Epithelioid Mesothelioma Research Articles

SPARC Is a Novel Positive Immunohistochemical Marker of Epithelioid Mesothelioma to Differentiate It From Lung Adenocarcinoma and/or Squamous Cell Carcinoma.

Epithelioid mesothelioma with a solid histologic pattern (solid epithelioid mesothelioma) is difficult to distinguish from a poorly differentiated squamous cell lung carcinoma and/or solid lung adenocarcinoma. Thus, immunohistochemical markers are essential for diagnosis; however, the sensitivity and specificity of pre-existing mesothelial markers are suboptimal, particularly for differentiation from squamous cell carcinoma. Using a cancer-dependency map, we analyzed gene expression data of pleural mesothelioma and non-small cell lung cancer cell lines (squamous cell carcinoma and adenocarcinoma) and identified secreted protein acidic and cysteine-rich (SPARC) as a promising candidate for the differential diagnosis of epithelioid mesothelioma from lung squamous cell carcinoma and/or lung adenocarcinoma. SPARC expression in mesothelioma and lung cancer cell lines was validated using reverse-transcription polymerase chain reaction, western blotting, and immunohistochemistry. Immunohistochemical staining was performed using anti-SPARC antibodies against solid epithelioid mesothelioma, solid lung adenocarcinoma, and poorly differentiated lung squamous cell carcinoma. SPARC positivity was seen in 42/45 (93.3%) of solid epithelioid mesothelioma, 2/40 (5%) solid lung adenocarcinoma, and 2/45 (4.5%) of lung squamous cell carcinomas. The sensitivity, specificity, and diagnostic accuracy for differentiating solid epithelioid mesothelioma from lung cancer (solid lung adenocarcinoma and poorly differentiated lung squamous cell carcinoma) were 93.3, 95.2, and 94.6%, respectively. In conclusion, SPARC is a novel mesothelial marker that can be used to differentiate epithelioid mesothelioma from squamous cell carcinoma and lung adenocarcinoma.

Updates on grading mesothelioma.

Mesothelioma is a rare disease with an historically poor prognosis. Over the past decade, a grading system has been developed that is a powerful prognostic tool in epithelioid mesothelioma. Grading of epithelioid mesothelioma is now required or strongly recommended by expert consensus, the College of American Pathologists, the World Health Organization, and the International Mesothelioma Interest Group. The original nuclear grading system for epithelioid mesothelioma, developed in the United States, split epithelioid mesotheliomas into three prognostic groups with marked differences in survival. Now, this three-tiered nuclear grading system has been combined with the presence or absence of necrosis to form the currently recommended two-tiered grading system of low- and high-grade epithelioid mesothelioma. This review will focus on the development of this grading system in mesothelioma, the grading system's shortcomings, and the application of the grading system to cytology specimens and other extra-pleural sites. Lastly, this review will briefly discuss alternative grading systems and future considerations.

The role of CD24 as a potential biomarker for malignant pleural mesothelioma

Abstract Objectives Pleural mesothelioma is a rapidly progressing pleural neoplasm caused by asbestos exposure of a long latency around 30-40 years. Patients with mesothelioma are usually diagnosed at a late stage with poor outcomes in terms of morbidity and mortality with 6–12 months’ median survival. Despite the prohibited use of asbestos, malignant pleural mesothelioma is still increasingly being occurred in young age and female patients. Different un-standardized biomarkers have been used to diagnose MPM as mesothelin and febulin with controversial results, so we used CD 24 as a biomarker to diagnose and differentiate between different subtypes of malignant pleural mesothelioma. Materials and methods Our cohort study included total of fifty-nine patients with exudative pleural effusion. All patients underwent full history taking, clinical examination, blood tests (CBC, coagulation profile, liver and kidney functions), tapping of pleural effusion and to send pleural fluid investigations for LDH, albumin, total protein and albumin, then confirmed exudative pleural effusion patients were subjected to thoracic ultrasonography and medical thoracoscopy for the majority of cases or ultrasound guided biopsy in selected cases to obtain pleural biopsies for histopathology and then the examination of pleural biopsies for CD24 expression. Results Our study demonstrated the possibility of using CD24 as a biomarker in the immunostaining of pleural biopsies to differentiate between malignant pleural mesothelioma and pleural malignancy other than mesothelioma (18 mesothelioma cases versus 2 nonmesothelioma malignant cases) with high statistical significance P value < 0.001 and also it can discriminate between subtypes of mesothelioma as it showed marked significance in epithelioid subtype (12 epithelioid versus 1 sarcomatoid versus 5 biphasic subtypes) with more uptake by score +2 in epithelioid mesothelioma. Conclusions CD24 can be supposed to be a routine biomarker for immunohistochemistry of pleural tissue samples in diagnosis of mesothelioma and it can be used to differentiate between subtypes of malignant mesothelioma subtypes.

