Diagnostics

Our medical research library holds 41 studies published in Diagnostics (2020–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 41 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: MDPI AG
• Published: 2011 to the present, Switzerland
• Language: English
• ISSN: 2075-4418 (electronic)
• Its record in the NLM Catalog

2020s

• AI-Driven Automated Detection of Pleural Plaques on Chest CT Scans in Retired Asbestos-Exposed Workers. Y. Petitpas, I. Benlala, F. Baldacci, et al. 2026;16(16). PubMed · Publisher · Free full text

  Abstract

  Background/Objective: This study aimed to develop and validate an automated framework for detecting pleural plaques (PPs) at the patient level using a single chest CT scan. Methods: A database of chest CT scans with corresponding individual binary annotations for PP presence was first established through expert visual assessment, based on consensus among a board of specialized radiologists. This dataset served to train and validate a patient-level classification framework for automated PP presence detection. This framework leverages a pre-trained PP segmentation network, thus obviating the need for retraining large-scale deep learning models. This segmentation backbone is supplemented by a lightweight classification module that integrates the network's outputs to infer the presence or absence of PPs at patient level. Furthermore, a patch-wise processing strategy was employed to optimize computational efficiency and training time while retaining critical local contextual information. Results: The framework was evaluated on a cohort of 1241 retired workers with documented occupational asbestos exposure, using 10-fold cross-validation (30% training, 10% validation, 60% testing). It achieved a balanced accuracy of 97.0%, sensitivity of 96.6%, and specificity of 97.4%, demonstrating performance slightly superior to that of two expert radiologists (balanced accuracy: 90.9%/91.4%, sensitivity: 88.0%/88.8%, specificity: 93.9%/94.1% for Expert1/Expert2) and substantially superior to that of a radiologist without specialized expertise in asbestos-related manifestations (balanced accuracy: 80.0%, sensitivity: 75.1%, specificity: 84.8%). Conclusion: The proposed framework demonstrates strong potential for automated patient-level identification of pleural plaques from a single CT scan. Our approach could be particularly useful in screening settings that involve compensation claims related to occupational diseases.

• Establishment and Prospective Validation of a Classification System for Surface Microvessels in Peritoneal Lesions Under Magnifying Endoscopy. X. Guo, L. Shen, R. Lei, et al. 2026;16(18). PubMed · Publisher · Free full text

  Abstract

  Background: Peritoneal nodules require abdominal exploration and biopsy. However, blind biopsies may yield false-negative results. We developed a magnifying endoscopy-based microvascular classification for peritoneal lesions, prospectively validated its pathological predictive accuracy, and explored a precision-targeted biopsy strategy. Methods: This two-phase study was conducted at three hospitals from June 2016 to May 2022 (retrospective classification development) and four hospitals from June 2022 to February 2023 (prospective validation). Two experienced endoscopists first extracted features independently under blinded conditions and then constructed the microvascular classification (Types 1-3D) through an unblinded iterative process. Retrospective patients undergoing white-light endoscopic exploration served as non-randomized controls. Diagnostic accuracy, biopsy number, and histological diagnostic yield were compared. Results: This retrospective cohort included 56 patients with 77 peritoneal lesions. Of the 29 prospectively enrolled patients, 25 patients with 76 peritoneal lesions were included in the final validation. Three out-of-scope cases were reported separately. At the patient level, magnifying endoscopy showed significantly higher accuracy in predicting lesion pathology than white-light endoscopy (83.93% vs. 46.00%, p < 0.001), with fewer biopsies (p = 0.002) and a higher histological diagnostic rate (p < 0.001). Prospectively, the classification accuracy was 96.05% for tuberculosis (Type 2C), 96.05% for tumor-like lesions (Type 3A), 96.05% for mesothelioma (Type 3B), 97.37% for Müllerian epithelial tumors (Type 3C), and 90.79% for metastatic carcinoma (Type 3D). Conclusions: The microvascular classification showed promising preliminary accuracy for predicting peritoneal lesion pathology and may support precision-targeted biopsy. External validation and formal reproducibility assessment are required before clinical implementation.

• Immunohistochemical Loss of MTAP as a Diagnostic and Prognostic Surrogate of CDKN2A/B Homozygous Deletion: A Narrative Review. S. Salzano, R. Caltabiano, A. Palicelli, et al. 2026;16(13). Review PubMed · Publisher · Free full text

  Abstract

  Methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) has emerged as a valuable diagnostic, prognostic, and therapeutic biomarker in modern oncologic pathology, primarily serving as a surrogate for CDKN2A/B homozygous deletion due to their close genomic proximity at chromosome 9p21. This review aims to systematically evaluate the clinical utility, diagnostic accuracy, and technical limitations of MTAP IHC across a diverse spectrum of human malignancies, while contextualizing its role within current molecular testing algorithms. We first examine the established diagnostic and grading performance of MTAP loss in central nervous system neoplasms and thoracic tumors, particularly malignant pleural mesothelioma, followed by an analysis of its emerging prognostic value in gastrointestinal, cutaneous, and genitourinary malignancies. Furthermore, we discuss the therapeutic implications of MTAP deficiency, focusing on the biological consequences of methylthioadenosine accumulation and the resulting synthetic vulnerabilities in the PRMT5/MAT2A pathway. By synthesizing diagnostic precision, prognostic relevance, and translational therapeutic insights, this review provides a comprehensive framework for integrating MTAP IHC into routine surgical pathology workflows and personalized oncology.

• Lung Cancer in Never-Smokers: Risk Factors, Driver Mutations, and Therapeutic Advances. P.M. Chen, Y.H. Huang, C.Y. Li. 2026;16(2). Review PubMed · Publisher · Free full text

  Abstract

  Background and Objectives: Lung cancer in never-smokers (LCINS) has become a major global health concern, ranking as the fifth leading cause of cancer-related mortality. Unlike smoking-related lung cancer, LCINS arises from complex interactions between environmental carcinogens and distinct genomic alterations. This review summarizes current evidence on environmental risks, molecular features, and therapeutic progress shaping lung cancer management. Methods: A narrative review was conducted to examine risk factors for lung cancer in non-smokers. Studies reporting driver mutations in never-smokers and smokers were identified across major lung cancer histological subtypes, including small-cell lung cancer (SCLC), lung adenocarcinoma (LUAD), squamous cell carcinoma (SCC), and large-cell carcinoma (LCC). In addition, PubMed was searched for phase III trials and studies on targeted therapies related to driver mutations published between 2016 and 2025. Results: Environmental factors such as cooking oil fumes, radon, asbestos, arsenic, and fine particulate matter (PM2.5) are strongly associated with LCINS through oxidative stress, DNA damage, and chronic inflammation. EGFR, PIK3CA, OS9, MET, and STK11 mutations are characteristic of never-smokers, in contrast to TP53 mutations, which are more common in smokers. Recent advances in targeted therapy and immunotherapy have improved survival and quality of life, emphasizing the importance of molecular profiling for treatment selection. Conclusions: LCINS represents a distinct clinical and molecular entity shaped by complex interactions between environmental exposures and genetic susceptibility. Genetic alterations promote tumor immune evasion, facilitating cancer development and progression. Continued advances in air quality control, molecular diagnostics, and precision therapies are essential for prevention, early detection, and reduction of the global disease burden.

