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EURACAN/IASLC Proposals for Updating the Histologic Classification of Pleural Mesothelioma: Towards a More Multidisciplinary Approach

Open ArchivePublished:September 20, 2019DOI:https://doi.org/10.1016/j.jtho.2019.08.2506

      Abstract

      Introduction

      Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes.

      Methods

      A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification.

      Results

      Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.

      Conclusions

      These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.

      Keywords

      Introduction

      Malignant pleural mesothelioma (MPM) is a challenging rare cancer comprising less than 0.3% of all malignances. It is aggressive and rarely curable. The WHO 2015 classifies MPM into three major histologic subtypes of prognostic importance: epithelioid, biphasic, and sarcomatoid (including those with desmoplastic features).
      WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.
      Clinically, these are viewed as two classes, epithelioid and nonepithelioid (sarcomatoid and biphasic). The sarcomatoid type is associated with the worst prognosis. MPM has an extremely poor prognosis with a median survival of 7 to 9 months if untreated and a 5-year survival rate of 5%, and all currently approved systemic or locoregional therapies fail in the vast majority of patients.
      • Tsao A.S.
      • Lindwasser O.W.
      • Adjei A.A.
      • et al.
      Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.
      These failures call for a better understanding of the disease, for multidisciplinary discussion, and consensus for the clinical care of these patients and for definition of key components that allow robust classification of the disease.
      There have been many recent molecular and immunologic additions to the pathologic diagnosis of malignancies in directing both targeted and immunologic therapies, in particular transforming the field of lung cancer, leading to a more multidisciplinary patient management structure. However, these advances have not been as marked in the management of patients with mesothelioma.
      • Tsao A.S.
      • Lindwasser O.W.
      • Adjei A.A.
      • et al.
      Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.
      Therefore, a multidisciplinary group was convened to review the histologic classification of MPM. Sponsored by the European Network for Rare Adult Solid Cancers (EURACAN) and the International Association for the Study of Lung Cancer (IASLC), a group of pathologists, molecular biologists, surgeons, radiologists, and oncologists met July 5-6, 2018, to critically review the current histologic classification of MPM in light of recent advances.
      Initial feedback from specialties other than pathology commented on the need for greater standardization in reporting, with classification based on evidence and validated to be useful in clinical practice. Classification also needed to be consistent among pathologists and to be comprised of biologically and clinically relevant subtypes and features which could be applied to routine practice and clinical trials. Specifically, it was believed that there could be more granularity than simply the three current subtypes. More precise histologic diagnosis with improved risk stratification could be important for patient selection for surgery, multimodal therapy, or chemotherapy alone. Inclusion of nontumoral features within the tumor micro-environment might also be of value in relation to understanding the molecular pathogenesis of MPM. Other suggestions included more consistent guidance for use of immunohistochemistry (IHC) and molecular analysis. Finally, all groups commented on a lack of standardization in tissue acquisition and how variability in the number and size of tissue samples might affect histologic classification.
      Each specialty, namely, pathology, surgery, imaging, molecular pathology, and oncology, then met to discuss gaps between the current histologic classification and their own practices, leading to a set of recommendations that will hopefully provide a template for future clinical management, WHO classification, and research across all specialties.
      The focus of the discussion was on pleural mesothelioma and prognostic features of MPM. Prognostic relevance of these features has yet to be validated in mesothelioma of extrapleural sites. Additionally, questions for further investigation included herein were developed from a thoracic perspective, but expansion to mesotheliomas involving extrapleural sites including peritoneal mesothelioma will be an important future direction.

      Pathology

      Sample Types and Classification

      WHO classifications are primarily based on resection specimens. For lung carcinoma, the 2015 edition was the first to include a specific classification system for biopsies as well as resections, following the 2011 IASLC/American Thoracic Society/European Respiratory Society updated adenocarcinoma classification proposals.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.
      Histologic classification of mesothelioma creates its own issues as often only biopsy samples, and sometimes only cytology samples, are available for many patients. In addition, there is considerable variation in the size and number of samples obtained, as biopsy samples may be transthoracic (needle biopsies and aspirates) or taken at thoracoscopy. The distinction where biopsy ends in terms of thoracoscopic biopsy and pleural decortication is not clearly defined, although there is recognition of specific operations that allow maximal surgical cytoreduction, including extended pleurectomy/decortication (EPD) and “extrapleural pneumonectomy (EPP)”.
      • Rice D.
      • Rusch V.
      • Pass H.
      • et al.
      Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer international staging committee and the International Mesothelioma Interest Group.
      A more detailed discussion on the many issues of tissue acquisition for mesothelioma diagnosis are provided in the section on surgery later in this paper. It was agreed that, where relevant, specific terminology and criteria should be proposed for biopsy and cytology specimens, to be distinguished from those undergoing definitive surgery EPD/EPP or diagnosis at autopsy. Furthermore, only those undergoing EPD/EPP would undergo pathologic staging, with the remainder being clinically staged via multidisciplinary team review (see section later on surgery).

      Recommendations

      (1) Pathologic classification should have terminology and criteria that allow classification across the spectrum of cytology/biopsy and definitively resected material. (2) Cases undergoing maximal surgical cytoreduction (EPD and EPP) should be pathologically staged. Cases sampled to a lesser degree should be clinically staged. (3) Recommendations on number and size of samples are discussed in the later section on surgery.

      Proposals for Updating the Histologic Subtyping of Mesothelioma

      Table 1 lists the current subtypes of MPM in the 2015 WHO classification.
      WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.
      Table 12015 WHO Classification of Mesothelioma
      TypeDescription
      Diffuse malignant mesothelioma
       Epithelioid mesotheliomaComposed of rounded rather than spindle-shaped cells usually showing a cohesive architecture, although epithelioid cells can show single cell growth within fibrous stroma.
       Sarcomatoid mesothelioma, including desmoplastic variantComposed of spindle-shaped (greater than two times longer than wide). The spindle cells may lie in varying amounts of fibrous stroma, or they can form solid sheets.
       Biphasic mesotheliomaShowing at least 10% of both epithelioid and sarcomatoid morphology. This rule is limited to definitive resections, namely, extended EPD and EPP. For smaller samples, until more data are collected, the group proposes that the diagnosis of “biphasic” can be rendered regardless of the percentages of each component present and that the diagnosis should be accompanied by a comment indicating the percentages of each component.
      Localized malignant mesothelioma
       Epithelioid mesothelioma
       Sarcomatoid mesothelioma
       Biphasic mesothelioma
      Well-differentiated papillary mesotheliomaA rare localized mesothelial neoplasm characterized by an exophytic papillary architecture lined by relatively bland mesothelium with no or only minimal areas of invasion. Diagnosis requires exclusion of diffuse malignant mesothelioma with papillary architecture.
      Adenomatoid tumor
      EPP, extrapleural pneumonectomy; EPD, extended pleurectomy/decortication.
      Adapted from the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.
      WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.

      Localized Malignant Mesothelioma

      Although rare, localized mesotheliomas are important to recognize as they are potentially treatable by complete (pR0) resection and carry a favorable prognosis compared to diffuse mesotheliomas.
      • Allen T.C.
      • Cagle P.T.
      • Churg A.M.
      • et al.
      Localized malignant mesothelioma.
      ,
      • Marchevsky A.M.
      • Khoor A.
      • Walts A.E.
      • et al.
      Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Interest Group.
      Classification requires correlation with imaging and surgical findings to ensure that there is no evidence of unsampled diffuse disease. Localized mesotheliomas have been shown to have distinctive genetic features, with both similarities to and differences from diffuse MPM.
      • Hung Y.P.
      • Dong F.
      • Dubuc A.M.
      • Dal Cin P.
      • Bueno R.
      • Chirieac L.R.
      Molecular characterization of localized pleural mesothelioma.

      Diffuse Malignant Mesothelioma

      The 2015 WHO classification divides diffuse malignant mesotheliomas into epithelioid, biphasic, and sarcomatoid subtypes (Table 1 and Fig. 1), recognizing desmoplastic features in the sarcomatoid subtype.
      WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.
      In addition, there have been numerous publications in the past 30 years that report prognostic relevance of both common and rare features seen in epithelioid, and to a lesser degree, sarcomatoid mesothelioma. Some of these carry adverse prognostic significance, such as solid, pleomorphic, rhabdoid, and transitional features, whereas others are reported as favorable, such as lymphohistiocytoid, and possibly myxoid features.
      • Alchami F.S.
      • Attanoos R.L.
      • Bamber A.R.
      Myxoid variant epithelioid pleural mesothelioma defines a favourable prognosis group: an analysis of 191 patients with pleural malignant mesothelioma.
      • Kadota K.
      • Suzuki K.
      • Sima C.S.
      • Rusch V.W.
      • Adusumilli P.S.
      • Travis W.D.
      Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma.
      • Ordonez N.G.
      Pleomorphic mesothelioma: report of 10 cases.
      • Ordonez N.G.
      Mesothelioma with rhabdoid features: an ultrastructural and immunohistochemical study of 10 cases.
      • Krasinskas A.M.
      • Borczuk A.C.
      • Hartman D.J.
      • et al.
      Prognostic significance of morphological growth patterns and mitotic index of epithelioid malignant peritoneal mesothelioma.
      • Galateau Salle F.
      • Le Stang N.
      • Nicholson A.G.
      • et al.
      New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
      • Galateau-Salle F.
      • Attanoos R.
      • Gibbs A.R.
      • et al.
      Lymphohistiocytoid variant of malignant mesothelioma of the pleura: a series of 22 cases.
      • Henderson D.W.
      • Attwood H.D.
      • Constance T.J.
      • Shilkin K.B.
      • Steele R.H.
      Lymphohistiocytoid mesothelioma: a rare lymphomatoid variant of predominantly sarcomatoid mesothelioma.
      • Leigh R.A.
      • Webster I.
      Lymphocytic infiltration of pleural mesothelioma and its significance for survival.
      Figure thumbnail gr1
      Figure 1A, Epithelioid malignant mesothelioma shows malignant rounded epithelioid cells. B, Sarcomatoid malignant mesothelioma shows malignant spindle cells lying within fibrous stroma. C, Biphasic malignant mesothelioma shows a combination of epithelioid and sarcomatoid areas. D, Well-differentiated papillary mesothelioma shows prominent papillary architecture, with the surface covered by bland mesothelial cells.

