Multidisciplinary EURACAN/IASLC Proposal for Revision of the Histologic Classification of Malignant Pleural Mesothelioma 

Sponsored by EURACAN and the IASLC, a multidisciplinary group comprised of pathologists, oncologists, surgeons, radiologists, and molecular biologists met July 5 and 6, 2018, to critically review the current histologic classification of malignant pleural mesothelioma (MPM) in light of recent molecular, immunologic, and therapeutic advances. The summary of discussions, with recommendations for histologic classification and future studies, has been published in the Journal of Thoracic Oncology.¹

Unlike with lung cancer, treatment of patients with MPM has not dramatically changed in the past decade, mostly because mesothelioma is a rare disease and experience in diagnosis and treatment outside of large academic and cancer centers is usually limited. The 2015 World Health Organization (WHO) classification of MPM includes three major histologic subtypes (epithelioid, sarcomatoid, biphasic) as well as different morphologic patterns of epithelioid mesothelioma. The multidisciplinary group believed that there could be more granularity than simply the three current subtypes and that the classification should be based on evidence and validation of its usefulness in clinical practice. Epithelioid mesothelioma is morphologically the most heterogeneous subtype, with different prognostic significance of various architectural patterns.^2,3,4 Transitional and pleomorphic patterns are included in the 2015 WHO classification under the epithelioid subtype; however, recent studies showed their prognosis to be similar to the sarcomatoid subtype. A multi-institutional study by the International Mesothelioma Panel and the MESOPATH Reference Center clearly showed genomic similarities between transitional pattern and sarcomatoid mesothelioma (Fig. 1).³ Furthermore, it is essential to recognize transitional pattern as sarcomatoid, as it may result in reclassification of epithelioid mesothelioma as biphasic—a decision that may have implications for treatment and prognosis.^4,5 Overall, these data provide strong support for the reclassification of transitional pattern as a cytological variant of sarcomatoid mesothelioma. Molecular studies in pleomorphic mesotheliomas are currently in progress, and therefore, the consensus of the group was to classify transitional pattern as a cytologic feature under both epithelioid and sarcomatoid subtypes. 

The major change recommended to the classification is the inclusion of malignant mesothelioma in situ (MMIS). Until recently, the consensus among pathologists was that MMIS cannot be separated from reactive surface mesothelial proliferations on the basis of morphology alone. However, the concept of MMIS was recently reintroduced for surface mesothelial proliferations that are largely a flat monolayer and that show loss of BRCA1-associated protein 1 (BAP1) nuclear staining by immunohistochemistry and/or CDKN2A homozygous deletion by fluorescence in situ hybridization (FISH), or methylthioadenosine phosphorylase (MTAP) immunohistochemistry as surrogate.^6-8 The diagnosis should be based on a combination of clinical, imaging, histologic, and molecular criteria and made only in the absence of radiologic or clinical evidence of invasive disease. The main question is who should be tested for BAP1 loss and CDKN2A homozygous deletion. The opinions have ranged from all patients with pleural effusions to more selected approaches: patients with a history of heavy asbestos exposure, those who have completed radiation, or those with familial predisposition, or when there is a clinical suspicion of MPM for patients with recurrent unexplained effusions. Overall, more aggressive search for loss of BAP1 or CDKN2A homozygous deletion in a high-risk population should lead to early detection of malignant mesothelial proliferations, which we hope would result in clinical trials investigating different therapeutic interventions in early disease. 

WHO classifications are traditionally based on resection specimens; however, advances in tissue acquisition, with smaller samples being obtained, have resulted in the need to refine the classification so that it could be relevant across all sample types, including cytology. Although the use of cytology in diagnosis of MPM traditionally has been controversial, the use of BAP1 and CDKN2A/MTAP testing has improved the diagnostic sensitivity of effusion specimens. It must be remembered that the cytologic diagnosis in pleural effusion is limited to epithelioid mesotheliomas, as cells from sarcomatoid mesotheliomas are rarely seen in this specimen type.  The identification of atypical and/or malignant cells as being of mesothelial origin historically has led to the diagnosis of “atypical mesothelial cells” or “suspicious for mesothelioma,” because for many years the diagnosis of mesothelioma required histologic confirmation of invasion. The greatest advancement in cytologic diagnosis of mesothelioma comes from the utilization of immunocytochemical stains for molecular alterations such as BAP1, and MTAP as surrogate for CDKN2A FISH.⁹ Loss of any of these markers in atypical mesothelial cells is diagnostic of a neoplastic process rather than a reactive one. However, intact BAP1/MTAP or the lack of CDKN2A homozygous deletion does not exclude the diagnosis of mesothelioma, and in these cases the degree of cellular atypia, in association with clinical–radiographic suspicion for the disease, should prompt a surgical biopsy.  

