Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers

Our plain-English summary of Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers, by D.W. Henderson, G. Reid, S.C. Kao, et al (Journal of Clinical Pathology, 2013).

The study

• Authors: D.W. Henderson, G. Reid, S.C. Kao, N. van Zandwijk, S. Klebe
• Journal: Journal of Clinical Pathology
• Published: 2013;66(10):847-53
• Type of article: Review
• Cited by: 96 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The detection of neoplastic invasion remains the linchpin for a clear diagnosis of malignant mesothelioma. Cytology-only diagnosis of epithelioid mesothelioma on aspirated effusion fluid remains controversial. A major problem is poor sensitivity, although cytodiagnosis is achievable in many cases at a high order of specificity, especially when a large volume of effusion fluid is submitted for cytological evaluation, enabling the preparation of cell-block sections for immunohistochemical investigation and when the cytological findings can be correlated with imaging studies to assess the anatomical distribution of the lesion and evidence of nodularity of the pleural disorder and, in some cases, to demonstrate evidence of invasion. Although 'positive' and 'negative' immunohistochemical markers have proved remarkably effective in distinguishing between epithelioid mesothelioma and secondary carcinoma and other malignant tumours metastatic to serosal membranes, no mesothelial marker has 100% sensitivity and specificity for mesothelioma diagnosis, so that panels of 'positive' antibodies and markers with negative predictive value are required. At present, no tissue or serum marker (including the molecular detection of p16/CDKN2A) has been proved to have sufficient specificity, consistency and reproducibility that it can replace evidence of invasion as the decisive marker for diagnosis when there is any uncertainty concerning a diagnosis of epithelioid mesothelioma and in the case of atypical fibrous lesions of the pleura (especially collagen-rich lesions, namely fibrous pleuritis vs desmoplastic mesothelioma), in which even the assessment of invasion can be problematical as illustrated in part 2 of this review.

In plain English

This was a selective review, part one of two, of how malignant mesothelioma, mainly pleural and diffuse, is diagnosed. Using published studies and their own experience, the authors discussed effusion cytology, biopsy choice, immunohistochemistry, distinguishing mesothelioma from benign reactive proliferations, and serum biomarkers. They noted reported sensitivity of cytology-only diagnosis of about 30–75%. They agreed that when all cytological criteria for epithelioid mesothelioma are met in effusion fluid, a highly probable to near-definite diagnosis is possible at high specificity, though detailed clinical-radiological-cytological correlation is still required. They recommended submitting at least 100 mL of effusion fluid but had reservations about how widely cytology-only diagnosis applies. They described core biopsies and VAT-guided biopsies as having a high diagnostic yield. Since no marker has 100% sensitivity and specificity, they recommended marker panels. They stated that no tissue marker, including FISH testing for p16/CDKN2A deletion, has proved reliable enough to replace evidence of invasion when a diagnosis of epithelioid mesothelioma is uncertain. Serum biomarkers likewise could not replace imaging, cytology and biopsy. The authors concluded that an unequivocal biopsy diagnosis requires demonstrating neoplastic invasion.

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, selective, part 1 of a two-part review
• Who was studied: Published literature and the authors' experience on the diagnosis of mesothelioma, focusing on pleural and diffuse malignant mesothelioma
• Exposure: Not applicable: the review covers diagnostic methods, not asbestos exposure
• Main results:
  • The authors reported that published studies put the sensitivity of cytology-only diagnosis on effusion fluid at about 30–75%
  • The authors agreed that when all cytological criteria for epithelioid mesothelioma are met in an effusion fluid specimen, a highly probable to near-definite diagnosis can be made at high specificity
  • Even so, the authors considered detailed clinical-radiological-cytological correlation to be required
  • The authors recommended submitting at least 100 mL of effusion fluid, and preferably the entire volume, for cytology
  • The authors had reservations about how widely cytology-only diagnosis can be applied
  • Core biopsies and VAT-guided biopsies were described as having a high diagnostic yield
  • For suspected mesothelioma with an epithelioid component, the authors recommended an immunohistochemistry panel with a cytokeratin marker, two or more mesothelial markers and two or more carcinoma-related markers
  • Homozygous deletion of p16/CDKN2A is detected by FISH (fluorescence in-situ hybridisation), and the authors described evidence that it may be useful for distinguishing mesothelioma from benign reactive mesothelial proliferation
  • The authors concluded there is insufficient evidence at present that these markers, alone or combined and including p16/CDKN2A, can replace neoplastic invasion as the decisive marker when a diagnosis of epithelioid mesothelioma is uncertain
  • Proposed serum biomarkers were judged not to meet the criteria for screening at-risk populations at present
  • For sarcomatoid mesothelioma, the authors stated that mesothelial cell markers are often negative
• The authors' conclusion: The authors concluded that an unequivocal biopsy diagnosis of mesothelioma requires showing neoplastic invasion by a mesothelial proliferation
• Limitations the authors state:
  • The authors stated the review is selective, not encyclopaedic
  • Well differentiated papillary mesothelioma and multicystic mesothelioma were excluded
  • The authors avoided discussing medicolegal aspects of mesothelioma diagnosis

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cytology, Immunohistochemistry, Reactive Mesothelial Hyperplasia, Biomarker, Epithelioid, Carcinoma, CDKN2A.

Related studies

• Challenges and controversies in the diagnosis of malignant mesothelioma: Part 2. Malignant mesothelioma subtypes, pleural synovial sarcoma, molecular and prognostic aspects of mesothelioma, BAP1, aquaporin-1 and microRNA — D.W. Henderson, G. Reid, et al. (2013)
• 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)
• Use of Anti-Noxa Antibody for Differential Diagnosis between Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia — K. Kushitani, V.J. Amatya, et al. (2016)
• Value of Glut-1 and Koc markers in the differential diagnosis of reactive mesothelial hyperplasia, malignant mesothelioma and pulmonary adenocarcinoma — Ö. Üçer, A.F. Dağli, et al. (2013)
• How useful is GLUT-1 in differentiating mesothelial hyperplasia and fibrosing pleuritis from epithelioid and sarcomatoid mesotheliomas? An international collaborative study — A.N. Husain, M.K. Mirza, et al. (2014)
• Claudin-4 immunohistochemistry is highly effective in distinguishing adenocarcinoma from malignant mesothelioma in effusion cytology — V.Y. Jo, E.S. Cibas, et al. (2014)

Browse more research in Journal of Clinical Pathology, or return to medical research.