• MiR-21 Is a Novel Diagnostic and Prognostic Circulating Biomarker in Pleural Mesothelioma. B. Mosleh, Y. Dong, E. Lang, et al. 2026;16(8). PubMed · Publisher · Free full text

  Abstract

  Background/Objective: The identification of novel non-invasive diagnostic and prognostic biomarkers is urgently needed in pleural mesothelioma (PM). While soluble mesothelin-related peptides (SMRP) are the most established circulating biomarker, their prognostic value is limited. A wide range of microRNAs (miRs) play diverse roles in regulating gene expression in PM. MiR-21 has been shown to be upregulated in mesothelioma tissue; nevertheless, the diagnostic and prognostic utility of miR-21 in the circulation and its association with survival in PM have not been extensively investigated to date. The objective of the current study was to evaluate miR-21 as a potential blood-based diagnostic and prognostic biomarker in PM. Methods: Plasma samples from PM patients (n = 94) were collected at the time of diagnosis, prior to treatment. Sex- and age-matched healthy individuals (n = 30) served as controls. MiR-21 levels were measured using quantitative RT-PCR and normalized to miR-16, and potential correlations with clinicopathological data were analyzed. Serum SMRP levels were measured in matched patients (n = 84), and a direct comparative analysis of miR-21 and SMRP was conducted. In situ hybridization (ISH) was used to confirm the presence of miR-21 in tumor cells. Results: Plasma miR-21 levels were significantly elevated in PM patients compared to healthy controls (p < 0.001), demonstrating good diagnostic performance (AUC 0.81). The localization of miR-21 in PM cells was confirmed by ISH. High miR-21 levels were associated with significantly shorter median overall survival (12.4 vs. 24.3 months, p < 0.001). Elevated SMRP levels were also associated with reduced survival (12.4 vs. 19.5 months, p = 0.032); however, SMRP did not retain independent prognostic significance in multivariable analysis. In contrast, high-circulating miR-21 was confirmed as an independent predictor for poor survival (HR 3.12, p < 0.001). Conclusions: Our findings highlight that circulating miR-21 is a potential non-invasive biomarker with both diagnostic and independent prognostic value in pleural mesothelioma and outperforms SMRP in multivariable survival analysis. Further research is warranted to validate its role in the biology of this disease and to assess its correlation with outcome and treatment responses.

• Non-Nodular CT Patterns of Solid Lung Cancer in the Early Growth Phase: A Two-Center Retrospective Study. X.F. Wu, X.D. Ge, T. Li, et al. 2026;16(20). PubMed · Publisher · Free full text

  Abstract

  Background/Objectives: Early diagnosis of solid lung cancer (SLC) is essential for better prognosis. However, non-nodular patterns, atypical CT manifestations of SLC in the early growth phase, are easily overlooked, potentially leading to delayed diagnosis. This study aimed to characterize the clinical features and CT findings of non-nodular patterns of SLC in the early growth phase. Methods: Between January 2015 and October 2025, 365 patients with 365 pathologically confirmed SLCs were retrospectively enrolled from two centers. Based on initial morphological appearances, lesions were classified into nodular and non-nodular groups (patch-like, strip-like, bead-like, pleural plaque-like, and cystic-cavity subtypes). Clinical data and CT findings were summarized and compared between the two groups. Results: Of the 365 SLCs, 107 (29.32%) initially presented as non-nodular lesions, among which patch-like lesions (56, 52.34%) were the most prevalent, followed by bead-like (20, 18.69%), strip-like (16, 14.95%), pleural plaque-like (9, 8.41%), and cystic-cavity lesions (6, 5.61%). Both nodular and non-nodular lesions were predominantly located in the upper lobes (55.04% vs. 58.88%, p = 0.611). Multivariable analysis revealed that smoking history (adjusted odds ratio [aOR], 2.93; 95% confidence interval [CI], 1.05-8.28; p = 0.040), subpleural distribution (aOR, 3.37; 95% CI, 1.61-7.72; p < 0.001), interstitial lung disease (ILD) (aOR, 66.45; 95% CI, 23.57-220.04; p < 0.001), and post-tuberculosis lung changes (aOR, 8.60; 95% CI, 2.37-32.64; p = 0.001) were independently associated with a non-nodular pattern (AUC: 0.869; p < 0.001). Conclusions: In smokers or patients with ILD/post-tuberculosis lung changes, subpleural non-nodular lesions in the upper lobes require close monitoring for growth.

• Pregnancy Deciduosis Mimicking Abdominal Tuberculosis and Peritoneal Carcinomatosis: A Case Report. A. Musarò, M.P. Bonasoni, M. Pati, et al. 2026;16(18). Case report PubMed · Publisher · Free full text