      Well-Differentiated Papillary Mesothelioma

      When localized, well-differentiated papillary mesotheliomas (WDPMs) (Fig. 1) are also potentially treatable by complete (pR0) resection, and carry a favorable prognosis compared to diffuse mesotheliomas.
      • Galateau-Salle F.
      • Vignaud J.M.
      • Burke L.
      • et al.
      Well-differentiated papillary mesothelioma of the pleura: a series of 24 cases.
      Likewise, classification requires correlation with imaging and surgical findings to ensure there is no evidence of different subtypes of disease. Diagnosis of WDPMs also requires application of strict criteria in order not to misdiagnose invasive diffuse mesotheliomas with prominent surface papillary architecture, which may be facilitated by the recent recognition of mutually exclusive mutations in TRAF7 and CDC42 reported to distinguish peritoneal WDPM from diffuse malignant mesothelioma.
      • Churg A.
      • Allen T.
      • Borczuk A.C.
      • et al.
      Well-differentiated papillary mesothelioma with invasive foci.
      ,
      • Stevers M.
      • Rabban J.T.
      • Garg K.
      • et al.
      Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42.
      Additionally, WDPMs in this study did not harbor alterations in BAP1, CDKN2A, NF2, and SETD2 genes, further distinguishing WDPM from diffuse malignant mesothelioma. These findings suggest that BAP1 IHC and p16 fluorescence in situ hybridization (FISH) may be diagnostically useful in identifying WDPM and that the diagnosis of WDPM should be questioned when BAP1 expression is lost by IHC or homozygous deletion in CDKN2A is detected by p16 FISH. PAX8 expression is also commonly seen in WDPM; however, it is rare in diffuse malignant mesothelioma, although extent of overexpression may differ between clones.
      • Sun M.
      • Zhao L.
      • Weng Lao I.
      • Yu L.
      • Wang J.
      Well-differentiated papillary mesothelioma: a 17-year single institution experience with a series of 75 cases.
      • Xing D.
      • Banet N.
      • Sharma R.
      • Vang R.
      • Ronnett B.M.
      • Illei P.B.
      Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study.
      • Chapel D.B.
      • Husain A.N.
      • Krausz T.
      • McGregor S.M.
      PAX8 Expression in a subset of malignant peritoneal mesotheliomas and benign mesothelium has diagnostic implications in the differential diagnosis of ovarian serous carcinoma.

      Current Patterns

      Epithelioid Mesothelioma

      A critical review of the literature shows that reported features in epithelioid mesothelioma can be stratified as a mixture of architectural patterns, and cytologic and stromal features (Tables 2 and 3, and Fig. 2).
      • Husain A.N.
      • Colby T.V.
      • Ordonez N.G.
      • et al.
      Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the International Mesothelioma Interest Group.
      Their identification is important for several reasons. First, they allow pathologists to diagnose epithelioid mesothelioma correctly and avoid misdiagnoses due to histologic similarity with other tumor types. Second, some features have prognostic value which could be incorporated into a grading system and/or a prognostic index.
      • Kadota K.
      • Suzuki K.
      • Sima C.S.
      • Rusch V.W.
      • Adusumilli P.S.
      • Travis W.D.
      Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma.
      However, most publications are small case cohorts and criteria are, to a degree, arbitrary. Nevertheless, more precise diagnostic criteria would likely improve both reproducibility and assessment of the individual significance of these features.
      Table 2Proposed Changes to Subtyping of Mesothelioma
      Diffuse malignant mesothelioma
      Some architectural patterns and cytologic and stromal features are important for prognostic significance whereas some are included only for clarity to avoid pathology misdiagnoses. When generating reports, please note that multiple architectural patterns and cytologic and stromal features may be present in a tumor and all patterns/features seen in a tumor should be included in the report.
      Epithelioid malignant mesothelioma
       Architectural patterns (Give percentages for EPD/EPP and document patterns present for all other samples)
        Tubulopapillary
        Trabecular
        Adenomatoid
        Microcystic
        Solid
        Micropapillary
        Transitional pattern
      Classification of transitional and pleomorphic patterns is currently difficult due to limited data available. Therefore, the consensus is to include transitional and pleomorphic patterns under both epithelioid and sarcomatoid types until more data emerge.
        Pleomorphic
      Classification of transitional and pleomorphic patterns is currently difficult due to limited data available. Therefore, the consensus is to include transitional and pleomorphic patterns under both epithelioid and sarcomatoid types until more data emerge.
       Cytologic features (Give percentages for EPD/EPP. For all other samples, state “with … features present”)
        Rhabdoid
        Deciduoid
        Small cell
        Clear cell
        Signet ring
        Lymphohistiocytoid
      Histiocytoid refers to morphology of actual tumour cells, not the presence of background macrophages.
       Stromal features (Give percentages for EPD/EPP. For all other samples, state “with … features present”)
        Myxoid
      Sarcomatoid malignant mesothelioma (Give percentages for EPD/EPP. For all other samples, state “with … features present”)
       Desmoplastic
       With heterologous differentiation
       Lymphohistiocytoid
      Histiocytoid refers to morphology of actual tumour cells, not the presence of background macrophages.
       Transitional pattern
      Classification of transitional and pleomorphic patterns is currently difficult due to limited data available. Therefore, the consensus is to include transitional and pleomorphic patterns under both epithelioid and sarcomatoid types until more data emerge.
       Pleomorphic
      Classification of transitional and pleomorphic patterns is currently difficult due to limited data available. Therefore, the consensus is to include transitional and pleomorphic patterns under both epithelioid and sarcomatoid types until more data emerge.
      Biphasic malignant mesothelioma (For EPD/EPP, any combination of patterns of epithelioid and sarcomatoid mesothelioma with at least 10% of each component. For all other samples, the consensus was to propose that the diagnosis of “biphasic” can be made regardless of percentages of each component and to include a comment indicating the percentages of each component in the sample.)
      Localized malignant mesothelioma (Any of the above subtypes may be present, with tumor limited to an isolated mass lesion)
      Well-differentiated papillary mesothelioma
      Adenomatoid tumor
      EPP, extrapleural pneumonectomy; EPD, extended pleurectomy/decortication.
      a Some architectural patterns and cytologic and stromal features are important for prognostic significance whereas some are included only for clarity to avoid pathology misdiagnoses. When generating reports, please note that multiple architectural patterns and cytologic and stromal features may be present in a tumor and all patterns/features seen in a tumor should be included in the report.
      b Classification of transitional and pleomorphic patterns is currently difficult due to limited data available. Therefore, the consensus is to include transitional and pleomorphic patterns under both epithelioid and sarcomatoid types until more data emerge.
      c Histiocytoid refers to morphology of actual tumour cells, not the presence of background macrophages.
      Table 3Definitions for Architectural Patterns, Cytologic Features and Stromal Characteristics in Pleural Mesothelioma
      Table 3 defines elements shown in Figure 2.
      Histologic patterns
      • A.
        Tubular: Round to oval spaces surrounded by a single layer of malignant epithelioid cells.
      • B.
        Papillary: Malignant epithelioid cells growing over a fibrovascular core.
      • C.
        Tubulopapillary: In many cases, tubular and papillary patterns are seen together.
      • D.
        Trabecular: An interconnected single or dual linear arrangement of malignant epithelioid cells
      • E.
        Solid: An architectural feature comprising continuous sheets of malignant epithelioid cells.
      • F.
        Micropapillary: Small groups of epithelioid cells forming a papillary structure, but lacking a fibrovascular core. Micropapillary can also include a single cell pattern.
      • G.
        Adenomatoid: A pattern of malignant mesothelioma composed of gland-like structures lined by flat to cuboidal malignant epithelioid cells resembling adenomatoid tumor.
      • H.
        Microcystic: A cribriform network of malignant epithelioid cells with small acinar spaces forming round holes like a sieve.
      Cytologic features
      • I.
        Pleomorphic: Tumor cells show marked nuclear atypia, often with bizarre nuclei and tumour giant cells.
      • J.
        Transitional: Tumor cells are intermediate between epithelioid and sarcomatoid morphologies, having lost their rounded morphology but not being overtly sarcomatoid.
      • K.
        Rhabdoid: Tumor cells resemble those seen in rhabdomyoblastic tumors, typically with a cytoplasmic eosinophilic globule that is positive for cytokeratins and generally negative for muscle markers.
      • L.
        Deciduoid: Tumors cells have a significant excess of richly eosinophilic cytoplasm resembling the decidua from the placenta. This carries no prognostic significance as a cytologic feature, but is important for avoiding misdiagnosis.
      • M.
        Small cell: Small hyperchromatic tumor cells morphologically resembling small cell carcinoma, but showing a mesothelial phenotype. This carries no prognostic significance but is important for avoiding misdiagnosis.
      • N.
        Clear cell: Tumor cells with clear cytoplasm. This carries no prognostic significance, but is important so metastatic clear cell carcinoma is not incorrectly diagnosed.
      • O.
        Signet ring: Tumor cells with intracytoplasmic vacuoles pushing the nucleus to the side. This carries no prognostic significance in mesothelioma, but is important so metastatic signet ring carcinomas from other sites are not incorrectly diagnosed.
      • P.
        Lymphohistiocytoid: This feature is seen in predominantly sarcomatoid mesothelioma where the neoplastic cells are histiocytoid in appearance but are obscured by a prominent infiltrate of lymphocytes. The morphology raises the differential diagnosis of malignant lymphoma. This definition requires that the actual tumour cells resemble histiocytes and does not simply represent prominent lymphocytic infiltration in an epithelioid mesothelioma. Focal lymphohistiocytoid features occur in otherwise conventional sarcomatoid mesotheliomas.
      Stromal features
      • Q.
        Myxoid: Tumour cells lie within a pale hematoxyphilic mucoid stroma. This should be noted when > 50% of a tumor with < 50% solid component shows this feature.
      • R.
        Desmoplastic: A sarcomatoid mesothelioma with prominent dense hyaline fibrous stroma, haphazard slit-like spaces, bland collagen necrosis, cellular proliferation nodules and invasive growth.
      • S.
        Heterologous elements: Sarcomatous elements such as osteosarcoma (as seen in figure), chondrosarcoma and rhabdomyosarcoma.
      a Table 3 defines elements shown in Figure 2.
      Figure thumbnail gr2ah
      Figure 2A-S, Architectural patterns and cytologic and stromal features in malignant mesothelioma (see for definitions).
      Figure thumbnail gr2ip
      Figure 2A-S, Architectural patterns and cytologic and stromal features in malignant mesothelioma (see for definitions).
      Figure thumbnail gr2qs
      Figure 2A-S, Architectural patterns and cytologic and stromal features in malignant mesothelioma (see for definitions).

