Malignant mesothelioma (MM) is uncommon, but very aggressive tumor arising from the mesothelial cells of pleura, pericardium, peritoneum, and tunica vaginalis. Despite multimodality treatments 5-year ...survival is only 5% after the diagnosis. Histology and TNM staging system are still the best prognostic factors. Furthermore, histologic subtype of MM determines the clinical management of the patients. According to the 2015 WHO classification, MM is divided into diffuse, localized and well differentiated papillary mesothelioma. Major histologic subtypes of diffuse MM, namely epithelioid, biphasic and sarcomatoid, have different prognosis. However, in the last decade it has become evident that more detailed subclassification and histologic/cytological characterization of MM have prognostic and perhaps predictive implications. In this review, major histologic subtypes and cytological features of MM are presented and their relation with prognosis and predictive biomarkers is discussed.
The separation of benign from malignant mesothelial proliferations is an important clinical but often a difficult morphologic problem. Over the last roughly 10 years a variety of new markers that aid ...in this separation have been published and some older recommended markers reconsidered. Unlike previous, and largely unusable, empiric immunohistochemical (IHC) stains, these new markers, some using IHC and some using fluourescent in situ hybridization (FISH), are largely based on documented genomic abnormalities in malignant mesotheliomas. However, no marker works in all situations; rather, markers need to be chosen by the morphology of the process in question (epithelial vs. spindled) and the body cavity of interest (pleural vs. peritoneal). It is also important to be familiar with the exact pattern, for example nuclear versus cytoplasmic loss, that indicates a positive test. Furthermore, no single marker is 100% sensitive even with the optimal morphology/location, so that combinations of markers are essential. This review covers the various new markers in the literature, highlights their advantages and limitations, and suggests morphology/site specific combinations that can produce sensitivities in the 80% to 90% (and perhaps higher) range. At present only BRCA-1 related protein-1 and methylthioadenosine phosphorylase IHC, and cyclin-dependent kinase inhibitor 2A (p16) FISH have sufficient publications and reproducibility of results to be considered as established markers. 5-Hydroxymethyl cytosine, enhancer of zeste homolog 2, cyclin D1, and programmed death-ligand 1 IHC, and NF2 FISH are all potentially useful but need further study. The newly described entity of malignant mesothelioma in situ sits at the interface of benign and malignant mesothelial process; criteria for this diagnosis are reviewed.
Ectopic decidua is a rare benign condition, believed to be associated with excessive progesterone stimulation such as in multiple gestations as in our case, it's usually asymptomatic and found ...incidentally during caesarean section. The lesions involute spontaneously in the postpartum period; therefore it usually doesn't require any therapeutic interventions. This condition could induce anxiety to surgeons intra-operatively, because of resemblance of more sinister lesions such as: carcinomatosis and granulomas. We report a clinical case of diffuse peritoneal deciduosis, identified during an emergency caesarean section, performed at 33 weeks of gestation, for a transverse lie, twins DCDA pregnancy in active labor.
Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of ...BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies.
To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients.
By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%).
Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.
The separation of sarcomatoid and desmoplastic malignant mesotheliomas from sarcomatoid carcinomas of the lung metastatic to the pleura may be difficult, since both types of tumor can be ...morphologically similar and are frequently positive only for pan-keratin. GATA binding protein 3 (GATA3) is most commonly used as an immunohistochemical marker of breast and urothelial carcinoma, but is also known to stain other types of tumors including some mesotheliomas. In this study we asked whether GATA3 stains could be used to distinguish sarcomatoid/desmoplastic malignant mesotheliomas (N=19) from sarcomatoid carcinomas of the lung (N=13). Tumor staining was scored for diffuseness and intensity, with a maximum possible score of 6. All 19 sarcomatoid/desmoplastic malignant mesotheliomas examined showed strong diffuse staining for GATA3 (no case scored <3, mean score±SD for all 19 cases 5.4±0.9), whereas only 2 of 13 sarcomatoid carcinomas of the lung stained positively for GATA3 and the staining was weak and patchy (score 2 for each case, mean±SD for all 13 cases 0.4±0.8). There was no correlation between the intensity and diffuseness of GATA-3 staining and staining for traditional mesothelioma markers. Overall, any positive staining for GATA3 was 100% sensitive and 85% specific for sarcomatoid/desmoplastic mesothelioma. We conclude that strong diffuse staining for GATA3 favors a diagnosis of sarcomatoid/desmoplastic malignant mesothelioma over metastatic sarcomatoid carcinoma of the lung; conversely, complete absence of GATA-3 staining is evidence against a diagnosis of sarcomatoid/desmoplastic malignant mesothelioma.
Malignant mesothelioma of the para-testis is a rare cancer which may be clinically undiagnosed for several years and found incidentally at cut up for presumed benign disease. It has a number of ...histological presentations to be aware of and pitfalls to avoid. It is important to be able to reliably distinguish para-testicular MM from various other less aggressive entities which have significantly different management strategies. We present a case of epididymis and tunica vaginalis MM that was incidentally diagnosed on histological examination following a hydrocelectomy.