Uroplakin-IIIb as a novel immunohistochemical marker for mesothelioma

Distinguishing mesothelioma from non-small cell lung carcinoma often requires a battery of immunohistochemical stains, as many traditional markers used in mesothelioma lack sufficient specificity to allow them to be used alone. A recent large-scale TMA screen identified uroplakin-IIIb (UpIIIb; clone MSVA-736M) as a potentially specific marker for mesothelioma. We examined the performance of this antibody using tissue microarrays containing a panel of 48 epithelioid mesotheliomas, 26 sarcomatoid mesotheliomas, and 144 non-small cell lung carcinomas (NSCLCs). Here we show that UpIIIb has good sensitivity (37/47 evaluable cases positive, 79%) and excellent specificity for distinguishing epithelioid mesothelioma from NSCLC (0/140 evaluable cases positive). UPIIIb sensitivity for epithelioid mesotheliomas was only slightly inferior to the established highly specific mesothelioma marker HEG1 (41/46 evaluable cases positive on the same TMA, 89%). However, UpIIIb did not stain any sarcomatoid mesotheliomas (0/24 evaluable cases positive). We also found that UpIIIb stained a proportion of high-grade serous ovarian carcinomas, a perennial diagnostic confounder in the context of mesotheliomas. Taken together, our data suggest that UpIIIb can be used as a highly specific and sensitive mesothelial marker when the diagnostic question is epithelioid mesothelioma versus NSCLC; in particular, UpIIIb staining will pick up some number of epithelioid mesotheliomas that are HEG1 negative. Since UpIIIb is known to stain some proportion of urothelial carcinomas as well as gynecologic and a few pancreatic tumors, it should be used with caution in the peritoneal cavity or when the differential diagnosis includes carcinomas from these locations.

New developments in mesothelial pathology.

This review article examines some new and some problem areas in mesothelial pathology, four of which are discussed, as follows. (1) The concept of mesothelioma in situ: this lesion is defined as a single layer of bland mesothelial cells without evidence of invasion, but that have lost BAP1 and/or MTAP by immunohistochemistry. Benign reactions can exactly mimic mesothelioma in situ, but a hint to the correct diagnosis is a story of recurrent pleural effusions/ascites of unknown aetiology without radiological or direct visual evidence of tumour. (2) The nature of well-differentiated papillary mesothelial tumour (WDPMT): WDPMT has a long history of arguments regarding its behaviour, and this uncertainty can now be seen to arise, in part, from the observation that some forms of mesothelioma in situ microscopically look exactly like WDPMT. Hence, it is recommended to always run at least a BAP1 stain on any lesion that looks like WDPMT. Both flat and WDPMT-like mesothelioma in situ are strongly associated with eventual development of invasive mesothelioma, but this process is relatively slow. (3) New immunostains for separating mesothelioma from other tumours: here, it is proposed that in most cases, and particularly when the differential is epithelioid mesothelioma versus non-small cell lung cancer, one can make this separation with extremely high sensitivity and specificity using just two stains: HEG1 and claudin-4. (4) Markers for separating benign from malignant mesothelial proliferations: this topic is briefly reviewed, with an indication of which markers are generally accepted and the best utilisation and possible limitations of each marker.

Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair.

DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival. A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status. Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS. The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.

Extrathoracic Metastases in Pleural Mesothelioma

IntroductionGuidelines recommend obtaining a computed tomography scan of the chest for the staging of pleural mesothelioma and for assessing response to treatment. Consensus is lacking regarding the necessity of serial imaging of distant extrathoracic sites. In this study, we determined the prevalence of extrathoracic metastases in patients with pleural mesothelioma. MethodsWe conducted a retrospective review of patients with pleural mesothelioma treated at Massachusetts General Hospital between 1999 and 2022 who were referred for extrathoracic imaging during their disease course. Imaging reports were reviewed to determine sites of metastasis and calculate the time to development of extrathoracic metastasis. Overall survival and prevalence of extrathoracic metastasis were compared for patients with epithelioid versus nonepithelioid mesothelioma. ResultsThe study included 148 patients, 69 (47%) of whom had undergone cytoreductive surgery. Histologic types included epithelioid (n = 82, 55%), biphasic (n = 49, 33%), and sarcomatoid (n = 10, 7%) mesothelioma. The median overall survival for the cohort was 24.0 months, specifically 34.7 months and 16.7 months for patients with epithelioid and nonepithelioid tumors, respectively (p < 0.001). There were 65 (44%) patients who developed extrathoracic metastases, with a median time to extrathoracic metastasis of 11.5 months. The most common sites of involvement were extrathoracic nodes (22%), peritoneum (20%), bone (11%), and liver (11%). Of the 76 patients referred for brain imaging, seven (9%) had brain metastases. The frequency of extrathoracic metastasis was identical for epithelioid and nonepithelioid mesothelioma (44%). Overall survival was shorter for patients who developed extrathoracic metastases (hazard ratio 5.9, p < 0.001). ConclusionsPatients with pleural mesothelioma often develop extrathoracic metastases, providing a rationale for routinely obtaining imaging that encompasses sites outside of the thoracic cavity.

Gastric carcinoma and peritoneal mesothelioma – a rare case of synchronous cancer. Clinical observation

Primary-multiple malignant neoplasms develop in about 9 % of cancer patients in the Russian Federation, while synchronous tumors are detected in a quarter of them, which dictates the need for a mandatory multidisciplinary approach to the choice of treatment. Localization of synchronous primary-multiple tumors in one anatomical zone requires a qualitative interpretation of instrumental diagnostic methods and morphological analysis after biopsy of each tumor. Along with this, there is a possibility of an erroneous opinion about the presence of different histological structures of the detected tumors and the data of visual assessment methods are interpreted in favor of a single disease.This paper presents a clinical observation of a rare combination of gastric adenocarcinoma and peritoneal mesothelioma. The case was discussed at a multidisciplinary consultation with the participation of a surgeon, a chemotherapist and a radiologist. Taking into account the clinical stage of gastric body cancer c T3N1M0, III stage, it was decided to conduct preoperative polychemotherapy at the first stage. Repeated diagnostic laparoscopy revealed no negative dynamics, multiple small dropouts in the peritoneum persisted. Subsequently, the operation was performed in the volume of gastrectomy, total parietal peritectomy and appendectomy without macroscopic signs of a residual tumor. It was decided to refrain from intra-abdominal chemoperfusion with hyperthermia due to the large volume of surgery and the previous 8 courses of polychemotherapy. Microscopic examination of the altered part of the stomach wall revealed residual adenocarcinoma (type according to Lauren – intestinal) with signs of therapeutic pathomorphosis G3 (according to Mandard), which had grown into the subserous layer and the fiber of the small omentum, with signs of perineural invasion, in the absence of vascular invasion; resection edges – R0. On the surface of the removed fragments of the peritoneum, various foci of malignant epithelioid mesothelioma were found. At the control examination a year later, according to computed tomography and esophagogastroduodenoscopy, there were no signs of progression, the patient’s condition was satisfactory.