      Biphasic Mesothelioma

      The current WHO classification requires at least 10% of the tumor to have sarcomatoid elements along with an epithelioid component for the diagnosis of biphasic mesothelioma. However, this cutoff is arbitrary and not based on evidence. One study suggested a less than 80% cutoff for sarcomatoid areas afforded a better prognosis, and another study showed prognostic significance with a cutoff of 50%.
      • Galateau Salle F.
      • Le Stang N.
      • Nicholson A.G.
      • et al.
      New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
      ,
      • Vigneswaran W.T.
      • Kircheva D.Y.
      • Ananthanarayanan V.
      • et al.
      Amount of epithelioid differentiation is a predictor of survival in malignant pleural mesothelioma.
      However, more data are required before changes are made to the WHO criteria. The consensus agreement was that the use of percentages to define biphasic mesothelioma should be limited to EPDs and EPPs. Because criteria have never been proposed for smaller samples, the group recommended that the definition for the diagnosis of biphasic mesothelioma should be changed for smaller samples, so that any sample can be diagnosed as biphasic mesothelioma with a comment providing the percentages of each component in the sample.
      A stricter definition of what constitutes sarcomatoid features also may improve interobserver reproducibility among pathologists for characterization of biphasic mesothelioma, which currently only has a kappa of 0.45.
      • Galateau Salle F.
      • Le Stang N.
      • Nicholson A.G.
      • et al.
      New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
      IHC staining for cytokeratins may be beneficial in identifying a sarcomatoid component, as well as FISH analysis for p16 deletion in suspicious but nondiagnostic cases.
      • Klebe S.
      • Brownlee N.A.
      • Mahar A.
      • et al.
      Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases.

      Sarcomatoid Mesothelioma

      The group concluded that the current definition should remain, although the diagnostic criteria should be strengthened to improve diagnostic reproducibility, particularly the difficult area of the desmoplastic variant. The WHO defines sarcomatoid mesothelioma tumor cells as “elongated and tapered” (Fig. 1). Sarcomatoid mesothelial cells can be difficult to identify and/or distinguish from reactive fibrosis in some cases by histology alone, and in these cases, the extent and distribution of cytokeratin IHC may be helpful in reaching a diagnosis of sarcomatoid MPM.
      There was also a focus on mesotheliomas with a transitional pattern. Given its cohesive nature, the transitional pattern is classified under epithelioid MPM in the current WHO classification. However, it is reported to have a prognostic significance closer to sarcomatoid as opposed to epithelioid subtypes.
      • Galateau Salle F.
      • Le Stang N.
      • Nicholson A.G.
      • et al.
      New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
      Because kappa values for diagnostic reproducibility were only 0.42, a stricter set of definitions to distinguish transitional from both epithelioid and sarcomatoid types is needed. The group concluded that there is insufficient data available currently to determine whether the transitional pattern should be classified under the epithelioid or sarcomatoid type of MPM. Therefore, the consensus was to include the transitional pattern under both epithelioid and sarcomatoid types until more data is available. A similar conclusion was reached for a pleomorphic pattern.

      Malignant Mesothelioma In Situ

      Malignant mesothelioma in situ (MMIS) was first proposed in 1992 based on a small series in which there was a single layer of small papillary projections of cytologically atypical mesothelial cells on the pleural surface associated with microscopically invasive mesothelioma.
      • Whitaker D.
      • Henderson D.W.
      • Shilkin K.B.
      The concept of mesothelioma in situ: implications for diagnosis and histogenesis.
      The group discussed whether this pattern of growth really represented mesothelioma in situ or surface growth of an underlying invasive mesothelioma that was not recognized or biopsied, and also the challenge of making this diagnosis and distinguishing it from reactive/atypical mesothelial proliferations. The consensus view was that MMIS must exist as a starting point for some tumors but, until recently, the issue has always been how to diagnose those MMIS without the presence of coexistent invasion.
      Advances in the molecular understanding of mesothelioma, in particular loss of BAP1 expression by IHC and/or the presence of a homozygous deletion of CDKN2A (p16) identified by either FISH or by methylthioadenosine phosphorylase (MTAP) IHC, potentially allow identification of genetic abnormalities in cases where the mesothelial proliferation is limited to the serosal surface and allow distinction between non-neoplastic and neoplastic cells.
      • Churg A.
      • Sheffield B.S.
      • Galateau-Salle F.
      New markers for separating benign from malignant mesothelial proliferations: are we there yet?.
      • Sheffield B.S.
      • Hwang H.C.
      • Lee A.F.
      • et al.
      BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations.
      • McGregor S.M.
      • McElherne J.
      • Minor A.
      • et al.
      BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.
      • Bruno R.
      • Ali G.
      • Fontanini G.
      Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review.
      • Bott M.
      • Brevet M.
      • Taylor B.S.
      • et al.
      The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.
      • Hatem L.
      • McIntire P.J.
      • He B.
      • et al.
      The role of BRCA1-associated protein 1 in the diagnosis of malignant mesothelioma in effusion and fine-needle aspiration cytology.
      • Cozzi I.
      • Oprescu F.A.
      • Rullo E.
      • Ascoli V.
      Loss of BRCA1-associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions.
      • Hwang H.C.
      • Sheffield B.S.
      • Rodriguez S.
      • et al.
      Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the diagnosis of malignant mesothelioma in effusion cytology specimens.
      • Hida T.
      • Hamasaki M.
      • Matsumoto S.
      • et al.
      BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests.
      • Walts A.E.
      • Hiroshima K.
      • McGregor S.M.
      • Wu D.
      • Husain A.N.
      • Marchevsky A.M.
      BAP1 immunostain and CDKN2A (p16) FISH analysis: clinical applicability for the diagnosis of malignant mesothelioma in effusions.
      • Berg K.B.
      • Dacic S.
      • Miller C.
      • Cheung S.
      • Churg A.
      Utility of methylthioadenosine phosphorylase compared with BAP1 immunohistochemistry, and CDKN2A and NF2 fluorescence in situ hybridization in separating reactive mesothelial proliferations from epithelioid malignant mesotheliomas.
      • Hida T.
      • Hamasaki M.
      • Matsumoto S.
      • et al.
      Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: comparison with 9p21 FISH and BAP1 immunohistochemistry.
      • Kinoshita Y.
      • Hamasaki M.
      • Yoshimura M.
      • et al.
      A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis.
      • Shahi M.
      • Eguchi T.
      • Zauderer M.G.
      • et al.
      Comparison of MTAP immunohistochemsitry (IHC) with P16/CDKN2A deletion/loss and utility of MTAP and BAP1 IHC in the diagnosis of malignant pleural mesothelioma (MPM).
      There has been recent publication of 11 cases of MMIS (9 pleural, 2 peritoneal) with only a surface single layer of mesothelial cells, no gross tumor on imaging or direct examination, and no invasive mesothelioma for at least 1 year.
      • Churg A.
      • Hwang H.
      • Tan L.
      • et al.
      Malignant mesothelioma in situ.
      ,
      • Churg A.
      • Galateau-Salle F.
      • Roden A.C.
      • et al.
      Malignant mesothelioma in situ: morphologic features and clinical outcome.
      In the larger series of 10 patients, 7 developed invasive disease 12 to 92 months after biopsy, with 3 patients still free of invasive disease at 12, 57, and 120 months, respectively (Fig. 3).
      Figure thumbnail gr3
      Figure 3Malignant mesothelioma in situ. A, The pleural surface is covered by a single layer comprising a mildly atypical mesothelial proliferation. B, The cells show loss of BAP1 staining. The patient developed an invasive mesothelioma at 36 months after initial presentation.
      The diagnosis of MMIS would be based on a combination of clinical, imaging, and histologic criteria, and only made in the absence of clinical and radiologic evidence of tumor. Patients may have a pleural effusion but would not show any mass lesions on imaging or thoracoscopy (unless biopsy specimens show the mass not to be mesothelioma), and the biopsy material shows a mesothelial proliferation limited to the serosal surface with either BAP1 loss and/or CDKN2A/p16 homozygous deletion. Testing should only be performed in laboratories with experience using validated tests and appropriate antibodies, with the committee view that the Santa Cruz C4 clone is currently the best commercially available option for BAP1 IHC, and that FISH for homozygous deletion of p16 should only be performed in accredited laboratories, with a cutoff of 20% being the most commonly used.
      Recognition of either BAP1 loss and/or CDKN2A/p16 homozygous deletion in cytologic material from a pleural effusion without any mass lesion should prompt histologic sampling to confirm a lack of invasion, although not all cases carry these molecular abnormalities; therefore, the diagnosis of MPM cannot be excluded in the absence of these molecular changes.
      Another major issue discussed, but without supporting evidence, is the challenge of what population of patients should be assessed for BAP1 loss and/or CDKN2A/p16 deletion. Opinions varied and potential patient populations that were suggested included those with exposure to asbestos, presence of morphologically atypical mesothelial proliferations, and clinical suspicion of MPM (e.g., repeated unexplained effusions). However, identification of these patient populations is subject to potential lack of consistency (germline versus somatic BAP1 mutations, definition of exposure, extent of atypia, etc.). The group consensus was that, at this point in time, a molecular work up using BAP1 IHC, p16 FISH, or MTAP IHC as a marker for p16 deletion should be limited to patients for whom there is clinical suspicion of MPM. More work is clearly needed in this area, and individual institutions were encouraged to embark on a detailed assessment of this topic and data accrual.
      There is currently insufficient evidence to support a category of minimally invasive MPM, but the group agreed this was a subject for research. It was recognized that data is limited but the clinical importance of identifying MMIS was a major factor in making this proposal at this early stage of literature accrual.