  Abstract

  Background and clinical significance: Gestational deciduosis is a benign, progesterone-related ectopic decidual reaction that commonly involves pelvic and peritoneal surfaces and usually regresses after delivery. Although generally asymptomatic, diffuse peritoneal deciduosis may present as multiple nodular implants and closely mimic peritoneal carcinomatosis, mesothelioma, or miliary tuberculosis, creating a challenging intraoperative differential diagnosis. Prompt histopathological assessment is essential to prevent unnecessary staging procedures or oncological treatment. Case presentation: A 30-year-old primigravida at 40 weeks' gestation underwent unplanned intrapartum cesarean section after a premature rupture of membranes, the induction of labor, and failed progression. Multiple friable, gray-yellow subcentimetric nodules were incidentally observed on the uterine serosa, adnexa, omentum, visceral intestinal peritoneum, and appendix. The macroscopic appearance raised concern for peritoneal carcinomatosis and abdominal miliary tuberculosis. No ascites or intra-abdominal masses were identified. CA-125 was elevated (207.7 U/mL), Quantiferon testing was indeterminate, and postoperative chest computed tomography showed no pulmonary disease. Histological examination showed ectopic decidual cells with abundant eosinophilic cytoplasm in a perivascular and septal distribution. The cells showed diffuse vimentin, CD10, and progesterone-receptor expression and lacked epithelial and mesothelial marker expression, supporting diffuse peritoneal deciduosis. The postoperative course was uncomplicated, and pelvic ultrasonography at 40 days postpartum showed no residual lesions. Conclusions: Diffuse peritoneal deciduosis should be considered when disseminated peritoneal nodules are encountered during pregnancy or cesarean delivery. In this setting, elevated CA-125 is nonspecific and may heighten concern for tuberculosis or malignancy without distinguishing among these entities. Correlation of the clinical context, operative findings, morphology, and targeted immunohistochemistry is essential to avoid unnecessary oncological treatment or extensive staging procedures.

• Simultaneous Occurrence of Well-Differentiated Papillary Mesothelial Tumor and Multicystic Mesothelioma. D. Miličić, S. Tomić, B. Delić, et al. 2026;16(14). PubMed · Publisher · Free full text

  Abstract

  We report a rare case of simultaneous well-differentiated papillary mesothelial tumor (WDPMT) and multicystic mesothelioma. The concurrent occurrence of these entities is exceptionally uncommon and may pose challenges during surgical intervention. Both lesions are rare mesothelial proliferations that are often identified incidentally during surgery. Well differentiated papillary mesothelial tumor (WDPMT) is a neoplastic mesothelial proliferation of low malignant potential, which predominantly involves the peritoneum of young women. Microscopically it is composed of branching plump papillae lined by a single layer of bland cuboidal mesothelial cells. Cytologic atypia is minimal, and mitoses usually absent (or at most 1 mitosis per 10 high power fields). Differential diagnosis includes: 1. diffuse malignant peritoneal mesothelioma, 2. localized malignant peritoneal mesothelioma, 3. serous borderline tumors. A 41-year-old patient was admitted for laparoscopic surgery due to a tumor mass localized near the left ovary. Ultrasound examination revealed solid lesion adjacent to the left ovary, exhibiting central vascularization. The patient was diagnosed with the solid tumor mass during routine gynecological examination. The mass was extraovarian and positioned between the left ovary and the uterus. Over the course of the next 18 months, the tumor increased 5 cm in size. Given the fact that the patient presented with no symptoms, such as abdominal pain, distension or ascites, and that the tumor markers were not elevated, additional radiological imaging such as CT or MRI of the abdomen and pelvis was not performed. Intraoperatively, the mass appeared as an extraovarian solid tumor of soft consistency positioned between the left ovary and the uterus. Extirpation of the tumor was performed. Frozen section analysis of the extirpated tumor mass confirmed the diagnosis of WDPMT. During the laparoscopic procedure, a left adnexectomy was also performed and multiple biopsies of white nodules were found dispersed in the peritoneal cavity. Final patohystological analysis concluded that these nodules were peritoneal inclusion cysts. Almost three years after the procedure, the patient is without symptoms and regular clinical and ultrasound examinations were performed every six months, which showed no signs of recurrence or dissemination of the primary tumor. Recognizing well-differentiated papillary mesothelial tumor and multicystic mesothelioma is critical for accurate differential diagnosis from malignant mesothelioma. Awareness of these entities informs appropriate surgical management and follow-up protocols.

• Two-Phase Occupational Screening in Coal-Fired Power Plant Workers: Anamnestic Risk Stratification and Targeted Low-Dose CT Findings. A. Cranta, E. Osiac, D.I. Gheonea, et al. 2026;16(19). PubMed · Publisher · Free full text

  Abstract

  Background: Employees at coal-fired power plants experience cumulative occupational exposure to respirable particulates alongside a high prevalence of smoking, both contributing to chronic respiratory disease and elevated lung cancer risk, and organized-screening implementation data remain scarce in this specific industrial setting outside asbestos-exposed cohorts. We evaluated a two-step occupational screening strategy integrating an anamnestic questionnaire with targeted low-dose CT (LDCT) imaging, assessing risk distribution, structured imaging findings, and the discriminative value of questionnaire-based triage relative to its underlying continuous predictors. Methods: In this cross-sectional study, all workers at a coal-fired power plant completed a structured questionnaire (F1) and were classified as high-risk or non-high-risk using a predefined eligibility rule (respiratory symptoms, or age ≥ 50 years with current/former smoking). All workers were invited to voluntary LDCT (F2), interpreted using Lung-RADS v2022 with structured emphysema and coronary artery calcium (CAC) assessment. Associations were assessed using Fisher's exact tests, multivariable logistic regression, and ROC analysis with DeLong's test; voluntary LDCT uptake was characterized with a multivariable propensity model. Results: Among 870 screened workers, 364 (41.8%) were high-risk. LDCT uptake was higher among high-risk workers (130/364, 35.7%) than non-high-risk workers (56/506, 11.1%), yielding 186 examinations. Only 14/186 (7.5%) had Lung-RADS ≥ 3. High-risk status was associated with higher prevalence of any nodule (80.8% vs. 62.5%; OR 2.52) and CAC (46.9% vs. 14.3%; OR 5.30); a composite abnormality outcome was present in 92.3% vs. 69.6% (OR 5.23). Only age (OR 1.11/year) and ever-smoking status (OR 4.38) independently predicted abnormalities on multivariable analysis; dichotomized risk classification showed reduced discrimination for CAC versus a continuous age-smoking model (AUC 0.647 vs. 0.779). Conclusions: Questionnaire-based triage effectively enriched the LDCT-screened population for smoking-related and cardiometabolic risk. Age and smoking history, rather than the full questionnaire, principally drove imaging abnormalities, supporting an integrated occupational model combining lung cancer screening with COPD and cardiovascular risk management.