Podoplanin is a type I transmembrane sialomucin‐like glycoprotein that is highly expressed in malignant mesothelioma. The rat‐human chimeric antibody NZ‐12 has high affinity for human podoplanin and ...antibody‐dependent cellular cytotoxicity and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ‐12 and the antitumor effect of RIT with 90Y‐labeled NZ‐12 in an NCI‐H226 (H226) malignant mesothelioma xenograft mouse model. 111In‐labeled NZ‐12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with 90Y‐labeled NZ‐12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of 90Y‐labeled NZ‐12 in patients compared with the H226 tumor xenografts. Our findings suggest that 90Y‐labeled NZ‐12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.
90Y‐labeled anti‐podoplanin antibody NZ‐12 significantly suppressed tumor growth without body weight loss in a mesothelioma mouse model. Considering the higher expression levels of podoplanin in human malignant mesothelioma specimens compared with H226 tumors, radioimmunotherapy with 90Y‐labeled NZ‐12 is a promising potential therapeutic option to provide greater clinical benefit to malignant mesothelioma patients.
Malignant pleural mesothelioma: recent developments Sinn, Katharina; Mosleh, Berta; Hoda, M Alireza
Current opinion in oncology,
2021-January, 2021-Jan, 2021-01-00, 20210101, Letnik:
33, Številka:
1
Journal Article
PURPOSE OF REVIEWMalignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with still poor prognosis. In this article, we focus on recent developments in the management of MPM including ...diagnosis, staging, biomarkers, and treatment strategies.
RECENT FINDINGSMolecular markers such as programmed death-ligand 1 (PDL-1), Breast Cancer gene 1-associated protein gene, and cyclin-dependent kinase inhibitor 2A (CDKN2A) have prognostic impact and should be considered for assessment in patient samples. In addition to histological subtype and tumor pattern, tumor volumetry plays an increasing important role in staging, assessment of treatment response, and prediction of survival. Several new blood-based biomarkers have been recently reported including peripheral blood DNA methylation, microRNAs, fibulin, and high-mobility group box 1, but have not been established in clinical routine use yet. Regarding treatment, targeted therapies, immunotherapy, and vaccination are considered as new promising strategies. Moreover, extended pleurectomy/decortication is favored over extrapleural pneumonectomy (EPP) and intensity-modulated radiotherapy represents a possible approach in combination with EPP and pleurectomy/decortication. Intracavitary treatment options are promising and deserve further investigations.
SUMMARYOverall, there has not been a real breakthrough in the treatment of MPM. Further research and clinical trials are needed to evaluate outcome and to identify new potential treatment candidates.
The separation of sarcomatous and desmoplastic mesotheliomas from benign organizing pleuritis can be morphologically very difficult. Deletion of p16 (CDKN2A) by fluorescence in situ hybridization ...(FISH) testing appears to be a reliable marker of malignancy in mesothelial proliferations, and more recently it has been reported that, in this setting, loss of BAP1 by immunohistochemistry is only seen in malignant mesotheliomas. To determine how useful these tests are with sarcomatous and desmoplastic mesotheliomas, we examined 20 such tumors. Loss of BAP1 was seen in 3/20 (15%) and deletion of p16 by FISH was seen in 16/20 (80%) cases. Loss of one or the other marker was observed in 17/20 (85%). We also examined 13 sarcomatoid carcinomas, an important differential diagnosis of sarcomatoid mesotheliomas, and found that BAP1 was never lost, but p16 was deleted in 3/11 (27%). We conclude that(1) BAP1 immunohistochemistry is relatively insensitive in the context of sarcomatous and desmoplastic mesotheliomas, but as a matter of time and cost efficiency may nonetheless be a useful first approach to the problem; (2) deletion of p16 by FISH is considerably more sensitive, but there remain a proportion of cases in which p16 is not deleted; (3) a small improvement in sensitivity can be achieved by using both markers; (4) in the context of a spindle cell malignant tumor in the pleura or peritoneum, which morphologically might be a metastatic sarcomatoid carcinoma or a mesothelioma, the finding of BAP1 loss favors mesothelioma, but p16 FISH cannot be used to separate sarcomatous mesotheliomas from sarcomatoid carcinomas.
Maligni mezoteliom (MM) pleure agresivna je maligna bolest čija je incidencija u porastu. Dijagnostika MM-a izazovna je zbog kasnog javljanja simptoma bolesti, a problem predstavljaju poteškoće ...razlikovanja benignih i malignih lezija što ponekad odgađa dijagnozu. Slikovna procjena najčešće se provodi CT (engl. Computed tomography) dijagnostikom, dok se konačna dijagnoza uspostavlja nakon biopsije i analize patohistološkog uzorka. Dijagnozu epiteloidnog mezotelioma moguće je uspostaviti citološkom analizom pleuralnog izljeva, gdje su potrebna dva pozitivna imunocitokemijska markera koji potvrđuju dijagnozu te dva negativna markera koji isključuju dijagnozu. Cilj je ovog rada prikazati trenutna saznanja o slikovnim, citološkim i patohistološkim metodama dijagnosticiranja MM-a.
Malignant pleural mesothelioma (MPM) is an agressive neoplasm with an increasing incidence rate. MPM has a delayed onset of symptoms, and diagnosis is often challenging because of the difficulties in the differentiation of the benign and malignant lesions. CT (Computed tomography) is used for imaging assessment of mesothelioma, while biopsy and histopathology give the definitive confirmation of the MPM. Cytology analyis of the pleural effusion with two immunocytochemistry markers in favor of MPM and two excluding the diagnosis are sufficient to diagnose MPM. The aim of this review is to summarize recent diagnostic methods in MPM diagnosis.
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