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Sarcomatoid mesothelioma—composed of variably pleomorphic spindled cells resembling other sarcomas (H&E × 200)
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The 2015 WHO classification of pleural mesotheliomas includes three major histologic subtypes—epithelioid, sarcomatoid, and biphasic. Recent genomic data has supported the need for a more granular and clinically valid classification beyond the three current subtypes. Because of tumor rarity and overlapping histologic features with other tumor types...
Similar publications
Due to the lack of both prospective trial and high-volume retrospective studies, the management of clinical N+ malignant pleural mesothelioma (MPM) patients remains highly debated. Node positive patients show poor survival compared with node-negative ones; thus, lymph node staging appears crucial in determining treatment strategy. Notwithstanding t...
Citations
... Therefore, FE-induced PM represents a rare and small subset of PM non directly linked to conventional asbestos fibers but sharing with conventional PM the same morphological and prognostic features [1][2][3][4][5]. Three different morphologies have been traditionally identified [6,7]: i) epithelioid subtype exhibiting a wide spectrum of lesions ranging from bland-looking and lowly-proliferative tumors with eosinophilic cytoplasm, rounded nuclei and inconspicuous nucleoli to poorly-differentiated ones with large cytoplasms and atypical nuclei; ii) sarcomatoid subtype, composed of fascicles of bland-looking to highly-pleomorphic spindled cells arranged haphazardly or in a fascicular pattern; and iii) mixed type. Although in the past years several studies aimed to identify some prognostic factors capable to predict the outcome of patients affected by FE-induced PM [1][2][3][4][5], this tumor still shares with its more conventional counterpart an invariably poor prognosis characterized by median survivals of approximately 6-12 months. ...
Fluoroedenite-induced pleural mesothelioma (FE-induced-PM) is a rare and small subset of PM that shares with its asbestos-induced counterpart the same aggressive biological behavior and poor prognosis, but that differs from it from a pathogenetic point of view as it is associated with exposure to fluoroedenite, a carcinogenic agent that shows similarities with tremolite amphibolic asbestos fibers. Although it has been demonstrated that asbestos-induced PMs frequently harbor CDKN2A homozygous deletion and that the immunohistochemical loss of MTAP may represent a cheap and reliable surrogate marker for this molecular alteration, little is known about the molecular landscape and the reliability of MTAP immunohistochemistry in this peculiar subset of PM. The study herein presented investigated the prevalence of CDKN2A homozygous deletion and its concordance with MTAP immunohistochemical status on a cohort of 10 cases of FE-induced-PM from patients with environmental exposure to FE fibers, who were residents in the small town of Biancavilla (Sicily, Italy) or nearby areas. CDKN2A homozygous deletions were found in 3 out of 10 cases (30%) and all these cases showed concomitant cytoplasmic loss of MTAP with a concordance rate of 100%. Despite the relatively low number of cases included in our series, MTAP immunohistochemistry seemed to represent a reliable immunohistochemical surrogate marker of CDKNA homozygous deletion even in this subset of PMs.
... Sarcomatoid mesothelioma is the second most common subtype of MPM, and it has been associated with only 4-month survival in patients who underwent surgical treatment [3]. The WHO classification defines it as a proliferation of spindle cells arranged in fascicles or in haphazard patterns invading the adipose tissue or lung parenchyma. ...
... Heterologous elements such as osteosarcoma, rhabdomyosarcoma, or chondrosarcoma can be present in rare cases. Sarcomatoid mesothelioma is morphologically heterogeneous, and the upcoming WHO classification includes variants (desmoplastic mesothelioma, sarcomatoid) and cytologic features (transitional, pleomorphic) [3,4]. Our case is of interest for two reasons. ...