Genomic sequencing for predictive or prognostic biomarkers in malignant mesothelioma is currently not recommended for routine clinical use. Bueno et al. have proposed a molecular classification that recapitulates the epithelial-to-mesenchymal transition and mostly supports the histologic classification, even though they do not match perfectly.¹⁰ Alcala et al. have demonstrated the existence of a continuum between genomically defined histologic subgroups, and they have shown that the expression profiles of genes involved in angiogenesis and immune response could be more discriminant, and they directed special attention toward cases of V-domain immunoglobulin suppressor of T-cell activation (VISTA) immune checkpoint protein overexpressed in epithelioid MPM.¹¹ These data confirm the potential impact of the microenvironment on the treatment for patients with MPM, while several promising trials based on anti–PD-L1 inhibitors alone or combined with anti–CTLA-4 antibodies are ongoing. Interestingly, some preliminary results suggest that the efficacy of immunotherapy could vary according to histologic subtypes, perhaps in relation to a higher level of PD-L1 expression observed in sarcomatoid MPM than in epithelioid MPM. 

All participants of the meeting agreed that there is a need for greater standardization in pathology reporting. All specialty groups recommended that favorable and unfavorable histologic characteristics (architectural patterns, cytologic features, and stromal features) should be reported (Fig. 2). Furthermore, grading of epithelioid MPMs should be routinely included in the pathology reports. Although there is no current targeted therapy that warrants standardized screening of mesotheliomas for a molecular signature, EURACAN and the IASLC recommend including in the pathology report all molecular data that may influence the clinical management (PD-L1 status, loss of BAP1, and CDKN2A deletion). 

In summary, the EURACAN/IASLC recommendations should enable the collection of more detailed morphologic, immunohistochemical, and molecular findings of pleural mesothelioma in a standardized approach, providing a strong foundation for future studies and the upcoming WHO classification. Moreover, standardized reporting of these findings will facilitate sharing and joining of data globally, allowing for larger and more influential multi-institutional studies of this rare disease. The costly clinical trials will, we hope, be paired with the collection of tumor material and blood before and after treatment and will include genomic characterization of different disease groups. The role of artificial intelligence and machine-based learning in improved diagnostic accuracy, as has been demonstrated for transitional pattern, remains to be tested in clinical trials and practice. The need for standardized testing for predictive biomarkers will largely depend on the results of future clinical trials.

References: 

1. Nicholson AG, Sauter JL, Nowak AK, et al. EURACAN/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more multidisciplinary approach. J Thorac Oncol. 2020;15(1):29-49.
2. Kadota K, Suzuki K, Sima CS, Rusch VW, Adusumilli PS, Travis WD. Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma. J Thorac Oncol. 2011;6(5):896-904.
3. Galateau Salle F, Le Stang N, Tirode F, et al. Comprehensive molecular and pathologic evaluation of transitional mesothelioma assisted by deep learning approach: a multi-institutional study of the International Mesothelioma Panel from the MESOPATH Reference Center. J Thorac Oncol. 2020;15(6):1037-1053.
4. Galateau Salle F, Le Stang N, Nicholson AG, et al. New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the International Mesothelioma Panel from the MESOPATH Reference Center. J Thorac Oncol. 2018;13(8):1189-1203.
5. Dacic S, Le Stang N, Husain A, et al. Interobserver variation in the assessment of the sarcomatoid and transitional components in biphasic mesotheliomas. Mod Pathol. 2020;33(2):255-262.
6. Churg A, Galateau-Salle F, Roden AC, et al. Malignant mesothelioma in situ: morphologic features and clinical outcome. Mod Pathol. 2019; 33(2):297-302.
7. Churg A, Hwang H, Tan L, et al. Malignant mesothelioma in situ. Histopathology. 2018;72(6):1033-1038.
8. Minami K, Jimbo N, Tanaka Y, et al. Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: a case report. Virchows Arch. 2020;476(3):469-473.
9. Monaco S, Mehrad M, Dacic S. Recent advances in the diagnosis of malignant mesothelioma: focus on approach in challenging cases and in limited tissue and cytologic samples. Adv Anat Pathol. 2018;25(1):24-30.
10. Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48(4):407-416.
11. Alcala N, Mangiante L, Le-Stang N, et al. Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions. EBioMedicine. 2019;48:191-202.