• When Lymph Nodes Don't Lie: Report of Three Unusual Presentations of Thoracic Tumors. S. Lucà, F. Barbato, A. Di Maio, et al. 2026;16(11). Case report PubMed · Publisher · Free full text

  Abstract

  Background and Clinical Significance: Lymph node metastases from carcinoma of unknown primary origin (CUP) are a rare and diagnostically challenging entity, particularly when arising from thoracic malignancies with atypical clinical presentations. This study aims to illustrate the essential nature of multidisciplinary integration, with a particular emphasis on the role of the pathologist in identifying occult thoracic tumors. Case Presentation: We report three cases of patients presenting with cervical or systemic lymphadenopathy as the initial clinical manifestation. Comprehensive diagnostic workups included advanced imaging (CT, MRI, and PET), comprehensive histopathological analysis, and next-generation sequencing of circulating tumor DNA. Case one and case two were diagnosed as occult primary non-mucinous lung adenocarcinomas, based on the integration of morphological features and immunohistochemical co-expression of TTF-1 and Napsin A, despite the absence of identifiable lung lesions. One case harbored an ALK rearrangement, guiding effective targeted therapy with alectinib. Case three involved metastatic pleural epithelioid mesothelioma, which presented with systemic lymphadenopathy and was initially misclassified as metastatic adenocarcinoma. Diagnosis was confirmed by the loss of BAP1 expression by immunohistochemistry and the detection of a BAP1 S160fs*1 mutation, emphasizing the role of molecular pathology. Conclusions: Lymphadenopathy as the first manifestation of thoracic malignancy is a rare but clinically significant occurrence. In such atypical presentations, pathologists play a pivotal role in diagnosis, often leading the process when clinical or radiological clues are minimal or absent. Accurate histopathological assessment is essential to establish a correct diagnosis and guide appropriate therapy. A multidisciplinary approach remains the cornerstone of diagnostic precision in CUP cases.

• Diagnosis of Mesothelioma Using Image Segmentation and Class-Based Deep Feature Transformations. S. Aydın, M. Ağar, M. Çakmak, et al. 2025;15(18). PubMed · Publisher · Free full text

  Abstract

  Background/Objectives: Mesothelioma is a rare and aggressive form of cancer that primarily affects the lining of the lungs, abdomen, or heart. It typically arises from exposure to asbestos and is often diagnosed at advanced stages. Limited datasets and complex tissue structures contribute to delays in diagnosis. This study aims to develop a novel hybrid model to improve the accuracy and timeliness of mesothelioma diagnosis. Methods: The proposed approach integrates automatic image segmentation, transformer-based model training, class-based feature extraction, and image transformation techniques. Initially, CT images were processed using the segment anything model (SAM) for region-focused segmentation. These segmented images were then used to train transformer models (CaiT and PVT) to extract class/type-specific features. Each class-based feature set was transformed into an image using Decoder, GAN, and NeRV techniques. Discriminative score and class centroid analysis were then applied to select the most informative image representation for each input. Finally, classification was performed using a residual-based support vector machine (SVM). Results: The proposed hybrid method achieved a classification accuracy of 99.80% in diagnosing mesothelioma, demonstrating its effectiveness in handling limited data and complex tissue characteristics. Conclusions: The results indicate that the proposed model offers a highly accurate and efficient approach to mesothelioma diagnosis. By leveraging advanced segmentation, feature extraction, and representation techniques, it effectively addresses the major challenges associated with early and precise detection of mesothelioma.

• Diagnostic Utility of Podoplanin Immunohistochemistry Combined with the NanoSuit-Correlative Light and Electron Microscopy Method for Thoracic Malignant Tumors. S.Y. Katsuragi, Y. Sakano, I. Ohta, et al. 2025;15(10). PubMed · Publisher · Free full text

  Abstract

  Background/Objectives: Differentiating thoracic malignant tumors, such as epithelioid malignant pleural mesothelioma (EMPM) and non-small-cell lung carcinoma (NSCLC), primarily comprising lung adenocarcinoma (LAC) and lung squamous cell carcinoma (LSCC), remains a challenge in routine pathological diagnosis. This study aimed to evaluate whether podoplanin (PDPN) immunohistochemistry combined with scanning electron microscopy (SEM) using the NanoSuit-correlative light and electron microscopy (CLEM) methods could serve as a reliable tool for distinguishing these thoracic malignancies. Methods/Results: Initially, PDPN expression was assessed by immunohistochemical analysis in 11 EMPM, 100 LAC, and 23 LSCC cases. PDPN positivity was predominantly observed in the cell membrane and was significantly more frequent in EMPM (100%) than in LAC (2%; p < 0.0001) or LSCC (43.5%; p = 0.0018). Subsequently, field emission-SEM (FE-SEM) observations of PDPN-positive sites on immunohistochemical slides, conducted using the NanoSuit-CLEM method, revealed distinctive ultrastructural features. EMPM exhibited densely packed, elongated microvilli, whereas such structures were absent in LAC and LSCC. Furthermore, analysis of thick-cut sections (20 μm) demonstrated extensive microvilli coverage characteristic of EMPM. Conclusions: These findings suggest that the combined approach of PDPN immunohistochemistry and FE-SEM observation of PDPN-positive sites, using the NanoSuit-CLEM method, constitutes an effective diagnostic strategy for enhancing the accuracy of distinguishing EMPM from NSCLCs.

• MOC31 for the Diagnosis of Metastatic Carcinoma and Mesothelial Lesions in Effusion Fluid-A Systematic Review and Meta-Analysis. A.H. Lin, M. Hsu, J.K.M. Ng, et al. 2025;15(21). Review PubMed · Publisher · Free full text

  Abstract

  Background/Objectives: MOC31 immunostain identifies carcinoma cells and is often used in effusion fluid cytology. This systematic review and meta-analysis aim to detail the diagnostic performance of MOC31 with subgroup analysis for different types of carcinomas. Methods: A literature search from five databases was performed. Relevant studies were reviewed for the calculation of pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve of hierarchical summary receiver operating characteristics (AUC-HSROC). Risk of bias, heterogeneity, and publication bias were assessed by the QUADAS-2, I2 index, and Deeks' funnel plot. Results: In total, 25 studies (10 retrospective cohorts, 10 case-control studies, and 5 case series) were included. The pooled sensitivity, specificity, NLR, PLR, and DOR were 0.926 (0.827-0.971), 0.932 (0.883-0.961), 0.079 (0.005-0.152), 13.610 (5.327-21.892), and 172.475 (83.150-428.100), respectively. The AUC-HSROC was 0.975, indicating excellent performance. Further analysis for adenocarcinomas, mesotheliomas, and benign/reactive mesothelial cells showed sensitivity for adenocarcinomas at 0.962 (0.948-0.975) and specificity for mesotheliomas and mesothelial cells at 0.934 (0.900-0.967) and 0.997 (0.994-1.000). Sensitivity in all four primary site subgroups (female genital, gastrointestinal/hepatobiliary, lung and breast) of adenocarcinoma were high (>0.910). Heterogeneity was observed, and meta-regression identified a trend for the year of publication. No evidence of publication bias was observed. Conclusions: Evidence shows that MOC31 could be a robust immunocytochemical marker for identifying and excluding metastatic carcinoma, with excellent diagnostic performance across types of adenocarcinomas. However, evidence is mainly from retrospective studies, highlighting the need for high-quality evidence to further establish MOC31diagnostic utility.