Malignant pleural mesothelioma (MPM) is a rare malignancy arising from the mesothelial or subthelial layer of the pleura, and it has increased in recent decades, mainly associated with asbestos exposure. Sarcomatoid mesothelioma is the second-most common subtype of MPM. It is usually difficult to differentiate MPM from benign mesothelial pleural proliferations or other cancers. Because of its nonspecific symptoms, MPM is often diagnosed at a late stage with distal metastases. However, it is extremely rare to see a metastatic lesion within subcutaneous tissue and muscles, which is most likely caused by hematogenous spread. We present a case of sarcomatoid mesothelioma with a metastatic lesion of the right gluteal muscles.
... It is recommended that the panel should have sensitivity or specificity greater than 80%, and the interpretation of immunostaining should consider the localization of the marker (membrane, nucleus, cytoplasm) and the proportion of positive cells, of which more than 10% has been suggested for cytoplasmic membranous markers. (16) In addition, negativity for the mentioned mesothelial antibodies does not exclude the diagnosis of pleural MM since 30% of these cases present a "null" phenotype. (17) When facing complex cases, pathologists should seek for an expert second opinion and refer to national mesothelioma panels, (16) which do not exist in Brazil. ...
... (16) In addition, negativity for the mentioned mesothelial antibodies does not exclude the diagnosis of pleural MM since 30% of these cases present a "null" phenotype. (17) When facing complex cases, pathologists should seek for an expert second opinion and refer to national mesothelioma panels, (16) which do not exist in Brazil. ...
Objective
To review the pathological diagnosis of possible cases and/or hidden cases of malignant mesothelioma (MM) between 2000 and 2012 using the Hospital-Based Cancer Registry database in the state of São Paulo, Brazil.
Methods
Possible cases were retrieved by assessing the database. Inclusion criteria were being older than 30 years of age and having ICD-O-3 topography and morphology codes related to MM. A board of expert pathologists reviewed the pathology reports and requested paraffin blocks in cases that demanded revision. After staining with calretinin, D2-40, WT-1 (as positive MM markers) and Ber-EP4 and MOC31 (as negative MM markers), cases were divided and studied independently by a pair of pathologists to confirm or discard the diagnosis of MM.
Results
Our sample comprised 482 cases from 25 hospitals, and 130 needed further histological revision. We received 73 paraffin blocks with adequate material. After board analysis, there were 9 cases with a definitive diagnosis of MM, improving the diagnostic rate in 12%. Two cases of previously diagnosed MM were discarded by review.
Conclusions
Our results confirm that part of MM underdiagnosis and underreporting in Brazil is due to incomplete or mistaken pathological diagnosis.
Keywords:
Mesothelioma, malignant/pathology; Mesothelioma, malignant/diagnosis; Immunohistochemistry; Registries
... Malignant tumors might be diffuse or localized [1]. Diffuse mesothelioma is an infrequent malignancy deriving from mesothelial cells which line the pleural and peritoneal cavities along with the tunica vaginalis testis and pericardium [2]. ...
... Over the past decade, PM incidence has increased firmly worldwide, while an estimation associated with 2008 data suggested an average of 14,200 cases globally every year [3]. The PM WHO classification has mainly identified three major subtypes of PM which are epithelioid, biphasic, and sarcomatoid [1,2,4]. Concerning symptoms, most of the subjects with PM might present breathlessness, chest pain or both, and making a diagnosis, via methods including radiological imaging and the sampling of pleural fluid for biochemical and cytological investigation, is quite challenging [3]. ...
... Epithelioid mesothelioma (EM) is related to approximately 80% of all PMs and includes epithelioid (rounded/polygonal) rather than spindle-shaped cells [2,4]. EM consists of deceptively bland, uniform cuboidal cells. ...
