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Corresponding author. Address for correspondence: Andrew G. Nicholson, DM, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, Department of Histopathology, London, SW3 6NP, United Kingdom.
Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom
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.
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).
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.
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.
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.
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)”.
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.
Composed 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 variant
Composed 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 mesothelioma
Showing 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 mesothelioma
A 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.
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.
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.
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.
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.
Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma.
New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
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.
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.
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.
PAX8 Expression in a subset of malignant peritoneal mesotheliomas and benign mesothelium has diagnostic implications in the differential diagnosis of ovarian serous carcinoma.
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).
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.
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
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)
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.
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”)
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.
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)
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.
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.
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%.
New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
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.
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.
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.
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.
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.
BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.
BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests.
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.
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.
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 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.
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.
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.
New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
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.
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 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).
Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma.
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.
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)
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.
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.
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.
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 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.
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.
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.
(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)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Dynamic contrast-enhanced MRI of malignant pleural mesothelioma: a feasibility study of noninvasive assessment, therapeutic follow-up, and possible predictor of improved outcome.
Pharmacokinetic analysis of malignant pleural mesothelioma-initial results of tumor microcirculation and its correlation to microvessel density (CD-34).
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.
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.
North American multicenter volumetric CT study for clinical staging of malignant pleural mesothelioma: feasibility and logistics of setting up a quantitative imaging study.
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.
(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.
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.
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.
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).
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.
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.
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.
Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial.
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.
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.
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.
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.
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.
(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.
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.
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.
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.
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).
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).
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.
Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
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
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.
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.
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
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.
Mesothelin may also be a target for chimeric antigen receptor–modified T cells, given its frequent expression in mesotheliomas, especially the epithelioid subtype.
Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1.
(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.
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.
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.
International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.
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.
Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Interest Group.
Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma.
New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the international mesothelioma panel from the MESOPATH reference center.
PAX8 Expression in a subset of malignant peritoneal mesotheliomas and benign mesothelium has diagnostic implications in the differential diagnosis of ovarian serous carcinoma.
Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the International Mesothelioma Interest Group.
BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.
BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests.
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.
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).
V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant mesothelioma.
Dynamic contrast-enhanced MRI of malignant pleural mesothelioma: a feasibility study of noninvasive assessment, therapeutic follow-up, and possible predictor of improved outcome.
Pharmacokinetic analysis of malignant pleural mesothelioma-initial results of tumor microcirculation and its correlation to microvessel density (CD-34).
North American multicenter volumetric CT study for clinical staging of malignant pleural mesothelioma: feasibility and logistics of setting up a quantitative imaging study.
The IASLC mesothelioma staging project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
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.
Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial.
Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial.
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.
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.
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
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.
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.
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.
Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1.
Disclosure: Dr. Nowak has received grants from AstraZeneca and Douglas Pharmaceuticals; has received honoraria from Bayer Pharmaceuticals, Roche, Boehringer Ingelheim, Merck Sharp & Dohme; has received consulting fees to institution from Douglas Pharmaceuticals; and has received travel funding from Beohringer Ingelheim and AstraZeneca. Dr. Armato has received personal fees from Aduro Biotech, Inc; and receives royalties and licensing fees from The University of Chicago related to computer-aided diagnostic technology. Dr. Bueno has received grants from Roche/Genentech, Epizyme, HTG, Gritstone, Merck Oncology, Novartis, Verastem, and Siemens. Dr. De Perrot has received personal fees from Bayer. Dr. Baas has received grants from Bristol-Myers Squibb, MSD, and Roche. Dr. Brcic has received grants from AstraZeneca; has received personal fees from MSD, Roche, and AstraZeneca; and has received nonfinancial support from Abbvie, MSD, Roche, AstraZeneca, and Pfizer. Dr. Chirieac has received personal fees from medicological work related to mesothelioma. Dr. Perol has received personal fees from Eli Lilly, Roche, Bristol-Myers Squibb, Merck, AstraZeneca, and Beohringer Ingelheim. Dr. Scherpereel has received grants from MSD and Sandoz; has received personal fees from AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, and Roche. Dr. Tazelaar has received personal fees from Cipla Ltd. Dr. Tsao has received grants from Merck, AstraZeneca, Pfizer, and Bayer; and has received personal fees from Merck, AstraZeneca, Bristol-Myers Squibb, Pfizer, Bayer, Takeda, and Roche Genentech. Dr. Rusch has received support from the National Institutes of Health Thoracic Malignancy Steering Committee. The remaining authors declare no conflict of interest.
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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