• Molecular Insights into Pleural Mesothelioma: Unveiling Pathogenic Mechanisms and Therapeutic Opportunities. T. Zahiu, C.M. Mihu, B.A. Bosca, et al. 2025;15(11). Review PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma (PM) is a rare disease, which is going to be a global medical concern in the 21st century, because of its aggressiveness, late diagnosis, and insufficient therapies. This review seeks to enhance the comprehension of medical professionals regarding the risk factors and environmental influences that contribute to the development of the disease, as well as its underlying mechanisms. In addition, we aim to provide a schematic yet thorough overview of diagnostic techniques in PM, emphasizing the significance of the immunohistochemical markers BAP1 and MTAP, with the latter serving as an almost ideal surrogate for the gold-standard diagnostic approach, FISH p16/CDKN2A deletion. The scientific world is grappling with BAP1, MTAP, and the tumour inflammatory microenvironment, because they are the key for personalized treatments and palliative care in this disease. Considering that the survival rate for patients with PM seldom surpasses five years, every moment is significant. Therefore, our article also highlights recent advancements in clinical assessments related to prognostic scoring and treatment options. PM is a complex disease, with gradual progression over decades, which requires further investigation covering the prevention, mutations, diagnosis and treatment.

• Pleural Metastasis as an Initial Presentation of Prostate Cancer: Case Report and Literature Review. K. Skrobisz, K. Miszewski, L. Miszewska, et al. 2025;15(6). Case report PubMed · Publisher · Free full text

  Abstract

  Background and Clinical Significance: Prostate cancer (PCa) is among the most commonly diagnosed malignancies in men worldwide. While bone and lymph nodes are the most frequent metastatic sites, prostate cancer cells have the potential to spread to virtually any organ, including the pleura, which is an exceedingly rare initial site of presentation that can mimic mesothelioma or primary lung cancer. Case Presentation: We describe a 77-year-old man who presented with exertional dyspnea and intermittent cough, initially suggesting a cardiopulmonary etiology. Imaging revealed multiple pleural nodules and an extensive right-sided pleural effusion. Despite a borderline serum prostate-specific antigen (PSA) level of 2.91 ng/mL, histopathology and immunohistochemistry of pleural biopsies confirmed metastatic prostate adenocarcinoma. Subsequent imaging identified a PIRADS 5 lesion in the prostate, and a biopsy confirmed ISUP Grade Group 5 disease (Gleason score 4 + 5 = 9). A bone scan showed no skeletal metastases, and a contrast-enhanced CT of the abdomen found no additional metastatic lesions. The patient was started on androgen deprivation therapy followed by abiraterone. This case underscores the diagnostic challenge posed by atypical metastatic presentations of prostate cancer. Low or moderately elevated PSA can obscure suspicion of prostate origin, especially with pleural-based lesions suggestive of mesothelioma. Immunohistochemical markers, including androgen receptors, AMACR, and Prostein, are critical for accurate diagnosis. Conclusions: Clinicians must maintain a high index of suspicion for prostate cancer in older men with unexplained pleural effusions, nodules, or masses, even with low-normal PSA levels. Early recognition and prompt treatment can improve outcomes, despite the rarity and aggressiveness of pleural metastases.

• Comments and Illustrations of the European Federation of Societies for Ultrasound in Medicine (EFSUMB) Guidelines: Rare Malignant Pulmonal and Pleural Tumors: Primary Pulmonary Sarcoma and Mesothelioma, Imaging Features on Transthoracic Ultrasound. K. Möller, F. Dietz, M. Ludwig, et al. 2024;14(20). Review PubMed · Publisher · Free full text

  Abstract

  Primary pulmonary sarcoma and mesothelioma are rare malignancies. The review article discusses the appearance of these tumors in B-mode ultrasound (US), color Doppler ultrasound and contrast-enhanced ultrasound (CEUS). In particular, the article is intended to inspire the examination of thoracic wall tumors and pleural masses with the possibilities of ultrasonography and to obtain histologically evaluable material using US or CEUS-guided sampling.

• Epithelial Cell Adhesion Molecule (EpCAM) Expression in Human Tumors: A Comparison with Pan-Cytokeratin and TROP2 in 14,832 Tumors. A. Menz, N. Lony, M. Lennartz, et al. 2024;14(10). PubMed · Publisher · Free full text

  Abstract

  EpCAM is expressed in many epithelial tumors and is used for the distinction of malignant mesotheliomas from adenocarcinomas and as a surrogate pan-epithelial marker. A tissue microarray containing 14,832 samples from 120 different tumor categories was analyzed by immunohistochemistry. EpCAM staining was compared with TROP2 and CKpan. EpCAM staining was detectable in 99 tumor categories. Among 78 epithelial tumor types, the EpCAM positivity rate was ≥90% in 60 categories-including adenocarcinomas, neuroendocrine neoplasms, and germ cell tumors. EpCAM staining was the lowest in hepatocellular carcinomas, adrenocortical tumors, renal cell neoplasms, and in poorly differentiated carcinomas. A comparison of EpCAM and CKpan staining identified a high concordance but EpCAM was higher in testicular seminomas and neuroendocrine neoplasms and CKpan in hepatocellular carcinomas, mesotheliomas, and poorly differentiated non-neuroendocrine tumors. A comparison of EpCAM and TROP2 revealed a higher rate of TROP2 positivity in squamous cell carcinomas and lower rates in many gastrointestinal adenocarcinomas, testicular germ cell tumors, neuroendocrine neoplasms, and renal cell tumors. These data confirm EpCAM as a surrogate epithelial marker for adenocarcinomas and its diagnostic utility for the distinction of malignant mesotheliomas. In comparison to CKpan and TROP2 antibodies, EpCAM staining is particularly common in seminomas and in neuroendocrine neoplasms.

• Well-Differentiated Papillary Mesothelial Tumor of the Scrotum with Suspicious Invasion. S. Im, J.M. Yoo, U. Cho. 2024;14(2). PubMed · Publisher · Free full text

  Abstract

  Well-differentiated papillary mesothelial tumor (WDPMT) is a distinct form of mesothelioma with low malignant potential and is mostly found in the peritoneal cavity. It consists of mesothelial cells with papillary structure and bland cytology. We report a rare case of WDPMT with suspicious invasive foci in the tunica vaginalis. WDPMT with invasive foci is known to have a tendency for recurrence. Therefore, careful attention should be given to properly diagnosing and treating this rare entity.

• A Novel Two-Gene Expression-Based Prognostic Score in Malignant Pleural Mesothelioma. V. Shivarov, G. Blazhev, A. Yordanov. 2023;13(9). PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is a rare cancer type with an increasing incidence worldwide. We aimed to develop a rational gene expression-based prognostic score in MPM using publicly available datasets.

  Methods: We developed and validated a two-gene prognostic score (2-PS) using three independent publicly available gene expression datasets. The 2-PS was built using the Robust Likelihood-Based Survival Modeling with Microarray Data method.

  Results: We narrowed down the model building to the analysis of 179 genes, which have been shown previously to be of importance to MPM development. Our statistical approach showed that a model including two genes (GOLT1B and MAD2L1) was the best predictor for overall survival (OS) (p < 0.0001). The binary score based on the median of the continuous score stratified the patients into low and high score groups and also showed statistical significance in uni- and multivariate models. The 2-PS was validated using two independent transcriptomic datasets. Furthermore, gene set enrichment analysis using training and validation datasets showed that high score patients had distinct gene expression profiles. Our 2-PS also showed a correlation with the estimated infiltration by some immune cell fractions such as CD8+ T cells and M1/2 macrophages. Finally, 2-PS correlated with sensitivity or resistance to some commonly used chemotherapeutic drugs.

  Conclusion: This is the first study to demonstrate good performance of only two-gene expression-based prognostic scores in MPM. Our initial approach for features selection allowed for an increased likelihood for the predictive value of the developed score, which we were also able to demonstrate.

• Clear-Cell Mesothelioma of Uterine Corpus: Diagnostic Challenges in Intraoperative Frozen Sections. T. Pongsuvareeyakul, K. Saipattranusorn, K. Sukpan, et al. 2023;13(6). PubMed · Publisher · Free full text

  Abstract

  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.

• Immunohistochemistry for Claudin-4 and BAP1 in the Differential Diagnosis between Sarcomatoid Carcinoma and Sarcomatoid Mesothelioma. L. Zuccatosta, T. Bizzarro, G. Rossi, et al. 2023;13(2). PubMed · Publisher · Free full text

  Abstract

  (1) Background. In the differential diagnosis between sarcomatoid carcinoma (SC) and sarcomatoid mesothelioma (SM), we aimed to investigate the role of Claudin-4 and BAP1, a panel recently used to distinguish conventional carcinoma from epithelioid mesothelioma. (2) Methods. We collected 41 surgical pleural biopsies of SM, 46 surgical resections of SC from different sites and 49 pleural biopsies of normal/hyperplastic mesothelium. All the cases were tested for Claudin-4 and BAP1 using immunohistochemistry. The statistical calculations of the sensitivity, specificity and positive and negative predictive values were performed. (3) Results: Claudin-4 was negative in 41/41 SMs, while it was positive in 18/36 (50.1%) SCs (eight diffusely, 10 focally) within their sarcomatous component. BAP1 was lost in 23/41 SMs, while it was regularly expressed in 46/46 SCs. All the cases of the normal/hyperplastic mesothelium were negative for Claudin-4 and retained the regular expression of BAP1. The Claudin-4 expression was useful for detecting SC (sensitivity, 39.1%; specificity, 100%) and the BAP1 loss was useful for diagnosing SM (sensitivity, 56.1%; specificity, 100%). (4) Conclusions. The staining for Claudin-4 and BAP1 exhibited a low/moderate sensitivity in diagnosing SC and SM (39.1% and 56.1%, respectively), but a very high specificity (100%). Claudin-4 was expressed only in SC and BAP1 loss was noted only in SM.

• New Immunohistochemical Markers for Pleural Mesothelioma Subtyping. I. Di Stefano, G. Alì, A.M. Poma, et al. 2023;13(18). PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma (PM) comprises three main subtypes: epithelioid, biphasic and sarcomatoid, which have different impacts on prognosis and treatment definition. However, PM subtyping can be complex given the inter- and intra-tumour morphological heterogeneity. We aim to use immunohistochemistry (IHC) to evaluate five markers (Mesothelin, Claudin-15, Complement Factor B, Plasminogen Activator Inhibitor 1 and p21-activated Kinase 4), whose encoding genes have been previously reported as deregulated among PM subtypes. Immunohistochemical expressions were determined in a case series of 73 PMs, and cut-offs for the epithelioid and non-epithelioid subtypes were selected. Further validation was performed on an independent cohort (30 PMs). For biphasic PM, the percentage of the epithelioid component was assessed, and IHC evaluation was also performed on the individual components separately. Mesothelin and Claudin-15 showed good sensitivity (79% and 84%) and specificity (84% and 73%) for the epithelioid subtype. CFB and PAK4 had inferior performance, with higher sensitivity (89% and 84%) but lower specificity (64% and 36%). In the biphasic group, all markers showed different expression when comparing epithelioid with sarcomatoid areas. Mesothelin, Claudin-15 and CFB can be useful in subtype discrimination. PAI1 and PAK4 can improve component distinction in biphasic PM.

• Analysis of More than 16,000 Human Tumor and Normal Tissues Identifies Uroplakin 3B as a Useful Diagnostic Marker for Mesothelioma and Normal Mesothelial Cells. M. Lennartz, D. Atug, S. Dwertmann Rico, et al. 2022;12(10). PubMed · Publisher · Free full text

  Abstract

  Uroplakin 3B (Upk3b) is involved in stabilizing and strengthening the urothelial cell layer of the bladder. Based on RNA expression studies, Upk3b is expressed in a limited number of normal and tumor tissues. The potential use of Upk3b as a diagnostic or prognostic marker in tumor diagnosis has not yet been extensively investigated. A tissue microarray containing 17,693 samples from 151 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. In normal tissues, Upk3b expression was largely limited to mesothelial cells, urothelial umbrella cells, and amnion cells. In tumor tissues, Upk3b was detectable in only 17 of 151 (11.3%) of tumor types. Upk3b expression was most frequent in mesotheliomas (82.1% of epithelioid and 30.8% of biphasic) and in urothelial tumors of the urinary bladder, where the positivity rate decreased from 61.9% in pTaG2 (low grade) to 58.0% in pTaG3 (high grade) and 14.6% in pT2-4 cancers. Among pT2-4 urothelial carcinomas, Upk3b staining was unrelated to tumor stage, lymph node status, and patient prognosis. Less commonly, Upk3b expression was also seen in Brenner tumors of the ovary (10.8%), as well as in four other subtypes of ovarian cancer (0.9-10.6%). Four additional tumor entities showed a weak to moderate Upk3b positivity in less than 5% of cases. In summary, Upk3b immunohistochemistry is a useful diagnostic tool for the distinction of mesotheliomas from other thoracic tumors and the visualization of normal mesothelial and umbrella cells.

• Big and Free Fractions of Gamma-Glutamyltransferase: New Diagnostic Biomarkers for Malignant Mesothelioma?. R. Foddis, M. Franzini, A. Bonotti, et al. 2022;12(2). PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, characterized by an extremely long latency and poor prognosis. Recently, researchers have focused on testing the diagnostic ability of several biomarkers. Gamma-Glutamyltransferase (GGT) has been demonstrated to be the sum of several GGT sub-fractions activity, classified based on their molecular weight in big-GGT, medium-GGT, small-GGT, and free-GGT. This work aims to evaluate whether specific GGT fractional enzymatic activity patterns could be helpful in MPM diagnosis. We analyzed blood samples from 175 workers previously exposed to asbestos, 157 non-exposed healthy subjects, and 37 MPM patients through a molecular exclusion chromatographic method. We found a specific profile of GGT fractions activity, significantly associated with MPM, resulting in an increase in b-, m- activity, along with an evident, yet not significant, decrease in f-activity. Receiver-operating characteristic (ROC) analysis showed that the best Area Under Curve (AUC) value resulted from the combined index b/f (0.679, 95% CI: 0.582-0.777). Combining the b-/f-GGT activity with the levels of serum mesothelin-related protein (SMRP; another promising MPM biomarker) improved the diagnostic accuracy, increasing the AUC value to 0.875 (95% CI: 0.807-0.943, p = <0.0001). Since MPM has a specific pattern of GGT enzymatic activity, we could hypothesize that GGT fractions play different specific biochemical roles. The improvement in the diagnostic power given by the combination of these two biomarkers confirms that the strategy of biomarkers combination might be a better approach for MPM diagnosis.

• Diagnostic and Therapeutic Challenges of Malignant Pleural Mesothelioma. J. Moro, S. Sobrero, C.F. Cartia, et al. 2022;12(12). Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma is a rare cancer characterized by a very poor prognosis. Exposure to asbestos is the leading cause of malignant pleural mesothelioma. The preinvasive lesions, the mesothelial hyperplasia and its possible evolution are the focus of the majority of the studies aiming to identify the treatable phase of the disease. The role of BAP-1 and MTAP in the diagnosis of mesothelioma in situ and in the prognosis of malignant pleural mesothelioma is the main topic of recent studies. The management of preinvasive lesions in mesothelioma is still unclear and many aspects are the subject of debate. The diagnosis, the disease staging and the accurate, comprehensive assessment of patients are three key instants for an appropriate management of patients/the disease.

• Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience. M. Sculco, M. La Vecchia, A. Aspesi, et al. 2022;12(7). PubMed · Publisher · Free full text

  Abstract

  Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

• Gene Expression Analysis of Biphasic Pleural Mesothelioma: New Potential Diagnostic and Prognostic Markers. R. Bruno, A.M. Poma, G. Alì, et al. 2022;12(3). PubMed · Publisher · Free full text

  Abstract

  Biphasic is the second most common histotype of pleural mesothelioma (PM). It shares epithelioid and sarcomatoid features and is challenging to diagnose. The aim of this study was to identify biphasic PM markers to improve subtyping and prognosis definition. The expression levels of 117 cancer genes, evaluated using the nanoString system, were compared between the three major histotypes (epithelioid, sarcomatoid, and biphasic), and expression differences within biphasic PM were evaluated in relation to the percentage of epithelioid components. Biphasic PM overexpressed CTNNA1 and TIMP3 in comparison to sarcomatoid, and COL16A1 and SDC1 in comparison to epithelioid PM. CFB, MSLN, CLDN15, SERPINE1, and PAK4 were deregulated among all histotypes, leading to the hypothesis of a gradual expression from epithelioid to sarcomatoid PM. According to gene expression, biphasic PM samples were divided in two clusters with a significant difference in the epithelioid component. ADCY4, COL1A1, and COL4A2 were overexpressed in the biphasic group with a low percentage of epithelioid component. Survival analysis using TCGA data showed that high COL1A1 and COL4A2 expression levels correlate with poor survival in PM patients. Herein, we identified markers with the potential to improve diagnosis and prognostic stratification of biphasic PM, which is still an orphan tumor.

• Identification of Novel Diagnostic Markers for Malignant Pleural Mesothelioma Using a Reverse Translational Approach Based on a Rare Synchronous Tumor. T. Naka, Y. Hatanaka, Y. Tabata, et al. 2022;12(2). PubMed · Publisher · Free full text

  Abstract

  Although the routine use of immunohistochemistry has improved the accuracy of histopathologic diagnosis in clinical practice, new methods for discovering novel diagnostic markers are still needed. We sought new diagnostic markers for malignant pleural mesothelioma (MPM) using a reverse translational approach with limited archival tissues from a very rare case. Total RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues of a synchronous collision tumor consisting of MPM and pulmonary adenocarcinoma (PAC) was employed for gene expression profiling (GEP) analysis. Among the 54 genes selected by GEP analysis, we finally identified the following two candidate MPM marker genes: PHGDH and TRIM29. Immunohistochemical analysis of 48 MM and 20 PAC cases showed that both PHGDH and TRIM29 had sensitivity and specificity almost equivalent to those of calretinin (sensitivity 50% and 46% vs. 63%, and specificity 95% and 100% vs. 100%, respectively). Importantly, of the 23 epithelioid MMs, all 3 calretinin-negative cases were positive for TRIM29. These two markers may be diagnostically useful for immunohistochemical distinction between MPMs and PACs. This successful reverse translational approach based on FFPE samples from one very rare case encourages the further use of such samples for the development of novel diagnostic markers.