      Recommendations

      (1) The current classification system should be updated to include architectural patterns and stromal and cytologic features that might improve prognosis, and permit early treatment and/or avoid misdiagnosis. (2) Subject to accrual of additional supportive data, MMIS could potentially be added as a category in future classification systems.
      A proposed update is presented in Tables 2 and 3. Questions for future investigation are provided in Supplementary data 1, section 1.2.7.

      Grading of MPM

      Since 2010, there have been several papers proposing a pathologic grading system for epithelioid MPM that would provide prognostic stratification.
      • Kadota K.
      • Suzuki K.
      • Colovos C.
      • et al.
      A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma.
      • Rosen L.E.
      • Karrison T.
      • Ananthanarayanan V.
      • et al.
      Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.
      • Pelosi G.
      • Papotti M.
      • Righi L.
      • et al.
      Pathologic grading of malignant pleural mesothelioma: an evidence-based proposal.
      Although grading does not yet have therapeutic implications because a uniform grading system has not been previously recommended, distinction between low and high grade has potential management implications such as intervals for imaging follow-up. Thus, grading may be of benefit as part of inclusion or stratification criteria when planning future trials, and may provide better risk stratification than assignment of some rare architectural, stromal, or cytologic features of epithelioid MPM (see previous section).
      The purpose of applying a grading system to epithelioid MPM would be to identify those tumors that behave more aggressively. This grading system can be applied to biopsy and resection specimens to determine prognosis.
      • Pelosi G.
      • Papotti M.
      • Righi L.
      • et al.
      Pathologic grading of malignant pleural mesothelioma: an evidence-based proposal.
      Although there have also been studies of grading mesotheliomas across all subtypes, including biphasic and sarcomatoid, there does not seem to be a role yet for more granular risk stratification of these tumors because data consistently show a poorer prognosis for tumors containing a sarcomatoid component and dividing sarcomatoid areas into low- and high-grade groups has shown low interobserver agreement.
      • Galateau Salle F.
      • Le Stang N.
      • Nicholson A.G.
      • et al.
      New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
      ,
      • Pelosi G.
      • Papotti M.
      • Righi L.
      • et al.
      Pathologic grading of malignant pleural mesothelioma: an evidence-based proposal.
      Therefore, the consensus view was that grading should be limited to epithelioid MPM because patients with epithelioid histology would benefit the most from improved risk stratification.
      Proposals for grading systems in the literature vary, but are primarily based on a combination of nuclear features, mitotic rate, and the presence or absence of necrosis. The pathology group favored a two-tier system of low and high grade based on an international multi-institutional paper that showed consistency among several institutions and provided risk stratification for epithelioid MPM.
      • Rosen L.E.
      • Karrison T.
      • Ananthanarayanan V.
      • et al.
      Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.
      Areas showing the highest grade features should be used to assign the tumor to low (any nuclear grade 1 and nuclear grade 2 without necrosis) or high grade (nuclear grade 2 with necrosis and any nuclear grade 3) (Fig. 4 and Table 4).
      Figure thumbnail gr4
      Figure 4Nuclear grading features. A, Nuclei are small, uniform, and round with inconspicuous nucleoli and finely granular chromatin. B, Nuclei are intermediate in size with limited anisonucleosis and pleomorphism. Nucleoli are more conspicuous and chromatin is coarser. C, Nuclei are large with anisonucleosis and pleomorphism. Nucleoli are prominent and chromatin is coarse.
      Table 4Grading of Pleural Epithelioid Malignant Mesothelioma
      Nuclear Grade:

      Nuclear atypia score: _____ (1 for mild, 2 for moderate, 3 for severe)

      Mitotic count: ____ (1 for low [≤1 per 2mm2], 2 for intermediate [2-4 per2mm2], 3 for high [5+ per 2mm2])

      Sum: _____ (2 or 3 = nuclear grade I, 4 or 5 = nuclear grade II, 6 = nuclear grade III)

      Necrosis: Present / Absent

      Low-grade = Nuclear grades I and II without necrosis

      High-grade = Nuclear grade II with necrosis, Nuclear grade III with or without necrosis
      The group considered the addition of certain published features that had been based on architectural patterns into the high-grade category (solid, pleomorphic, rhabdoid, micropapillary, and transitional).
      • Alchami F.S.
      • Attanoos R.L.
      • Bamber A.R.
      Myxoid variant epithelioid pleural mesothelioma defines a favourable prognosis group: an analysis of 191 patients with pleural malignant mesothelioma.
      • Kadota K.
      • Suzuki K.
      • Sima C.S.
      • Rusch V.W.
      • Adusumilli P.S.
      • Travis W.D.
      Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma.
      • Ordonez N.G.
      Pleomorphic mesothelioma: report of 10 cases.
      • Ordonez N.G.
      Mesothelioma with rhabdoid features: an ultrastructural and immunohistochemical study of 10 cases.
      ,
      • Rosen L.E.
      • Karrison T.
      • Ananthanarayanan V.
      • et al.
      Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.
      Deciduoid mesotheliomas have also been reported as being more aggressive, but this was associated with high-grade nuclear features; therefore, the application of grading to these tumors would place them into the higher-grade category.
      • Ordonez N.G.
      Deciduoid mesothelioma: report of 21 cases with review of the literature.
      ,
      • Shanks J.H.
      • Harris M.
      • Banerjee S.S.
      • et al.
      Mesotheliomas with deciduoid morphology: a morphologic spectrum and a variant not confined to young females.
      However, it was decided that these should be documented separately until there was evidence that adding patterns to a two-tier grading system added sufficient value in prognostication (Supplementary data 2, Table 1).

      Recommendations

      (1) All specialty groups recommended that grading of epithelioid MPMs should be routinely part of reporting for all types of samples, favoring a two-tier system of low and high grade based on nuclear atypia, mitotic activity, and the presence or absence of necrosis. (2) Favorable and unfavorable histologic characteristics (architectural patterns, cytologic features, and stromal features) should also be reported (a template is proposed in Supplementary data 2, Table 2)
      Questions for future investigation are in Supplementary data 1, section 1.3.3.