Pleural mesothelioma (PM) is a tumor related to adverse prognosis. The PM WHO classification has mainly identified three major subtypes of PM which are epithelioid, biphasic, and sarcomatoid. Sarcopenia is a medical issue related to a reduction in muscle mass and strength. It represents a major health issue globally because it is related to adverse effects such as hospitalization, increased length of stay, disability, increased morbidity and mortality and augmented health care expenditures. In this literature review, we attempted to examine the upcoming association between sarcopenia and PM. As recorded by the current literature, muscle loss in PM subjects was related to poorer survival and lower levels of activity. Subjects with PM had increased rates of pre-sarcopenia and malnutrition, while pre-sarcopenia was related to worse activity levels, and malnutrition was related to worse quality of life (QoL). Both tumor volume and sarcopenia were related to long-term mortality in surgically treated PM subjects, while sarcopenia was present both pre-operatively and post-operatively in these subjects. In addition, post-operative sarcopenic subjects showed a decreased 3-year overall survival (OS) in comparison with those who did not have sarcopenia, while pre-operative sarcopenia was importantly related to an increased rate of post-operative adverse outcomes. More studies are needed to validate these claims.
... This importance of VEGF in the tumor process has also led to different heterotypic spheroid cultures comprising tumor cells and endothelial cells. For this effect, a 3D spheroid model of malignant pleural mesothelioma (MPM) was produced from either SPC111 cells obtained from biphasic MPM or P31 cells that are derived from epithelioid MPM [151,152], representing the main cell types observed in MPM [153,154]. P31 epithelioid MPM cells co-cultured with HUVEC cells permitted endothelial sprouting while SPC111 co-cultured spheroids repealed endothelial sprouts leading to anisotropic sprout arborization [152]. In another heterotypic spheroid model, long-term spheroids of up to 30 days of culture were developed from HCC1954 tumor cells, human fibroblasts, and ECs [155]. ...
Cancer remains a serious burden in society and while the pace in the development of novel and more effective therapeutics is increasing, testing platforms that faithfully mimic the tumor microenvironment are lacking. With a clear shift from animal models to more complex in vitro 3D systems, spheroids emerge as strong options in this regard. Years of development have allowed spheroid-based models to better reproduce the biomechanical cues that are observed in the tumor-associated extracellular matrix (ECM) and cellular interactions that occur in both a cell–cell and cell-ECM manner. Here, we summarize some of the key cellular interactions that drive tumor development, progression and invasion, and how successfully are these interactions recapitulated in 3D spheroid models currently in use in the field. We finish by speculating on future advancements in the field and on how these can shape the relevance of spherical 3D models for tumor modelling.
... Pleural mesothelioma (PM) is a rare, fatal disease that origins from the pleural membranes lining the lungs. According to the World Health Organization (WHO) 2015 histological classification, PM has been distinguished into three main morphological subtypes: epithelioid, characterized by a better prognosis, sarcomatoid, that has the most aggressive clinical behavior, and biphasic type that shows features of both epithelioid and sarcomatoid histology (1,2). More recently, molecular and epigenetic findings have been also included in the most recent classification of PM (WHO 2021) (3). ...
Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PM patients. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced PM.
... The diagnosis of PM can be extremely challenging both for small tissue biopsies if tissue invasion is not clearly assessable and for pleural effusions [9,10]. In particular, the morphologic differentiation of PM from reactive mesothelial hyperplasia (MH) is not always possible for effusions so a tissue sample can be required first to confirm malignancy and then to subtype PM [5,11]. ...
... However, the absence of BAP1, p16 or MTAP alterations does not rule out the possibility of PM [2,5,14]. In addition, the cytological diagnosis of biphasic PM is even more challenging than that of epithelioid PM, considering that cells from the sarcomatoid component do not shed into the effusions [14] and the efficacy of available markers has not been completely investigated for this subtype [4,9,20]. ...
... Pleural effusions are among the first clinical manifestations of PM and can provide important diagnostic information [4,11,13,14]. However, the diagnosis of PM on pleural effusions is still a controversial issue and several factors must be taken into account: cytomorphologic features overlap between PM and MH cells, and this fact, along with the lack of standardization [9] in the collection and preparation procedures, can result in variable interpretations across cytopathologists. The introduction of BAP1, MTAP and p16 tests has greatly improved the diagnostic accuracy of pleural effusions, but it is necessary to perform at least two of these tests (i.e., BAP1 and MTAP) to reach a good sensitivity [4,5,14,17,25,26]. ...
