Original contributionThe differential diagnosis between pleural sarcomatoid mesothelioma and spindle cell/pleomorphic (sarcomatoid) carcinomas of the lung: evidence-based guidelines from the International Mesothelioma Panel and the MESOPATH National Reference Center☆
Introduction
Malignant mesotheliomas are currently classified by the World Health Organization (WHO) based on their gross appearance into diffuse and localized mesotheliomas [1]. Diffuse and localized mesotheliomas are classified based on their histopathology into epithelioid, sarcomatoid, and biphasic lesions [1]. Most malignant mesotheliomas are epithelioid lesions composed of tubular, papillary, or tubulopapillary structures, but they can present as poorly differentiated neoplasms composed of solid sheets of pleomorphic epithelioid cells. Recent studies have suggested that lesions composed of diffuse/solid sheets of anaplastic or prominent giant cells, often multinucleated, epithelioid cells, be designated as “pleomorphic mesotheliomas” and classified as a variant of epithelioid malignant mesothelioma [1], [2]. The WHO defined sarcomatoid malignant mesotheliomas (SMM) in 2015 as a proliferation of spindle cells mainly arranged in fascicles and exhibiting a wide range of morphological features from plump to thin long cells [1]. Nuclear atypia can vary from minimal to severe, and mitotic activity varies considerably. Atypical mitoses are frequent. Sarcomatoid mesotheliomas comprise approximately 10% of malignant mesothelial lesions and are subclassified into sarcomatoid mesotheliomas, desmoplastic mesothelioma, and mesothelioma with heterologous elements [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Desmoplastic mesotheliomas exhibit dense fibrosis, are composed of atypical spindle cells arranged in a patternless pattern and showing areas of bland necrosis, with this pattern involving >50% of the tumor. Lymphohistocytoid mesotheliomas exhibit heavy lymphoid infiltrates that often obscure the malignant mesothelial cells and masquerade as a malignant lymphoma; it is somewhat controversial whether they should be categorized as sarcomatoid or epithelioid lesions [1], [2]. Sarcomatous mesotheliomas with heterologous elements exhibit, in addition to the neoplastic spindle cells, osteosarcomatous, chondrosarcomatous, and/or rhabdomyosarcomatous components.
Carcinomas previously labeled by the 2004 WHO classification of lung neoplasms as sarcomatoid carcinomas are currently designated as spindle cell carcinomas or pleomorphic carcinomas (SPC) to avoid confusion with sarcomas [1]. They generally appear as a well-circumscribed lesion, but they can infiltrate or metastasize to serosal membranes as diffuse or multifocal lesions [1]. SPC are characterized by the proliferation of spindle or markedly atypical epithelioid cells arranged in solid cohesive sheets. The tumor cells often have irregularly shaped nuclei with hyperchromasia and/or eosinophilic macronucleoli. Focal areas of adenocarcinoma or squamous cell carcinoma differentiation are often detected by thorough histologic sampling in SPC.
The differential diagnosis between malignant epithelioid mesothelioma, including pleomorphic mesotheliomas, and SPC can usually be established without much difficulty with the aid of immunostains for mesothelial markers such as calretinin, Wilms tumor–1 (WT-1), and/or D2-40 and carcinoma markers such as Ber-EP4, monoclonal CEA, CD15, BG8, p40, p63, Napsin A, TTF-1, claudin-4, synaptophysin and/or chromogranin. However, mesothelial markers are often negative or only focally positive in SMM. Moreover, although immunoreactivity for keratin antibodies such as CAM5.2, AE1/AE3, OSCAR, and/or CK5/6 can be seen up to 93% of SMM, this finding can be seen in only a few immunoreactive cells in some cases [12]. The expression of broad-spectrum epithelial markers such as MOC31, Ber-EP4, Claudin 4, and others is also limited in SPC.
There are no current expert opinion–based or evidence-based guidelines for the differential diagnosis between SMM and SPC [3]. Indeed, the 2015 World Health Organization Classification of Tumours of the Lung, Pleura, Thymus, and Heart explains that it may be impossible to distinguish SMM from SPC, as both lesions exhibit similar histopathological features, and their immunophenotype can be inconclusive [1]. For example, SMM can exhibit negative immunoreactivity for mesothelial markers, and epithelial markers such as MOC31, BerEP4, or monoclonal CEA and others may be negative in SPC [1].
The International Mesothelioma Panel is a group of experts led by Professor Francoise Galateau-Salle´ and sponsored by the MESOPATH Central Reference Center in Lyon Cedex, France. It is composed of several American, European, Japanese, and Australian pathologists who meet periodically to share their experiences with the diagnosis of malignant mesotheliomas. The study was designed to review the experience at MESOPATH with the differential diagnosis between SMM and SPC, query the English literature for “best available evidence” regarding the immunophenotype of SMM and SPC and analyze these data with meta-analysis to formulate evidence-based diagnostic guidelines for the differential diagnosis between these unusual tumors. Only panel members that participated in the meeting and/or contributed to the discussion and the manuscript were included in the study.
Section snippets
Materials and methods
Selected clinicopathologic features of SPC and SMM patients diagnosed at the MESOPATH National Reference Center from January 1998 until June 2016 were reviewed after IRB approval. They included the age and gender of the patients, results of the immunostains used in the diagnosis of SPC and SMM and 2-year overall survival (OS) data. Demographic data and immunohistochemical results were compared using χ2 statistics. OS survival was analyzed with Kaplan-Meier statistics and the log-rank test. A
Results
Table 1 shows the demographics of patients diagnosed with SMM and SPC at MESOPATH from 1998 to 2016. There was no significant difference in gender and SMM were slightly more prevalent in older patients (mean age, 74 years). Routine practice at the MESOPATH Central Reference Center in Lyon Cedex, France, during the interpretation of these lesions has been to use 2 pancytokeratin and 2 mesothelial markers, aided by carcinoma markers such as BEREP4 (clone Ber-EP4, monoclonal CEA, EMA (clone E29),
Discussion
Systematic review of the literature and discussion regarding diagnostic practices by various panel members shows that the diagnostic criteria used for the classification of neoplasms into either SMM or SPC of the lung have not been explicitly described in the past [4], [5], [6], [7], [8], [9], [10], [11], [12]. Moreover, studies in the literature did not explicitly describe whether the results of the immunostains being evaluated were used to establish the diagnoses of SMM or SPC prior to the
Acknowledgements
We thank all the experts at the MESOPATH National Reference Center who have participated in the diagnosis and certification of all the cases included in the data analysis: I Abdalsamad, H Begueret, E Brambilla, MC Copin, F Capron, D Damotte, C Danel, A Foulet, L Garbe, S Giusiano, V Hofman, JM Piquenot, I Rouquette, C Sagan, and F Thivolet.
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Funding/Support: The work of the International Mesothelioma Panel has been supported by The National French Cancer Institute (INCA) and Santé Publique France (SPF) core grant.