      Use of Diagnostic and Predictive IHC and Molecular Assays

      There is considerable literature on the use of IHC in the diagnosis of mesothelioma, until recently all relating to problems in diagnosis, such as distinguishing mesothelioma from reactive mesothelial hyperplasia and reactive fibrous pleuritis, epithelioid MPM from metastatic carcinoma, and sarcomatoid mesothelioma from the other spindle cell neoplasms. These have been exhaustively reviewed elsewhere.
      • Husain A.N.
      • Colby T.V.
      • Ordonez N.G.
      • et al.
      Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the International Mesothelioma Interest Group.
      The recent introduction of IHC for BAP1 and use of p16 FISH and MTAP IHC to identify CDKN2A deletion, however, offer exciting new tools to distinguish benign from malignant mesothelial proliferations, including MMIS (see previous section), both in histology and cytology specimens.
      • Berg K.B.
      • Dacic S.
      • Miller C.
      • Cheung S.
      • Churg A.
      Utility of methylthioadenosine phosphorylase compared with BAP1 immunohistochemistry, and CDKN2A and NF2 fluorescence in situ hybridization in separating reactive mesothelial proliferations from epithelioid malignant mesotheliomas.
      • Hida T.
      • Hamasaki M.
      • Matsumoto S.
      • et al.
      Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: comparison with 9p21 FISH and BAP1 immunohistochemistry.
      • Kinoshita Y.
      • Hamasaki M.
      • Yoshimura M.
      • et al.
      A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis.
      • Shahi M.
      • Eguchi T.
      • Zauderer M.G.
      • et al.
      Comparison of MTAP immunohistochemsitry (IHC) with P16/CDKN2A deletion/loss and utility of MTAP and BAP1 IHC in the diagnosis of malignant pleural mesothelioma (MPM).
      ,
      • Yatabe Y.
      • Dacic S.
      • Borczuk A.C.
      • et al.
      Best practices recommendations for diagnostic immunohistochemistry in lung cancer.
      ,
      • Pulford E.
      • Huilgol K.
      • Moffat D.
      • Henderson D.W.
      • Klebe S.
      Malignant mesothelioma, BAP1 immunohistochemistry, and VEGFA: does BAP1 have potential for early diagnosis and assessment of prognosis?.
      There are no current targeted treatment options for routine use that warrant standardized screening of mesotheliomas for a molecular signature, and pathologists were not in agreement on whether such testing should be routinely recommended. A minority of individuals with loss of BAP1 may have a germline rather than a somatic mutation, although IHC screening was not considered the best methodology for identifying such patients.
      • Klebe S.
      • Driml J.
      • Nasu M.
      • et al.
      BAP1 hereditary cancer predisposition syndrome: a case report and review of literature.
      The consensus view on BAP1 staining was that, although it clearly has value in confirming MPM in atypical mesothelial proliferations, further work is required to understand why some mesotheliomas show discordance between epithelioid and sarcomatoid areas. Furthermore, it was noted that some institutions report partial loss and it is uncertain whether this is due to a lack of standardization in application of the antibody, or a true reflection of tumoral heterogeneity.
      Several trials are ongoing on the utility of programmed death ligand 1 (PD-L1) IHC, and there are early data to suggest some correlation between positive staining and sarcomatoid subtypes.
      • Nguyen B.H.
      • Montgomery R.
      • Fadia M.
      • Wang J.
      • Ali S.
      PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma.
      • Forest F.
      • Patoir A.
      • Dal Col P.
      • et al.
      Nuclear grading, BAP1, mesothelin and PD-L1 expression in malignant pleural mesothelioma: prognostic implications.
      • Mansfield A.S.
      • Roden A.C.
      • Peikert T.
      • et al.
      B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis.
      However, the majority of epithelioid mesotheliomas generally show a low level of positivity and other markers of tumor response should be sought.
      • Kao S.C.
      • Cheng Y.Y.
      • Williams M.
      • et al.
      Tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in malignant pleural mesothelioma.
      Currently, if requested, pathologists should score PD-L1 IHC in mesotheliomas in similar fashion to lung cancers, providing a percentage of positively staining tumor cells. Scoring should be undertaken according to the recommendations for the clone of antibody used, most being based on membrane staining of tumor cells, reporting the number of positively staining tumor cells within the tumor cell population as a percentage.
      • Chapel D.B.
      • Stewart R.
      • Furtado L.V.
      • Husain A.N.
      • Krausz T.
      • Deftereos G.
      Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays.

      Recommendations

      (1) Although BAP1 IHC is recommended as part of the diagnostic work-up of mesothelial proliferations, it should not be used in isolation from other clinical, morphologic, and IHC data to distinguish malignancy from reactive mesothelial hyperplasia. (2) No biologic markers are currently sufficiently clinically validated to warrant a recommendation for routine use, but should be undertaken on request and data collection is encouraged within the context of research trials (see molecular section)
      Questions for future investigation are in Supplementary data 1, section 1.4.3.

      Molecular Pathology

      Current Inter-Relationship Between Molecular Pathology and Cellular Pathology

      The limited use of molecular testing in mesothelioma compared to other cancers might be explained by the lack of knowledge of the molecular characteristics of this disease. Studies have proposed using gene expression tests to predict prognosis, but these have not become part of routine reporting.
      • Gordon G.J.
      • Dong L.
      • Yeap B.Y.
      • et al.
      Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma.
      Recently, there have been several sequencing efforts to provide insights into the genomic characteristics of these understudied diseases. In a recent study including a large number of cases, Bueno et al.
      • Bueno R.
      • Stawiski E.W.
      • Goldstein L.D.
      • et al.
      Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.
      reported a molecular classification of MPM based on expression patterns, which partially matched the three types in the 2015 WHO histologic classification. In this study, four molecular cluster groups were identified: sarcomatoid (consisting of all sarcomatoid, numerous biphasic, and a few epithelioid samples), epithelioid (consisting almost exclusively of epithelioid samples), epithelioid-biphasic (predominantly epithelioid, with some biphasic samples) and biphasic-sarcomatoid (predominantly biphasic samples, with some sarcomatoid samples). These groups were shown to recapitulate the epithelial-to-mesenchymal transition. The epithelioid and sarcomatoid groups constituted the most distinct molecular groups, with the epithelioid group having the longest overall survival. In line with the fact that CLDN15 and VIM were among the most significantly upregulated genes in the epithelioid and sarcomatoid groups, respectively, the authors found that the log2 ratio of CLDN15/VIM gene expression was significantly different between the four groups, allowing their distinction.
      • Bueno R.
      • Stawiski E.W.
      • Goldstein L.D.
      • et al.
      Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.
      In a recent study, in which Alcala et al (submitted for publication). re-analyzed the expression data of 211 MPM from Bueno et al.
      • Bueno R.
      • Stawiski E.W.
      • Goldstein L.D.
      • et al.
      Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.
      and 73 from The Cancer Genome Atlas,
      • Hmeljak J.
      • Sanchez-Vega F.
      • Hoadley K.A.
      • et al.
      Integrative molecular characterization of malignant pleural mesothelioma.
      the authors found that the molecular profile and the prognosis of MPM was better explained by a continuous model rather than by one based on discrete groups. They also found that the main source of variation of this continuum was explained by immune and vascular pathways. The authors found that the extreme of this continuum had very specific molecular profiles, with specific expression patterns of genes involved in angiogenesis and immune response. These findings were replicated in an independent series of 77 MPM cases from the French MESOBANK, and may assist the clinical management of MPM. The overexpression of the V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA) immune checkpoint protein has been validated by IHC by The Cancer Genome Atlas in an independent series of MPM samples.
      • Hmeljak J.
      • Sanchez-Vega F.
      • Hoadley K.A.
      • et al.
      Integrative molecular characterization of malignant pleural mesothelioma.
      ,
      • Muller S
      • Victoria Lai W
      • Adusumilli PS
      • et al.
      V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant mesothelioma.
      They found VISTA overexpressed in epithelioid MPM, correlated with mesothelin expression, and diffusely expressed in benign mesothelium. In the same line, unpublished targeted RNA sequencing data suggest the existence of subsets of MPMs with very characteristic immune environment signatures: one enriched for pleomorphic mesotheliomas with a CD8 T-lymphocyte signature, and a set of epithelioid samples with a very strong signature of B lineage cells (Franck Tirode, personal communication, 2018). Overall, the available genomic data suggest that while the molecular and histologic classifications do not match perfectly, both classifications can complement each other and also provide unique information for the clinical management of this deadly disease.
      The use of blood-based biomarkers for either the diagnosis or prognosis of mesothelioma remains exploratory. The gold standard biomarker, soluble mesothelin-related peptides (SMRP) or mesothelin, has consistent sensitivities and specificities of 40% and 98%, respectively. Essentially, only 16% to 40% of asbestos-exposed individuals will be detected by the marker to have mesothelioma on longitudinal follow-up, and only 15% will have a change in the marker within 6 months before diagnosis of the disease. SMRP is useful, however, for the monitoring of disease after or during treatment. SMRP is elevated in the majority of epithelioid mesotheliomas and a portion of biphasic but will not be able to detect sarcomatoid tumors. The use of fibulin 3 to diagnose mesothelioma remains controversial, but levels are generally elevated in all types of mesothelioma. There are no validated data on using microRNAs in serum or plasma to predict types of tumor, and the use of immuno-oncologic methods to diagnose MPM using transcriptional panels is in its infancy. Most recently, serum levels of calretinin measured by enzyme-linked immunosorbent assay in males with mesothelioma have been able to differentiate MPM types in a case-control study: differences between sarcomatoid (n = 28) and epithelioid (n = 103) (p = 0.0041) as well as sarcomatoid and biphasic (n = 44) (p = 0.0001) were statistically significant. These promising data should lead to further validation trials.
      • Johnen G.
      • Gawrych K.
      • Raiko I.
      • et al.
      Calretinin as a blood-based biomarker for mesothelioma.

      Tissue Acquisition for Molecular Studies

      The success of future research strongly relies on the quality of the tissue specimens and the levels of detail of the clinical and epidemiologic annotations. Close collaboration between experts from different disciplines is therefore warranted. As discussed in the pathologic and surgical sections, there is a need to better define what constitutes an adequate biopsy, as well as providing as much reproducible and detailed information about the sample as possible (i.e., type, subtype, tumor content, percentage of sarcomatoid content, fibrosis, and detailed information about the microenvironment such as percentage and type of inflammatory cells, etc.). This will hopefully allow accrual of information that will inform what is required to ensure successful genomic testing. Depending on the type of scan, the radiologist can provide information about the maximum metabolic activity (standardized uptake value), distribution, and extent of disease from positron-emission tomography (PET) scans, tumor distribution, invasion into adjacent structures, and quantitative measures such as tumor volume and fissure thickness from computed tomography (CT) scan and tumor heterogeneity, cellularity, and perfusion parameters from magnetic resonance imaging (MRI) scans. Oncologists would need to work much closer with molecular biologists and ensure that the costly clinical trials are always paired with the collection of tumor material and blood before and after treatment. Finally, an overview with detailed information regarding available bio-repositories and datasets would promote collaborations and help in advancing the research in this field.