Primary peritoneal epithelioid mesothelioma with a STK11 gene mutation: report of a case

Primary peritoneal epithelioid mesothelioma with a STK11 gene mutation: report of a case

Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma.

Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy. Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit.

Pembrolizumab (Anti-PD-1) in the management of malignant pleural mesothelioma: A systematic review of the current literature

Malignant pleural mesothelioma is an infrequent and aggressive type of cancer that is difficult to treat, and standard therapies have shown limited effectiveness. There have been recent advances in the development of targeted therapies for malignant pleural mesothelioma, including immunotherapy with pembrolizumab. This is a systematic review of the current role of pembrolizumab in the treatment of this disease. A systematic search was conducted through the databases and search engines. The eligible studies to be included were those that primarily focused on the outcomes of treating this disease with pembrolizumab, regardless of study design, line of therapy, mode of therapy, and ECOG performance status. After the initial and full-text screenings, 15 studies were reviewed. The number of cases was 454 with a mean age of 68.13 years, of which males (79.7%) were the predominant gender. Most of the cases were affected by epithelioid mesothelioma (76.7%). Pembrolizumab had been used as the first line of treatment in 62 (13.7%) cases. In 92.73% of cases, the therapy mode was pembrolizumab monotherapy. A total of 68 different adverse events were recorded. The most commonly associated adverse events were fatigue (14.8%), pruritis/rash (13.7%), and diarrhea (9.7%). Two patients died due to adverse events. The overall objective response was 17.8%, stable disease was 35.7%, progression-free survival was about 47.6% with a mean of 4.73 months, and 117 cases (25.8%) could reach treatment-related survival. Pembrolizumab can serve as a viable alternative in the management of malignant pleural mesothelioma, offering satisfactory outcomes and acceptable safety profiles

Association of somatic mutations and histologic subtype/grade on prognosis and PD-L1 expression in mesothelioma.

8507 Background: Mesothelioma includes epithelioid, sarcomatoid, and biphasic histologic subtypes, and the epithelioid subtype is histologically graded based on mitotic count and nuclear atypia. Correlation between the most common somatic mutations ( BAP1, NF2, TP53, CDKN2A), and overall survival is poorly understood. High PD-L1 expression is a poor prognostic factor for survival and may be a predictor of response to immunotherapy. Few studies have evaluated the relationships between these factors. Methods: We performed a retrospective study in 217 patients with pleural, peritoneal and bicavitary mesothelioma as part of an IRB-approved biobanking protocol. Histologic subtype, grade of epithelioid mesothelioma, tumor stage, and overall survival time were determined. Next-generation DNA sequencing (NGS) was used to identify the prevalence of somatic mutations. PD-L1 immunohistochemistry was obtained on 184 samples and quantified as percentage of tumor cells. Histologic subtype, nuclear grade, clinical stage, PD-L1 expression, survival time, and the prevalence of each mutation were compared using chi-squared, Kruskal-Wallis, or Cox proportional hazard tests. All p-values were determined in R version 4.2.0 using a two-sided alpha error of 0.05 to mark statistical significance. Results: The most frequent somatic mutations were found in BAP1 (99/217, 45.6%), CDKN2A (47/217, 21.7%), TP53 (37/217, 17.1%), and NF2 (31/217, 14.3%). Patients with CDKN2A-mutated mesothelioma experienced shorter survival (p=0.032). TP53 mutations were associated with higher nuclear grade (p=0.015), higher mitotic count (p=0.013), and greater nuclear atypia (p=0.015). TP53 mutations were more prevalent in pleural than peritoneal mesothelioma (p=0.016) and in tumors without lymph node metastasis (p=0.05). As expected, patients with epithelioid mesothelioma had superior overall survival (p=0.02) and their tumors had lower PD-L1 expression (p=0.007) than either sarcomatoid or biphasic mesotheliomas. Neither PD-L1 expression nor mutations in BAP1, NF2, CDKN2A, or TERT were associated with nuclear grade, atypia, or mitotic count. No association was found between BAP1 or NF2 mutations and tumor stage, lymph node metastasis, or PD-L1 expression. Conclusions: To our knowledge, this is the first study of this scale to correlate PD-L1 expression, somatic mutation data, histologic features, and survival in mesothelioma patients. The most significant findings were that patients with CDKN2A mutations had shorter survival and TP53 mutations, which were more prevalent in pleural mesotheliomas, were associated with higher nuclear grade, higher mitotic count, and greater nuclear atypia. An ongoing analysis evaluates the contribution of germline mutations, which occurred in a significant proportion (15.7%) of this mesothelioma patient cohort.

