Update of pathological diagnosis of pleural mesothelioma using genomic-based morphological techniques, for both histological and cytological investigations

Pathol Int. 2022 Aug;72(8):389-401. doi: 10.1111/pin.13235. Epub 2022 May 21.


As more than 80% of pleural mesothelioma (PM) cases start with pleural effusions, diagnosis with effusion smear cytology or pleural biopsy is important. For diagnosing PM, a three-step approach is used: (1) detecting atypical cells; (2) verifying their mesothelial origin using immunohistochemistry (IHC); and (3) discriminating PM from benign mesothelial proliferations (BMP). The third step is critical for diagnosing early lesions. In small biopsy or cytologic specimens in which tumor cell fat invasion cannot be assessed, genomic-based assays, including IHC-detected BAP1 loss and fluorescence in situ hybridization (FISH)-detected homozygous deletion (HD) of CDKN2A/p16, are effective for differentiation. Both BAP1 IHC and CDKN2A FISH can equally be applied to histologic and cytologic specimens, with 100% specificity in discriminating PM from BMP. We found that methylthioadenosine phosphorylase (MTAP) loss as detected by IHC could serve as a feasible alternative in tissue and cytologic preparations for CDKN2A FISH. However, a combination including FISH was still most effective: the addition of NF2 FISH to CDKN2A FISH and BAP1 IHC yielded a greater sensitivity of close to 100% in diagnosing PM tissues. Although IHC is more feasible than FISH, owing to remaining challenges in data interpretation, caution and familiarity are warranted when diagnosing PM.

Keywords: BAP1; CDKN2A; FISH; MTAP; NF2; cytology; histology; pleural mesothelioma.

Publication types

  • Review

MeSH terms

  • Biomarkers, Tumor / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Genomics
  • Homozygote
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms* / pathology
  • Mesothelioma* / diagnosis
  • Mesothelioma* / genetics
  • Mesothelioma* / pathology
  • Mesothelioma, Malignant* / diagnosis
  • Pleural Neoplasms* / diagnosis
  • Pleural Neoplasms* / genetics
  • Pleural Neoplasms* / pathology
  • Sequence Deletion
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics


  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase