. Bodemeyer, M.E. Mierzwa, J. Seraphin, R. Maroun, W. Körber, C. Engelke, F. Bremmer, T. Rosenthal, T. Heißenberg, K. Reuter-Jessen, P. Ströbel, A. Marx, H. Bohnenberger
• Journal: Pathology International
• Published: 2026;76(10):e70190
• Type of article: Case report
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma is an aggressive tumor with a poor prognosis and limited therapeutic options. While histological heterogeneity is common, true squamous differentiation is extremely rare and diagnostically challenging. We report an 81-year-old man with asbestos exposure who presented with recurrent right-sided pleural effusion. Thoracoscopic biopsies revealed two distinct tumor components. The first expressed mesothelial immunohistochemical markers, whereas the second showed a squamous profile. Both components demonstrated loss of BAP1 expression and homozygous deletion of CDKN2A, supporting a common mesothelial origin. Whole-exome sequencing revealed a tumor mutational burden above the average reported for mesothelioma (8-9 mutations per megabase), with 69 somatic mutations in total, 43 shared between the two components. In addition to canonical mesothelioma alterations (BAP1, CHEK2), the squamous component harbored 18 unique variants, including oncogenic alterations in NFE2L2 and PIK3CA. A novel SOX9 missense variant of uncertain significance (p. Thr243Pro) was also identified within the transactivation middle (TAM) domain; its functional consequence remains unknown. This case highlights a rare histological variant of pleural mesothelioma with partially squamous differentiation, characterized by a mutational burden above the mesothelioma average and squamous carcinoma-associated alterations. Integrated histology, immunohistochemistry, and genomic profiling are essential to avoid misdiagnosis and to improve understanding of tumor plasticity in mesothelioma.

© 2026 The Author(s). Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

In plain English

This case report described an 81-year-old man, a never-smoker, who reported 8 years of occupational asbestos exposure. The article does not name the asbestos fiber type. His right-sided pleural effusion recurred within 4 weeks. Thoracoscopic biopsies showed two components: one stained for mesothelial markers such as calretinin, the other strongly for squamous markers p40 and p63. Both components showed loss of BAP1 and homozygous deletion of CDKN2A. Whole-exome sequencing found 69 somatic mutations, 43 shared by both components. Eighteen were unique to the squamous component, including likely pathogenic NFE2L2 and PIK3CA changes and a novel SOX9 variant of uncertain significance. Tumor mutational burden was 8.1 mutations per megabase in the mesothelial component and 9.5 in the squamous component. The authors called this above the mesothelioma average, not TMB-high. The diagnosis was high grade epithelioid pleural mesothelioma with partially squamous differentiation. The disease progressed within three months of immunotherapy; the patient was alive 7 months after diagnosis. The authors concluded that squamous-associated genetic alterations may drive such transdifferentiation. They noted the small biopsy and slightly limited sequencing quality for the mesothelial component, which may affect variant calling.

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: Case report of a single patient, with immunohistochemistry, FISH and whole-exome sequencing of two tumor components
• Who was studied: One 81-year-old man, a never-smoker with a history of pulmonary tuberculosis in childhood, who presented with a 2 L right-sided pleural effusion
• Exposure: Occupational asbestos exposure for 8 years, as reported by the patient; fiber type, job and dose are not stated
• Main results:
  • The second (squamous) tumor component was strongly positive for p40, p63 and CK5/6 and negative for mesothelial markers. The first component was positive for calretinin, GATA3 and CK7.
  • Both tumor components showed loss of BAP1 expression
  • FISH showed homozygous CDKN2A deletion in both tumor components
  • Whole-exome sequencing found 69 somatic mutations in total, 43 shared by both components
  • The squamous component had 61 mutations, 18 of them unique to it. The mesothelial component had 51 mutations, including 8 exclusive variants.
  • 14 mutations were classified as likely pathogenic or oncogenic: 8 shared, 2 only in the mesothelial component, and 4 only in the squamous component
  • The four likely pathogenic or oncogenic mutations found only in the squamous component were in NFE2L2, PIK3CA, ANK3 and FIG4
  • Tumor mutational burden was 8.1 mutations per megabase in the mesothelial component and 9.5 mutations per megabase in the squamous component
  • The authors noted that mesotheliomas average less than 2 mutations per megabase, and that this case's values should not be regarded as TMB-high (threshold of 10 or more per megabase)
  • A previously undescribed SOX9 variant (p.Thr243Pro) was found only in the squamous component. The authors regarded it as a variant of uncertain significance.
  • PD-L1 expression differed between the components: approximately 80% in the mesothelial component vs. 5% in the squamous component
  • Diagnosis: high grade epithelioid pleural mesothelioma with an unusual partially squamous differentiation
  • Treatment began with first-line nivolumab and ipilimumab. At three months, CT showed progressive disease, and treatment was switched to pemetrexed and carboplatin.
  • The patient was alive 7 months after the initial diagnosis
• The authors' conclusion: The authors concluded that transdifferentiation in mesothelioma, though rare, may be driven by squamous-associated genetic alterations in the context of increased genomic instability. They also concluded that combined histopathological, immunohistochemical and molecular assessment is diagnostically important in unusual presentations.
• Limitations the authors state:
  • The overall tumor architecture could not be assessed because the biopsy material was limited
  • DNA sequencing quality was slightly limited for the mesothelial component, which may affect variant calling, so the genomic findings should be interpreted with some caution
  • The functional consequence of the SOX9 variant is unknown

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: Pleural Mesothelioma, Prognosis, Asbestos Exposure, Pleural Effusion, BAP1, Homozygous Deletion, CDKN2A, Tumor Mutational Burden (TMB).

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