Neoadjuvant immunotherapy in sarcomatoid mesothelioma (Alliance A082101).

TPS8602 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS). For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Clinical trial information: NCT05647265 .

Durvalumab with chemotherapy as first line treatment in advanced pleural mesothelioma: A phase 3, randomised trial (DREAM3R).

TPS8599 Background: Two phase 2 trials of durvalumab plus chemotherapy in advanced pleural mesothelioma exceeded pre-specified efficacy criteria. The recent CM 743 trial showed overall survival (OS) was longer in those assigned ipilimumab and nivolumab (ipi nivo) than standard chemotherapy, however the benefits were primarily in the subgroup with non-epithelioid histology. DREAM3R will determine the effectiveness of durvalumab plus chemotherapy as first line treatment for advanced pleural mesothelioma. The DREAM3R protocol was recently amended to allow treatment with ipi nivo as per CM 743 in the control group, and to confine further accrual to epithelioid subtype. Methods: Treatment-naïve patients with advanced, epitheloid pleural mesothelioma will be randomized (1:1) to either experimental group treatment: durvalumab 1500 mg every 3 weeks plus chemotherapy (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin AUC 5) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, or control group treatment: physician’s choice of either chemotherapy or ipi nivo (up to 2 years). The target sample size of 480 recruited over 33 months, with follow up for another 18 months provides over 85% power if the true hazard ratio for OS is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 18 months in the control group. Key eligibility criteria: Epithelioid pleural mesothelioma; measurable disease per RECIST 1.1 modified for mesothelioma; ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for pleural mesothelioma, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Participants are stratified at randomization for: age (18-70 years vs. &gt; 70), sex, planned control regimen (chemotherapy or ipi nivo), platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and use of healthcare resources in ANZ. Tertiary objectives are to identify potential prognostic and/or predictive biomarkers (including those identified in prior phase 2 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes), validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN12620001199909 .

Value of Glypican-1 Expression in Pleural Epithelioid Mesothelioma, Adenocarcinoma and Squamous Cell Carcinoma of the Lung

Background: Distinguishing between pleural epithelioid mesothelioma, lung adenocarcinoma, and poorly differentiated squamous cell carcinoma (SCC) is a challenge in some cases. A panel of markers has been recommended by the International Mesothelioma Interest Group (IMIG) guideline to differentiate epithelioid mesothelioma from lung adenocarcinoma and SCC. However, the use of novel highly specific immunohistochemical (IHC) markers is still required. Objectives: This study aimed to evaluate glypican-1 (GPC1) expression in epithelioid mesothelioma, lung adenocarcinoma, and SCC, correlating its expression with some known clinicopathological parameters to clarify its diagnostic and prognostic value.Methods: This study included seventy specimens designated as 20 cases of pleural epithelioid mesothelioma, 30 cases of lung adenocarcinoma, and 20 cases of lung SCC. GPC1 expression was evaluated using immunohistochemistry (IHC). The data was analyzed statistically by SPSS software 25. GPC1 expression was correlated to different clinicopathologic data using Chi-square test. The study was conducted according to local Ethical Committee regulations. Results: This study detected positive GPC1 reactivity in all cases (100%) of pleural mesothelioma and lung SCC, in which increased GPC1 expression was correlated to large-sized, high grade, advanced stage tumors, and the presence of lymph node metastasis (LNM). In contrast, GPC1 expression was absent in about 93% of lung adenocarcinoma cases, and only 2 cases exhibited weak focal expression. Conclusion: Our findings demonstrated that GPC1 expression is upregulated in advanced pleural mesothelioma and pulmonary SCC; tumors with high GPC1 expression exhibited more advanced biological behavior.