      Recommendations

      For the use of the molecular characteristics and blood biomarkers to inform the histologic classification include: (1) Molecular characteristics that might inform clinical management (PD-L1 status, loss of BAP1, and CDKN2A deletion) should be incorporated into reports, if undertaken. (2) Although molecular analysis currently is primarily a research topic, molecular data should be part of future trials looking at prognostic indices. This includes data on the tumor microenvironment. (3) As calretinin levels in the blood might inform histologic classification, further validation studies should be considered.
      Questions for future investigation are in Supplementary data 1, section 2.1.4.

      Surgery

      Tissue Acquisition, Volume, and Processing

      As discussed in the pathology section, there is a need to refine classification so that it has relevance across all sample types received from the thorax, with recognition of distinction between maximal cytoreductive surgery, namely EPD and EPP, versus smaller samples.
      • Rice D.
      • Rusch V.
      • Pass H.
      • et al.
      Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer international staging committee and the International Mesothelioma Interest Group.
      Although the use of cytology specimens for the diagnosis of MPM remains controversial, occasionally, the combination of both pleural effusion cytology and pleural biopsy can complement one another diagnostically, particularly when a pleural biopsy shows mainly fibrosis and the cell block shows a cellular effusion. Emerging data suggest that the use of ancillary tests including BAP1 IHC, p16 FISH, and/or MTAP IHC can be helpful in the diagnosis of MPM on pleural effusion cytology specimens, which can be important in patients who are unable to undergo transthoracic or thoracoscopic biopsy procedures.
      • Hatem L.
      • McIntire P.J.
      • He B.
      • et al.
      The role of BRCA1-associated protein 1 in the diagnosis of malignant mesothelioma in effusion and fine-needle aspiration cytology.
      • Cozzi I.
      • Oprescu F.A.
      • Rullo E.
      • Ascoli V.
      Loss of BRCA1-associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions.
      • Hwang H.C.
      • Sheffield B.S.
      • Rodriguez S.
      • et al.
      Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the diagnosis of malignant mesothelioma in effusion cytology specimens.
      ,
      • Kinoshita Y.
      • Hamasaki M.
      • Yoshimura M.
      • et al.
      A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis.
      However, given the limitations inherent to cytology specimens as well as limitations in the application and interpretation of these ancillary tests, MPM cannot always be reliably diagnosed on cytology specimens.

      Depth, Number, and Location of Surgical Samples

      It was emphasized that ideal biopsy samples included subpleural fat (as opposed to chest wall fat), so that the extent of invasion can be assessed as this is a particularly useful diagnostic feature in better-differentiated superficial mesotheliomas. It was also believed that there was minimal published data and no standardization on the optimal number of biopsy specimens to ensure the presence of histologic subtypes that might impact on future management, such as sarcomatoid areas in patients being considered for surgery. A higher number of tissue blocks in biopsy specimens have been shown to provide better concordance with tumor subtype in resection specimens, as well as thoracoscopic biopsy specimens showing better concordance than needle biopsy specimens.
      • Chirieac L.R.
      • Hung Y.P.
      • Foo W.C.
      • et al.
      Diagnostic value of biopsy sampling in predicting histology in patients with diffuse malignant pleural mesothelioma.
      There may also be value in the assessment of tumor volume derived from CT scans as a prognostic factor and maximum PET avidity for targeting particularly active areas that may have prognostic relevance.

      Staging

      Discussion also included staging issues, and there was agreement that mesotheliomas diagnosed by maximal cytoreductive surgery (i.e., EPD and EPP) should be pathologically staged, whereas any smaller samples should be clinically staged. The importance of discussing intraoperative findings with the surgeon before completion of the pathologic staging was also emphasized.

      Recommendations

      (1) Studies to assess the ideal number of samples are needed to obtain an accurate assessment of tumor type should be undertaken. Until available, expert consensus was that at least three separate areas should be sampled from the pleural cavity, if not compromised by fibrosis, including any area of interest identified on pre-surgical imaging. Samples should also include subpleural fat, if feasible. (2) Additional tumor and normal control samples should be taken and stored as appropriate for molecular testing, with appropriate consent if for research. Pathologists need to ensure this can be enabled. (3) Maximal cytoreductive surgical resections (EPD and EPP) should be pathologically staged. Cases sampled to a lesser degree should be clinically staged.
      Questions for future investigation are in Supplementary data 1, section 3.1.5.

      Imaging

      The radiologic appearance of MPM is nonspecific, ranging from pleural effusion in early stages to lobulated circumferential pleural thickening and/or lobulated pleural masses in later stages of disease. Imaging findings include unilateral pleural effusion, circumferential nodular pleural thickening, and thickening of the interlobular septa.
      • Gill R.R.
      • Gerbaudo V.H.
      • Sugarbaker D.J.
      • Hatabu H.
      Current trends in radiologic management of malignant pleural mesothelioma.
      Although the tumor tends to grow as circumferential pleural thickening, MPM also may present as localized pleural masses. Occasionally, the involved hemithorax exhibits significant volume loss due to circumferential tumor without obvious chest wall invasion (“contracted hemithorax”); these cases generally show infiltrative tumor involvement through diffuse invasion of the endothoracic fascia. In advanced disease, the tumor may invade adjacent structures including the chest wall, mediastinum, pericardium, and diaphragm, or the tumor may metastasize to lymph nodes, lungs, bones, or distant sites.
      • Wang Z.J.
      • Reddy G.P.
      • Gotway M.B.
      • et al.
      Malignant pleural mesothelioma: evaluation with CT, MR imaging, and PET.
      Contrast-enhanced CT is the most widely available modality for evaluation of MPM, whereas MRI and 18F-fluorodeoxyglucose (FDG)–PET provide complementary information, especially in the assessment of resectability and response to therapy.
      • Gill R.R.
      • Gerbaudo V.H.
      • Sugarbaker D.J.
      • Hatabu H.
      Current trends in radiologic management of malignant pleural mesothelioma.
      The diagnostic performance of CT is influenced by the scanning conditions. Special mention should be made to venous phase imaging at single- or dual-energy CT.
      • Tsim S.
      • Stobo D.B.
      • Alexander L.
      • Kelly C.
      • Blyth K.G.
      The diagnostic performance of routinely acquired and reported computed tomography imaging in patients presenting with suspected pleural malignancy.
      MRI is superior to CT in detecting occult chest wall and diaphragmatic involvement, particularly with contrast-enhanced T1-weighted sequences with fat suppression, and can result in reclassification of up to 30% of surgical candidates into an unresectable stage.
      • Marom E.M.
      • Erasmus J.J.
      • Pass H.I.
      • Patz Jr., E.F.
      The role of imaging in malignant pleural mesothelioma.
      MRI also has been reported superior to CT for detecting involvement of bone, interlobar fissures, diaphragm (particularly transmural involvement and extension through the diaphragm), and endothoracic fascia.
      • Gill R.R.
      • Gerbaudo V.H.
      • Jacobson F.L.
      • et al.
      MR imaging of benign and malignant pleural disease.
      Diffusion-weighted MRI can provide information on MPM tumor histology.
      • Coolen J.
      • De Keyzer F.
      • Nafteux P.
      • et al.
      Malignant pleural disease: diagnosis by using diffusion-weighted and dynamic contrast-enhanced MR imaging—initial experience.
      ,
      • Gill RR
      • Umeoka S
      • Mamata H
      • et al.
      Diffusion-weighted MRI of malignant pleural mesothelioma: preliminary assessment of apparent diffusion coefficient in histologic subtypes.
      Perfusion CT and MRI also have been explored for the enhancement of diagnostic accuracy and for assessment of response to therapy.
      • Tsim S.
      • Humphreys C.A.
      • Cowell G.W.
      • et al.
      Early contrast enhancement: a novel magnetic resonance imaging biomarker of pleural malignancy.
      • Giesel F.L.
      • Bischoff H.
      • von Tengg-Kobligk H.
      • et al.
      Dynamic contrast-enhanced MRI of malignant pleural mesothelioma: a feasibility study of noninvasive assessment, therapeutic follow-up, and possible predictor of improved outcome.
      • Giesel F.L.
      • Choyke P.L.
      • Mehndiratta A.
      • et al.
      Pharmacokinetic analysis of malignant pleural mesothelioma-initial results of tumor microcirculation and its correlation to microvessel density (CD-34).
      • Gudmundsson E.
      • Labby Z.
      • Straus C.M.
      • et al.
      Dynamic contrast-enhanced CT for the assessment of tumour response in malignant pleural mesothelioma: a pilot study.
      The diagnosis of localized mesothelioma and MMIS is especially problematic. No reported studies have evaluated the role of imaging in this setting. Diagnosis would benefit from a temporal sequence of images to track change, with diffusion-weighted MRI as perhaps the most promising modality in this regard; however, the role of diffuse-weighted imaging in early disease has not been assessed previously. An unexplained pleural effusion (particularly in a patient with a history of asbestos exposure) should prompt the need for a pleural biopsy as the effusion might mask underlying tumor. In the event of a nondiagnostic or benign result on pathology, longitudinal follow-up with CT in 6 to 12 months should be considered to ensure resolution of the pleural effusion and exclude progression to malignancy.
      The main benefit of FDG-PET/CT is its ability to detect distant and occult metastatic lesions that would not be apparent by other modalities and that, when present, contraindicate surgery. FDG-PET/CT may have a role in the assessment of tumor histology, with epithelioid tumors being less FDG avid than their sarcomatoid or biphasic counterparts; higher metabolic activity is prognostic of shorter survival.
      • Gerbaudo V.H.
      • Katz S.I.
      • Nowak A.K.
      • Francis R.J.
      Multimodality imaging review of malignant pleural mesothelioma diagnosis and staging.
      In early MPM, the effusion tends to lack avidity, especially if there is no associated pleural thickening or nodularity. FDG-PET/CT should not primarily be used for follow-up in patients who have undergone prior pleurodesis. Positive PET findings following pleurodesis must be interpreted with caution, as the resulting inflammatory response can cause increased FDG avidity in the pleura for a prolonged period and could potentially increase the size and FDG uptake of mediastinal and hilar lymph nodes.
      Image guidance is a useful tool to aid acquisition of tissue at biopsy, with the various methods having both advantages and disadvantages. In addition to CT, ultrasound is a useful modality for the guidance of diagnostic and intraoperative biopsies. FDG-PET/CT and/or MRI can be used to assist in the initial identification of target sites for biopsy and to guide thoracoscopy. A multidisciplinary discussion with the surgeon before an intraoperative pleural biopsy is needed to maximize the diagnostic yield.
      Clinical staging, which is based predominantly on CT imaging, continues to be problematic primarily due to the qualitative nature of the current approach. Therefore, quantitative measures derived from imaging such as tumor volume and fissural, pleural, and diaphragmatic thickness are being explored for their potential to enhance clinical staging.
      • Gill R.R.
      • Yeap B.Y.
      • Bueno R.
      • Richards W.G.
      Quantitative clinical staging for patients with malignant pleural mesothelioma.
      • Gill R.R.
      • Naidich D.P.
      • Mitchell A.
      • et al.
      North American multicenter volumetric CT study for clinical staging of malignant pleural mesothelioma: feasibility and logistics of setting up a quantitative imaging study.
      • de Perrot M.
      • Dong Z.
      • Bradbury P.
      • et al.
      Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma.
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC mesothelioma staging project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      CT-derived tumor volume also provides prognostic information, and a quantitative stage derived from volume and maximum fissural thickness showed improved prognostic performance relative to the current clinical standard.
      • Gill R.R.
      • Yeap B.Y.
      • Bueno R.
      • Richards W.G.
      Quantitative clinical staging for patients with malignant pleural mesothelioma.
      ,
      • Labby Z.E.
      • Nowak A.K.
      • Dignam J.J.
      • Straus C.
      • Kindler H.L.
      • Armato 3rd, S.G.
      Disease volumes as a marker for patient response in malignant pleural mesothelioma.
      ,
      • Pass H.I.
      • Temeck B.K.
      • Kranda K.
      • Steinberg S.M.
      • Feuerstein I.R.
      Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma.
      PET/CT does not substantially improve clinical staging and has very low sensitivity and specificity for the detection of nodal involvement.
      • Erasmus J.J.
      • Truong M.T.
      • Smythe W.R.
      • et al.
      Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: Staging implications.
      Modified Response Evaluation Criteria in Solid Tumors version 1.1, as recently updated, are most suited to assess response in these tumors.
      • Armato 3rd, S.G.
      • Nowak A.K.
      Revised Modified Response Evaluation Criteria in Solid Tumors for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1).
      • Byrne M.J.
      • Nowak A.K.
      Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
      • Tsao A.S.
      • Gladish G.W.
      • Gill R.R.
      Revised Modified RECIST Criteria in Malignant Pleural Mesothelioma (Version 1.1): a step forward in a long race.