Simple Summary
Pleural effusions are common clinical manifestations of pleural mesothelioma (PM) and often constitute the only available biological material for diagnosis. However, the cytological diagnosis of PM can be challenging. Over the years, ancillary tests, mainly based on the analysis of single biomarkers, have been developed to differentiate malignant from benign effusions, but their sensitivity is limited. In this study, we validated, on a consecutive series, a previously defined 117-gene expression panel as a diagnostic tool for the cytological diagnosis of PM. This gene panel proved to be useful not only in the differential diagnosis of PM and mesothelial hyperplasia but also in the discrimination of the two most common PM subtypes (epithelioid and biphasic) on cytology. Once the malignancy is assessed, the PM subtype definition strongly impacts therapy and prognosis. In this context, the 117-gene panel could be a powerful diagnostic tool to improve the clinical management of PM patients.
Abstract
Cytological diagnosis of pleural mesothelioma (PM) is controversial, even using ancillary markers (BAP1, MTAP and CDKN2A). Here, we aimed to prospectively validate a previously developed 117-gene expression panel for the differential cytological diagnosis of epithelioid, biphasic PM and mesothelial hyperplasia. Seventy-seven pleural effusions were classified using the 117-gene expression levels (NanoString system). Sixty-eight cases were also screened for ancillary markers. The performance of both gene panel and ancillary markers was evaluated using ROC metrics. A score using the top consistently deregulated genes between epithelioid and biphasic PM was built to subtype malignant effusions. The panel alone reached a diagnostic accuracy (0.89) comparable to the best marker combination (BAP1 plus MTAP: 0.88). Ancillary tests missed 8 PMs, 7 of which were correctly classified by the panel. The score built by averaging the expression levels of MSLN, CLDN15 and CFB showed an accuracy of 0.80 in subtyping epithelioid and biphasic effusions. The 117-gene panel is effective for PM cytological diagnosis of epithelioid and biphasic PM. This tool can be complementary to ancillary markers, reducing invasive procedures and allowing an earlier diagnosis. Finally, the possibility to subtype PM on effusions strengthens the panel’s role in PM diagnosis and management.
... MPM is classified according to cell origin into three histological subtypes: epithelioid, sarcomatoid, and biphasic [24] which in turn reflect distinct epithelia-mesenchymal transition marker expression profiles associated with a miscellaneous predictive value [25]. The critical role has been assigned to Twist (TWIST1) and ZEB-1, whose overexpression has been associated with a poor prognosis and worse survival rate [26,27]. ...
Purpose:
To determine the mechanism of EPE in downregulating TYMS in MPM cancer.
Methods:
The TYMS mRNA expression with epithelial-to-mesenchymal transition biomarkers and nuclear factor SP1 was assessed using the GEO database in a data set of MPM patients (GSE51024). Invasive MPM cell lines were in vitro models for the investigation of TYMS expression after EPE treatment. The tyms promoter SP1 binding sequences were determined using Genomatix v 3.4 software Electrophoretic mobility shift and dual-luciferase reporter assays revealed specific SP1 motifs in the interaction of EPE and reference compounds. Chromatin immunoprecipitation and Re-ChIP were used for the co-occupancy study.
Results:
In MPM patients, a positive correlation of overexpressed TYMS with mesenchymal TWIST1, FN1 and N-cadherin was observed. EPE and its major components, gallic and ellagic acid (GA and EA, respectively), downregulated TYMS in invasive MPM cells by interacting with particular SP1 motifs on the tyms promoter. The luciferase constructs confirmed the occupation of two SP1 regulatory regions critical for the promotion of TYMS expression. Both EPE and reference standards influenced SP1 translocation into the nucleus.