Reliability of assessing morphologic features with prognostic significance in cytology specimens of epithelioid diffuse pleural mesothelioma and implications for cytopathology reporting.

The World Health Organization incorporates morphologic features with prognostic significance in the 2021 classification of epithelioid diffuse pleural mesothelioma (E-DPM). Although cytology specimens are often the first and occasionally the only specimen available for patients with DPM, these features have not yet been investigated in cytology. Nuclear atypia, pleomorphic features, necrosis, and architectural patterns were retrospectively assessed in 35 paired cytology and concurrent/consecutive surgical pathology specimens of E-DPM. Agreement between pairs was determined via unweighted κ scores. Discordant cases were re-reviewed to determine the reasons for disagreement. Interpretation of nuclear atypia in cytology was concordant with histology in all cases (κ=1.000; p<.001). The presence of pleomorphic features and necrosis was concordant in 97.1% (κ=0.842; p<.001) and 85.7% (κ=0.481; p=.001) of paired cases, respectively. Assessment of architectural patterns in cytology showed only slight agreement with histology (κ=0.127; p=.037). In cytology cases (n=23) with cell block material available, assessment of nuclear atypia and the presence of pleomorphic features showed perfect agreement (κ=1.000; p<.001, each), the presence of necrosis showed moderate agreement (κ=0.465; p=.008), and assessment of architectural patterns showed slight agreement (κ=0.162; p=.15) in paired specimens. Most disagreements were due to sampling differences between cytology and histology specimens. Although complete nuclear grading of E-DPM is not possible given the unreliability of mitotic counts in cytology, assessment of nuclear atypia in cytology specimens is shown to be reliable. Identification of pleomorphic features and necrosis is also reliable despite occasional sampling issues. Assessment of architectural patterns is more limited in cytology.

Comprehensive epithelial biomarker analysis of malignant mesothelioma: EpCAM positivity is a potential diagnostic pitfall.

Epithelial cell adhesion molecule (EpCAM) is frequently used to distinguish carcinoma from background mesothelial cells during cytologic examination of body cavity fluids. Previously, the authors identified one malignant mesothelioma case with strong and diffuse membranous EpCAM staining, making it indistinguishable from carcinoma. In this study, the authors evaluated all available effusion specimens from patients with malignant mesothelioma, including the above-mentioned index case, obtained at Stanford Health Care, from 2011 to 2021 (N=17) as well as control cases (N=5). Analyses included an immunohistochemistry (IHC) assay for EpCAM and claudin-4, a multiplexed immunofluorescent (IF) assay for EpCAM, and an RNA in situ hybridization assay targeting EpCAM. The authors detected EpCAM positivity of variable intensity and percentage in four malignant mesothelioma cases (23.5%; although only two showed positivity for the epithelial-specific IHC marker MOC31 in ≥40% of cells) and claudin-4 negativity in all cases, with two cases displaying focal and weak claudin-4 staining in <1% of cells. Multiplexed IF staining on the cases with EpCAM IHC positivity showed strong, membranous EpCAM staining in one of four cases. RNA in situ hybridization also was used to assess the correlation between EpCAM positivity by IHC/IF and RNA expression levels. Strong EpCAM RNA expression was detected in the three malignant mesothelioma cases. The current findings revealed that a subset of epithelioid malignant mesothelioma cases mimic or exhibit the immunophenotypic features of carcinoma when evaluating for EpCAM only. Additional biomarker testing, such as claudin-4, may help avoid this potential pitfall to yield accurate diagnoses.