      Recommendations

      (1) Standardize image-acquisition protocols across centers to allow for the pooling of imaging data for future research. For CT, the contrast delay should be set to optimize the visualization of tumor (the timing of contrast administration during arterial [40 seconds] and venous [55 to 70 seconds] phases, with less than or equal to 1.25-mm axial sections (to allow for multiplanar reformatting and reliable volumetric estimation) displayed in a soft tissue window. (2) Develop a standard imaging lexicon to harmonize reporting and improve clinical staging. (3) A multidisciplinary discussion of tumor distribution and involvement of adjacent chest wall, diaphragm, and mediastinal structures (and, in particular, involvement of the endothoracic fascia) is necessary for surgical planning and for the assessment of resectability.
      Questions for future investigation are in Supplementary data 1, section 4.2.

      Medical Oncology

      The Impact of Histopathologic Subtypes of Mesothelioma on Decision Making for Systemic Treatment

      Decisions on the systemic treatment of advanced mesothelioma require consideration of timing of initiation, selection of agent, as well as consideration of individual patient issues that may affect treatment tolerance or supportive care requirements. The prognostic value of histopathologic subtypes has been assessed primarily in early-stage, resected mesothelioma. Nevertheless, histologic subtyping also plays a role in the decision making as sarcomatoid and biphasic histologic subtypes of mesothelioma are associated with poor outcome, which may reinforce the importance of earlier initiation of systemic therapy.
      • Rusch V.W.
      • Giroux D.
      • Kennedy C.
      • et al.
      Initial analysis of the International Association for the Study of Lung Cancer mesothelioma database.
      ,
      • Brims F.J.H.
      • Meniawy T.M.
      • Duffus I.
      • et al.
      A novel clinical prediction model for prognosis in malignant pleural mesothelioma using decision tree analysis.
      Conversely, selected patients with epithelioid subtype of disease who are not candidates for surgical treatment may be considered for active surveillance before initiation of systemic therapy.
      • Kindler H.L.
      • Ismaila N.
      • Armato 3rd, S.G.
      • et al.
      Treatment of malignant pleural mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline.

      Recommendations

      Multidisciplinary tumor boards should include pathologists to ensure that appropriate treatment options are considered, especially if classification is further refined (see the section on pathology).
      Questions for future investigation are in Supplementary data 1, section 5.1.3

      The Impact of Histopathologic Subtypes of Mesothelioma on the Outcome After Cytotoxic Chemotherapy

      The current standard-of-care for first-line chemotherapy is the combination of cisplatin and pemetrexed for which there has been no clear interplay between histology and outcomes.
      • Vogelzang N.J.
      • Rusthoven J.J.
      • Symanowski J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      In the pivotal EMPHACIS study that showed the benefit of this combination, approximately 68% of patients on each arm had epithelioid histology, approximately 10% sarcomatoid histology, and approximately 16% biphasic histology; however, efficacy of chemotherapy was not reported according to subtype. Similarly, other historical clinical trials of systemic chemotherapy either did not report, or did not show any differences in outcome by histologic subtype.
      • van Meerbeeck J.P.
      • Gaafar R.
      • Manegold C.
      • et al.
      Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada.
      ,
      • Muers M.F.
      • Stephens R.J.
      • Fisher P.
      • et al.
      Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial.

      Recommendations

      Based on current evidence, patients with all histologic subtypes should be considered potential candidates for chemotherapy.
      • Kindler H.L.
      • Ismaila N.
      • Armato 3rd, S.G.
      • et al.
      Treatment of malignant pleural mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline.
      Overall, despite the prognostic impact of sarcomatoid elements, there is no clear evidence that chemotherapy, based on cisplatin and third-generation cytotoxic agent, provides less proportional benefit to patients with biphasic or sarcomatoid disease.

      Histopathologic Subtype as a Criterion for Treatment With Antiangiogenic Agents

      Clinical trials of antiangiogenic agents in mesothelioma included histologic subtypes as stratification or selection criteria. The first positive randomized phase III trial with antiangiogenics was the MAPS study, assessing cisplatin and pemetrexed with or without bevacizumab.
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      In this trial, patients were stratified by histology — epithelioid versus sarcomatoid or mixed histology — with approximately 80% in each arm of epithelioid histology, and 20% of sarcomatoid or mixed histology. The trial showed the benefit of bevacizumab in the intent-to-treat population with a hazard ratio of 0.77 (95% CI, 0.62–0.95) (p = 0.0167). Histology had a nonsignificant interaction with outcomes, with sarcomatoid and biphasic subtypes being associated with a more favorable hazard ratio for overall survival (OS) as compared to epithelioid histology, but a nonsignificant interaction test.
      In trials assessing nintedanib, histologic subtype was used as selection criteria for enrollment of patients. The LUME-Meso phase II study tested cisplatin/pemetrexed with nintedanib or placebo, enrolling only those with epithelioid (89%) or biphasic (n = 10, 11%) histology and excluding patients with sarcomatoid disease.
      • Grosso F.
      • Steele N.
      • Novello S.
      • et al.
      Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial.
      The trial showed a statistically significant benefit of nintedanib in terms of progression-free survival (PFS) and a trend toward improved OS. The observation of greater benefit in epithelioid subtypes triggered restriction of the phase III study to epithelioid histology only, despite the low numbers on which this decision was based.
      • Scagliotti G.V.
      • Gaafar R.
      • Nowak A.K.
      • et al.
      LUME-Meso: design and rationale of the phase III part of a placebo-controlled study of nintedanib and pemetrexed/cisplatin followed by maintenance nintedanib in patients with unresectable malignant pleural mesothelioma.
      However, the subsequent LUME-Meso phase III study in epithelioid-only patients did not confirm any benefit of adding nintedanib to chemotherapy.
      • Scagliotti G.V.
      • Gaafar R.
      • Nowak A.K.
      • et al.
      Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial.

      Recommendations

      (1) Based on evidence as of 2019, all histologic subtypes are candidates for chemotherapy with or without bevacizumab based on clinical eligibility. (2) Patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling biological rationale to do so. Where subgroups in clinical trials are defined based on epithelioid versus non-epithelioid histologies, the relevance of such clustering has to be assessed.

