The 2015 World Health Organization Classification of Tumors of the Pleura: Advances since the 2004 Classification

J Thorac Oncol. 2016 Feb;11(2):142-54. doi: 10.1016/j.jtho.2015.11.005.


A new World Health Organization (WHO) Classification of Tumors of the Pleura has recently been published. While the histologic classification of pleural malignant mesothelioma remains the same in the 2015 WHO classification as it was in the 2004 classification, multiple new observations have been recorded. First, more detailed study has been performed of histologic subtyping of epithelioid mesothelioma. In particular, it has been recognized that the pleomorphic subtype is associated with a poor prognosis, similar to that of sarcomatoid malignant mesothelioma. Second, there is improved understanding of the role of immunohistochemistry in distinguishing mesothelioma from carcinomas of various sites. Third, the criteria for distinguishing malignant mesothelioma from reactive mesothelial proliferations has been further refined. Fourth, additional studies of sarcomatoid mesothelioma have defined the frequency and spectrum of various histologic and immunohistochemical features, including heterologous elements. Finally, pleural well-differentiated papillary mesotheliomas are better defined and cases with invasive foci are recognized. In addition, several promising observations in mesothelioma pathology and genetics have been made in the past decade. These are now the subject of further investigation to determine if they can be validated in ways that will significantly impact clinical practice. These include a preliminary study of grading, suggesting that nuclear atypia and mitotic count are independent prognostic markers. The discovery of inactivating mutations in the BRCA1-associated protein 1 gene in sporadic and hereditary mesothelioma has opened up a variety of novel molecular, clinical, and diagnostic investigations. One possible diagnostic application includes the setting of separating mesothelioma from reactive mesothelial proliferations, where it may play a role in conjunction with p16 FISH. Another useful discovery was that the NAB2-STAT6 fusion is characteristic of solitary fibrous tumors. This led to development of a STAT6 antibody that is a reliable immunohistochemical marker for solitary fibrous tumors. Genetic studies also led to the finding that WWTR1-CAMTA1 fusions are useful diagnostic markers for epithelioid hemangioendotheliomas, which can present as pleural-based masses. Finally, desmoid type fibromatosis, a locally aggressive tumor that can present in the pleura, has been shown to frequently have CTNNB1 gene mutations and express β-catenin by immunohistochemistry.

Keywords: BAP1; Biphasic; CTNNB1 gene mutations; Desmoid; Desmoplastic; Epithelioid; Epithelioid hemangioendothelioma; Grading; Mesothelioma; STAT6; Sarcomatoid; Solitary fibrous tumor; WWTR1–CAMTA1; p16; β-catenin.

Publication types

  • Review

MeSH terms

  • Calcium-Binding Proteins / genetics
  • Gene Fusion
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Mesothelioma / pathology
  • Neoplasm Grading
  • Pleural Neoplasms / chemistry
  • Pleural Neoplasms / classification*
  • Pleural Neoplasms / genetics
  • Pleural Neoplasms / pathology
  • STAT6 Transcription Factor / analysis
  • Trans-Activators / genetics
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Tumor Suppressor Proteins / analysis
  • Ubiquitin Thiolesterase / analysis
  • World Health Organization
  • beta Catenin / genetics


  • BAP1 protein, human
  • CAMTA1 protein, human
  • CTNNB1 protein, human
  • Calcium-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Tumor Suppressor Proteins
  • WWTR1 protein, human
  • beta Catenin
  • Ubiquitin Thiolesterase