High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma.

Mesothelin (MSLN) is a cancer-associated antigen that is overexpressed in malignancies such as mesothelioma, pancreatic and ovarian cancer. It is also a target for novel personalised therapies, including antibodies, antibody-drug conjugates and chimeric antigen receptor T cells. Immunohistochemistry may predict those who would best respond to anti-mesothelin therapies and guide decisions in therapeutic strategy. This study aimed to assess the intensity and distribution of MSLN immunostaining in mesothelioma, and to determine the prognostic value of MSLN expression by histochemical-score (H-score). The MN1 anti-MSLN antibody was used to stain a formalin-fixed paraffin-embedded tissue microarray of histologically confirmed mesothelioma from 75 consecutive patients who had undergone pleurectomy with or without decortication. MSLN positivity, the staining intensity, distribution of staining and H-score were evaluated. The correlation of H-score with prognosis was investigated. Sixty-six per cent of epithelioid tumours were MSLN-positive (with expression in > 5% tumour cells). Of MSLN-expressing epithelioid tumours, 70.4% had moderate (2+) or strong (3+) intensity MSLN immunostaining, although only 37% of samples had staining in ≥ 50% of tumour cells. In multivariate analysis, MSLN H-score as a continuous variable and an H-score ≥ 33 were independent predictors of improved survival (P = 0.04 and P < 0.001, respectively). MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin-targeted personalised therapies, such as chimeric antigen receptor T cells.

KRAS Mutations Are Associated with Shortened Survival in Patients with Epithelioid Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural surface that includes three major histologic subtypes, epitheliod, sarcomatoid and biphasic. Epithelioid mesothelioma is usually associated with better prognosis. The genetic mechanisms driving MPM, the possible target mutations and the correlation with overall survival remain largely unsettled. We performed target exome sequencing in 29 cases of MPM aimed at identifying somatic mutations and, eventually, their correlation with phenotypic traits and prognostic significance. We found that KRAS mutations, occurring in 13.7% of cases, were associated with shortened median survival (7.6 versus 32.6 months in KRAS wild-type; p = 0.005), as it was the occurrence of any ≥3 mutations (7.6 versus 37.6 months; p = 0.049). Conversely, the presence of KDR single nucleotide polymorphism p.V297I (rs2305948) resulted in a favorable variable for survival (NR versus 23.4 months; p = 0.026). With the intrinsic limitations of a small number of cases and patient heterogeneity, results of this study contribute to the characterization of the mutation profile of MPM and the impact of selected somatic mutations, and possibly KDR polymorphism, on prognosis.

Clear-Cell Mesothelioma of Uterine Corpus: Diagnostic Challenges in Intraoperative Frozen Sections

The clear-cell variant of epithelioid mesothelioma is an extremely rare neoplasm of the peritoneum. It shares histomorphologic features overlapping with a wide variety of tumors including carcinomas and other non-epithelial neoplasms. The diagnosis of peritoneal clear-cell mesothelioma is not always straightforward, despite known immunohistochemistry (IHC) markers. Due to its rarity, this entity may be diagnostically confused with other clear-cell neoplasms, particularly in intraoperative frozen sections. Here, we present a case of clear-cell mesothelioma originating in the uterine serosa that was initially misdiagnosed as clear-cell adenocarcinoma in the intraoperative frozen section. Microscopically, the tumor showed diffuse tubulocystic spaces of variable size lined by clear cells with moderate nuclear atypia. Immunohistochemical staining confirmed the diagnosis of clear-cell mesothelioma. Recognition of this entity, albeit rare, is important as the diagnosis may significantly affect the management considerations. The judicious use of an IHC panel helps to distinguish this tumor from other mimickers.