      Does Histopathologic Subtype Modulate the Efficacy of Immune Checkpoint Inhibitors in Mesothelioma?

      Immunotherapy using immune checkpoint inhibitors targeting programmed death 1/PD-L1 or CTLA-4 is, as of 2019, not approved in the treatment of mesothelioma; however, results from phase I/II trials have been made available in the advanced, refractory setting, leading to the off-label use of some of those agents.
      • Metaxas Y.
      • Rivalland G.
      • Mauti L.A.
      • et al.
      Pembrolizumab as palliative immunotherapy in malignant pleural mesothelioma.
      • Forde P.M.
      • Scherpereel A.
      • Tsao A.S.
      Use of immune checkpoint inhibitors in mesothelioma.
      • Ettinger D.S.
      • Wood D.E.
      • Akerley W.
      • et al.
      NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016.
      CTLA-4 inhibition using tremelimumab alone was assessed in the large randomized phase 2b trial DETERMINE, which enrolled 564 patients in the second-/third-line setting versus placebo.
      • Maio M.
      • Scherpereel A.
      • Calabro L.
      • et al.
      Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
      This trial found no benefit of tremelimumab in the predominantly epithelioid (83%) intent-to-treat population. The MAPS2 study randomized 125 patients (83% epithelioid) in the second-/third-line setting to treatment with nivolumab or nivolumab plus ipilimumab.
      • Scherpereel A.
      • Mazieres J.
      • Greillier L.
      • et al.
      Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.
      The primary endpoint was disease control rate at 12 weeks. Disease control rate was 44% with nivolumab and 50% for nivolumab plus ipilimumab with median PFS of 4.0 and 5.6 months, respectively, and median OS of 13.6 months and not reached, respectively. Subgroups analyses showed a tendency towards greater OS benefit from nivolumab plus ipilimumab for sarcomatoid/biphasic histologies. Other phase II studies assessing nivolumab, pembrolizumab, or combining durvalumab plus tremelimumab, enrolled limited numbers of patients, most with epithelioid disease, precluding clear assessment of the role of histologic subtypes on outcomes.
      • Calabro L.
      • Morra A.
      • Giannarelli D.
      • et al.
      Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study.
      • Goto Y.
      • Okada M.
      • Kijima T.
      • et al.
      A phase II study of nivolumab: a Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT).
      • Quispel-Janssen J.
      • van der Noort V.
      • de Vries J.F.
      • et al.
      Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma.
      • Desai A.
      • Karrison T.
      • Rose B.
      • et al.
      Phase II trial of pembrolizumab (P) in patients with previously treated mesothelioma (MM).
      A real-world cohort of 93 patients who received pembrolizumab second-line or beyond reported greater efficacy in non-epithelioid mesotheliomas (n = 73), with a response rate of 24% versus 16% (p = 0.54), and a median PFS of 5.6 versus 2.8 months (p = 0.02) in epithelioid mesotheliomas (n = 27).
      • Metaxas Y.
      • Rivalland G.
      • Mauti L.A.
      • et al.
      Pembrolizumab as palliative immunotherapy in malignant pleural mesothelioma.
      Finally, a single-center phase 2 trial using a combination of nivolumab plus ipilimumab showed marked efficacy in patients with recurrent MPM.
      • Disselhorst M.J.
      • Quispel-Janssen J.
      • Lalezari F.
      • et al.
      Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial.

      Recommendations

      As of 2019, there is evidence of efficacy for immunotherapy with anti–programmed death 1/PD-L1 inhibitors alone or combined with anti–CTLA-4 antibodies in all histologic subtypes of mesothelioma, although the efficacy of immunotherapy may vary according the histologic subtype (non-epithelioid subtypes may be associated with a more prolonged duration of response).
      Questions for future investigation are in Supplementary data 1, section 5.4.3.

      The Use of Biomarkers in the Clinic for Systemic Treatments

      Biomarker studies have been important components of recent phase III trials: notably, angiogenesis serum biomarkers and PD-L1 expression by IHC. Exploratory analyses of vascular endothelial growth factor concentration as a predictor of the benefit of bevacizumab and nintedanib were conducted part of the MAPS and the LUME-Meso phase II trial, not reporting significant predictive value for the benefit of antiangiogenics.
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      ,
      • Pavlakis N.
      • Grosso F.
      • Steele N.
      • et al.
      Nintedanib + pemetrexed/cisplatin in malignant pleural mesothelioma (MPM): phase II biomarker data from the LUME Meso study.
      In the MAPS trial, patients with higher baseline vascular endothelial growth factor concentrations than the median value treated in the bevacizumab group derived a 2.3-month, nonstatistically significant benefit. Expression of PD-L1 by IHC is observed in 16% to 40% of mesothelioma cases
      • Scherpereel A.
      • Mazieres J.
      • Greillier L.
      • et al.
      Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.
      ; PD-L1 expression is associated with non-epithelioid histology and poorer outcome.
      • Mansfield A.S.
      • Roden A.C.
      • Peikert T.
      • et al.
      B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis.
      ,
      • Muller S
      • Victoria Lai W
      • Adusumilli PS
      • et al.
      V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant mesothelioma.
      In the MAPS2 trial, positive PD-L1 tumor expression (with a cutoff of 1%) was associated with objective response in both treatment groups, whereas high PD-L1 tumor expression (≥25% of tumor cells) was associated with objective response or disease control in both groups. Conversely, positive PD-L1 tumor expression (≥1%) tended to result in a longer OS only in the nivolumab group. Similar trends were reported in some of the other smaller trials.
      • Calabro L.
      • Morra A.
      • Giannarelli D.
      • et al.
      Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study.
      • Goto Y.
      • Okada M.
      • Kijima T.
      • et al.
      A phase II study of nivolumab: a Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT).
      • Quispel-Janssen J.
      • van der Noort V.
      • de Vries J.F.
      • et al.
      Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma.
      • Desai A.
      • Karrison T.
      • Rose B.
      • et al.
      Phase II trial of pembrolizumab (P) in patients with previously treated mesothelioma (MM).
      PD-L1 expression was a selection criterion in a pembrolizumab phase I trial.
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      The need for the characterization of predictive biomarkers will depend on the results of future clinical trials; currently, the potential observed predictive value of PD-L1 for the efficacy of immunotherapy in the late line setting remains to be validated in phase III trials.
      Other promising predictive biomarkers include mesothelin, as anetumab ravtansine is a drug-conjugated antibody targeting mesothelin
      • Kindler H.
      • Novello S.
      • Fennell D.A.
      • et al.
      Randomized phase II study of anetumab ravtansine or vinorelbine in patients with metastatic pleural mesothelioma.
      ; BAP1 deficiency, which may predict the efficacy of EZH2 inhibitors
      • Zauderer M.G.
      • Szlosarek P.
      • Le Moulec S.
      • et al.
      Phase 2, multicenter study of the EZH2 inhibitor tazemetostat as monotherapy in adults with relapsed or refractory (R/R) malignant mesothelioma (MM) with BAP1 inactivation.
      ; and NF2 alterations in use of FAK inhibitors. When mesothelioma develops in carriers of germline BAP1 mutations, these malignancies have a better prognosis.
      • Baumann F.
      • Flores E.
      • Napolitano A.
      • et al.
      Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival.
      Mesothelin may also be a target for chimeric antigen receptor–modified T cells, given its frequent expression in mesotheliomas, especially the epithelioid subtype.
      • Eguchi T.
      • Kadota K.
      • Mayor M.
      • et al.
      Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1.
      • Tano Z.E.
      • Chintala N.K.
      • Li X.
      • Adusumilli P.S.
      Novel immunotherapy clinical trials in malignant pleural mesothelioma.
      • O'Hara M.
      • Stashwick C.
      • Haas A.R.
      • Tanyi J.L.
      Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy.

      Recommendations

      (1) Routine incorporation of the above biomarkers into standard reports is not recommended, but data should be accrued in a regulated manner within clinical trials and recorded in reports, if requested. (2) Given the rarity of germline BAP1 mutations, systematic screening of all patients for germline mutations is not proposed in the absence of family history suspicious for BAP1 syndrome; oncogenetic counseling is not recommended in a systematic manner.
      Questions for future investigation are in Supplementary data 1, section 5.5.3.

      Acknowledgments

      The authors and participants thank Pr. Jean Yves Blay for hosting the congress at the Cancer Center Leon Berard, and Dr. Y.-Z. Zhang for his help in selecting the images. The French National Cancer Institute (INCA) and National Health Institute (SpF), and LYRICAN (INCA-DGOS-INSERM 12563), LabEx DEvweCAN (ANR-10-LABX-0061), Ligue de L’Ain contre le Cancer, La Region Rhônes Alpes, le Cancéropole Clara, EURACAN (EC 739521) funded this study. Authors affiliated with the International Agency for Research on Cancer/World Health Organization are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.

      Supplementary Data

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      Linked Article

      • Is the Deciduoid Variant of Pleural Mesothelioma Significant?
        Journal of Thoracic OncologyVol. 15Issue 6
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          We read with great interest the recent proposals for an update on the histologic classification of mesothelioma and salute the authors for such a detailed piece of work.1 As health care practitioners working in the Northeast England with one of the United Kingdom’s highest rates of pleural mesothelioma,2 we welcome such proposals. Nevertheless, we must disagree with one of the points in Table 3, cytology point L, that the deciduoid variant of pleural mesothelioma has no prognostic significance. We agree that deciduoid cytology needs to be distinguished from carcinomas, but we have recently come across a case of deciduoid pleural mesothelioma which was associated with a very poor response to chemotherapy and a very limited life span in a patient with, initially, excellent performance status.
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