Conclusion:
EPE components reduced TYMS expression by occupation of SP1 motifs on the tyms promoter and reversed the EMT phenotype of invasive MPM cells. Further in-depth analysis of the molecular docking of polyphenol compounds with SP1 regulatory motifs is required.
... The patients present non-resolving pleural effusions and show no thoracoscopic or imaging evidence of the tumor [21,23]. After a median follow-up time of 60 months, up to 70% of mesotheliomas in situ will progress into an invasive form [25,27]. The diagnosis of benign and preinvasive mesothelial tumors is mostly based on histopathology, immunohistochemistry (IHC), and FISH [21,23,24,26]. ...
... Clinical manifestations include cough, dyspnea, chest pain, weight loss, and malaise [31,32]. The median patient survival time is 9-12 months with a 5-year survival rate of 5% [27]. ...
Simple Summary
The current imaging method recommended in patients with a suspicion of pleural malignancy is CT which has been shown to have certain downsides and limitations—from requiring the administration of the contrast agent and a relatively high radiation dosage to its restricted capacity for the differentiation of the pleural malignancies from the surrounding tissues. During the last few years, numerous studies have suggested that MRI could provide a solution to some of these issues, as various MRI sequences could not only detect and delineate pleural tumors more effectively than CT but also provide additional data on the tumors’ physiology or histology. In this review we summarize current knowledge on the primary pleural neoplasms and discuss potential applications of MRI in patients with pleural malignancies, as well as the current limitations of both the method itself and the research involving it.
Abstract
The primary pleural neoplasms constitute around 10% of the pleural tumors. The currently recommended method for their imaging is CT which has been shown to have certain limitations. Strong development of the MRI within the last two decades has provided us with a number of sequences that could potentially be superior to CT when it comes to the pleural malignancies’ detection and characterization. This literature review discusses the possible applications of the MRI as a diagnostic tool in patients with pleural neoplasms. Although selected MRI techniques have been shown to have a number of advantages over CT, further research is required in order to confirm the obtained results, broaden our knowledge on the topic, and pinpoint the sequences most optimal for pleural imaging, as well as the best methods for reading and analysis of the obtained data.
... 9 According to the World Health Organization (WHO) Classification of 2021, MM has three major histological subtypes, namely epithelioid, biphasic, and sarcomatoid. [10][11][12] MM has to be distinguished from primary or secondary lung tumors, and then evidently the MM subtypes have to be differentiated from each other. Proper distinction may be a challenging task for the pathologist, due to the unspecific morphology. ...
Malignant mesothelioma (MM) is a rare tumor of mesothelial cells, with an increasing incidence both in developed and developing countries. MM has three major histological subtypes, in order of frequency, according to the World Health Organization (WHO) Classification of 2021: epithelioid, biphasic, and sarcomatoid MM. Distinction may be a challenging task for the pathologist, due to the unspecific morphology.
Here, we present two cases of diffuse MM subtypes to emphasize the immunohistochemical (IHC) differences, and to facilitate diagnostic difficulties. In our first case of epithelioid mesothelioma, the neoplastic cells showed cytokeratin 5/6 (CK5/6), calretinin, and Wilms-tumor-1 (WT1) expression, while remaining negative with thyroid transcription factor-1 (TTF-1). BRCA1 associated protein-1 (BAP1) negativity was seen in the neoplastic cells' nucleus, reflecting loss of the tumor suppressor gene. In the second case of biphasic mesothelioma, expression of epithelial membrane antigen (EMA), CKAE1/AE3, and mesothelin was observed, while WT1, BerEP4, CD141, TTF1, p63, CD31, calretinin, and BAP1 expressions were not detected.
Due to the absence of specific histological features, the differentiation between MM subtypes could be a challenging task. In routine diagnostic work, IHC may be the proper method in distinction. According to our results and literature data, CK5/6, mesothelin, calretinin, and Ki-67 should be applied in subclassification.
