Diagnostic Challenges in the Pathological Approach to Pleural Mesothelioma

Our plain-English summary of Diagnostic Challenges in the Pathological Approach to Pleural Mesothelioma, by S. Lucà, G. Pignata, A. Cioce, et al (Cancers, 2025).

The study

• Authors: S. Lucà, G. Pignata, A. Cioce, C. Salzillo, R. De Cecio, G. Ferrara, C.M. Della Corte, F. Morgillo, A. Fiorelli, M. Montella, R. Franco
• Journal: Cancers
• Published: 2025;17(3)
• Type of article: Review
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) still represents a complex diagnostic challenge for pathologists in routine practice. This diagnosis requires a multidisciplinary approach, and pathological evaluation is mandatory. The histopathological diagnosis is stepwise and should be based on morphological and immunohistochemical assessment, sometimes associated with molecular tests, and supported by clinical and radiological findings. A correct morphological approach aims to exclude pleural metastasis or benign mesothelial proliferations, which are the main differential diagnoses. While certain histological features are diagnostic of MPM, others are highly suggestive but not definitive. Immunohistochemistry plays a pivotal role, with a panel of both traditional and newer markers being used to assess mesothelial differentiation and to differentiate malignant from benign proliferations. In more challenging cases, molecular tests, such as fluorescent in situ hybridization (FISH) to detect CDKN2A deletion, can be helpful in distinguishing malignant from benign pleural lesions. This review summarizes the key morphological, immunohistochemical, and molecular features that should be considered when pleural biopsy samples are examined, with the aim of improving diagnostic accuracy in this complex area.

In plain English

This article was a narrative review, by authors based mainly in Naples, Italy, of how malignant pleural mesothelioma is diagnosed from tissue samples. It reported no new patients or data and did not study asbestos exposure. Citing international guidelines, it noted that a history of asbestos exposure should not influence the pathologist's evaluation. The review described the three main subtypes (epithelioid, sarcomatoid and biphasic) and the main look-alikes: cancers that have spread to the pleura, and benign or reactive changes. Summarizing published studies, it reported that no standard mesothelial marker is 100% specific. It also reported that, in mesothelial proliferations, loss of BAP1 staining in cell nuclei is regarded as 100% specific for malignancy, but with low sensitivity, at 50 to 60% for mesothelioma. It described loss of MTAP as a further marker, and a FISH test for CDKN2A deletion when both proteins are retained. Newer markers such as HEG1, Merlin and 5-hmC were also covered, and the authors said Merlin and 5-hmC still need validation. The authors concluded that diagnosis almost always requires a multidisciplinary approach, guided by the tissue's appearance and confirmed with additional tests.

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: Narrative review of the pathological diagnosis of pleural mesothelioma (no original data)
• Who was studied: No study population; the review covered published literature and guidelines on diagnosing malignant pleural mesothelioma from pleural biopsy and effusion samples
• Exposure: Not studied. The review stated, citing the 2023 International Mesothelioma Interest Group guidelines, that asbestos exposure history should not influence pathological evaluation
• Main results:
  • Citing the literature, the review stated that epithelioid mesothelioma is the most frequent subtype (60–70% of diagnosed cases), sarcomatoid 5–15% and biphasic 15% to 30%
  • Common mesothelial markers (podoplanin/D2-40, WT1, calretinin, CK5/6) were described as sensitive, but none as 100% specific for mesothelial origin
  • In their own routine practice, the authors use at least two or three mesothelial markers (primarily podoplanin and WT1, possibly calretinin) plus at least two carcinoma markers
  • Loss of BAP1 nuclear expression was described as 100% specific for malignancy in mesothelial proliferations, with 50–60% sensitivity for malignant pleural mesothelioma
  • Loss of cytoplasmic MTAP expression was reported as 43–65% sensitive for mesothelioma diagnosis. The text gives 100% specificity, while the review's Table 6 gives 96–100%. Table 6 lists 74–90% sensitivity for BAP1 plus MTAP combined
  • For FISH testing of CDKN2A, the review stated that at least 100 tumor cells should be evaluated, with a 10% cut-off for homozygous 9p21 deletion
  • The authors stated that Merlin immunohistochemistry needs independent validation before routine use
  • The authors stated that advanced gene sequencing is not indicated for routine use, because of cost and limited laboratory availability
• The authors' conclusion: The authors concluded that mesothelioma diagnosis almost always requires a multidisciplinary approach. In their view, the tissue's appearance guides suspicion and immunohistochemistry and/or molecular tests confirm it.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Multidisciplinary Team, Metastasis, Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), CDKN2A, Pleural Biopsy.

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