• New Insights in Pleural Mesothelioma Classification Update: Diagnostic Traps and Prognostic Implications. M.G. Mastromarino, A. Lenzini, V. Aprile, et al. 2022;12(12). Review PubMed · Publisher · Free full text

  Abstract

  The 2021 WHO Classification of Tumors of the Pleura has introduced significant changes in mesothelioma codification beyond the three current histological subtypes-epithelioid, sarcomatoid and biphasic. Major advances since the 2015 WHO classification include nuclear grading and the introduction of architectural patterns, cytological and stromal features for epithelioid diffuse mesothelioma. Mesothelioma in situ has been recognized as a diagnostic category. Demonstration of loss of BAP1 or MTAP by immunohistochemistry, or CDKN2A homozygous deletion by FISH, is valuable in establishing the diagnosis of epithelioid mesothelioma. Recent emerging data proved that grading and histological subtypes have prognostic implications and may be helpful to patient risk stratification and clinical management. Nevertheless, the latest mesothelioma classification increases the already non-negligible diagnostic pitfalls, especially concerning differential diagnosis of pre-invasive tumors. In this review, recent changes in histologic classification of mesothelioma and advances in molecular markers are presented and their relation to diagnostic challenges and prognostic implications is discussed.

• Sarcopenia, Precardial Adipose Tissue and High Tumor Volume as Outcome Predictors in Surgically Treated Pleural Mesothelioma. O.G. Verhoek, L. Jungblut, O. Lauk, et al. 2022;12(1). PubMed · Publisher · Free full text

  Abstract

  Background: We evaluated the prognostic value of Sarcopenia, low precardial adipose-tissue (PAT), and high tumor-volume in the outcome of surgically-treated pleural mesothelioma (PM).

  Methods: From 2005 to 2020, consecutive surgically-treated PM-patients having a pre-operative computed tomography (CT) scan were retrospectively included. Sarcopenia was assessed by CT-based parameters measured at the level of the fifth thoracic vertebra (TH5) by excluding fatty-infiltration based on CT-attenuation. The findings were stratified for gender, and a threshold of the 33rd percentile was set to define sarcopenia. Additionally, tumor volume as well as PAT were measured. The findings were correlated with progression-free survival and long-term mortality.

  Results: Two-hundred-seventy-eight PM-patients (252 male; 70.2 ± 9 years) were included. The mean progression-free survival was 18.6 ± 12.2 months, and the mean survival time was 23.3 ± 24 months. Progression was associated with chronic obstructive pulmonary disease (COPD) (p = <0.001), tumor-stage (p = 0.001), and type of surgery (p = 0.026). Three-year mortality was associated with higher patient age (p = 0.005), presence of COPD (p < 0.001), higher tumor-stage (p = 0.015), and higher tumor-volume (p < 0.001). Kaplan-Meier statistics showed that sarcopenic patients have a higher three-year mortality (p = 0.002). While there was a negative correlation of progression-free survival and mortality with tumor volume (r = 0.281, p = 0.001 and r = -0.240, p < 0.001; respectively), a correlation with PAT could only be shown for epithelioid PM (p = 0.040).

  Conclusions: Sarcopenia as well as tumor volume are associated with long-term mortality in surgically treated PM-patients. Further, while there was a negative correlation of progression-free survival and mortality with tumor volume, a correlation with PAT could only be shown for epithelioid PM.

• Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma. Z. Lu, W. Zhang, K. Huang, et al. 2022;12(9). Review PubMed · Publisher · Free full text

  Abstract

  In previous studies, non-invasive diagnostic biomarkers showed great benefit in the early-stage diagnosis of malignant pleural mesothelioma (MPM). However, the accuracy of different biomarkers was controversial. In this study, meta-analysis and bioinformatics analysis were conducted to compare the accuracy of the following three biomarkers and explore the relationship between the gene expression levels and MPM. A systematic search of meta-analysis was conducted using PubMed, EMBASE and Cochrane Library to identify relevant studies from the inception to March 2021. QUADAS-2 for Quality Assessment of Diagnostic Accuracy Studies was used to evaluate the quality of eligible studies. The meta-analysis was performed utilizing Stata 15.0 and Review Manager 5.4 software. The meta-analysis results showed that 31 studies that involved 8750 participants were included. The pooled sensitivity and specificity (SPE) were 0.90 (95% CI: 0.74, 0.97) and 0.91 (95% CI: 0.84, 0.95) for Fibulin-3, 0.66 (95% CI, 0.51-0.78) and 0.91 (95% CI, 0.82-0.96) for mesothelin (MSLN), 0.68 (95% CI: 0.63,0.73) and 0.86 (95% CI: 0.82,0.90) for soluble mesothelin-related peptides (SMRP), and 0.74 (95% CI, 0.66-0.80) and 0.89 (95% CI, 0.85-0.91) for MSLN + SMRP + Fibulin-3. Compared with the other two biomarkers, Fibulin-3 may be more appropriate to be one of the indicators for combined diagnosis. Bioinformatics analysis showed that the low expression level of the MSLN gene was significantly related to longer survival time and better prognosis of MPM patients. However, considering the limitation in the quality and sample size of the included research, further studies are required.

• The Use of Chest Magnetic Resonance Imaging in Malignant Pleural Mesothelioma Diagnosis. F. Volpi, C.A. D'Amore, L. Colligiani, et al. 2022;12(3). Review PubMed · Publisher · Free full text

  Abstract

  In recent years, many articles have demonstrated that magnetic resonance imaging (MRI) may be performed successfully in the study of the chest. The aim of this study was to evaluate the potential role of MRI in the differentiation of benign from malignant pleural disease with a special focus on malignant pleural mesothelioma and on MRI protocols. A systematic literature search was performed to find original articles about chest MRI in patients with either benign or malignant pleural disease. We retrieved 1246 papers and 17 studies were finally identified as being in accordance with our purpose. For a morphologic assessment, T1-weighted and T2-weighted sequences were usually performed, eventually associated with T1 post-contrast sequences for better detection of pleural lesions. Functional sequences such as Diffusion Weighting Imaging (DWI), associated with the evaluation of Apparent Diffusion Coefficient (ADC) maps, were lately and gradually introduced in chest MRI protocols and their potentiality in differentiating benign from malignant disease has been investigated by many authors. Many progresses have been performed to improve quality images and diagnostic performances of MRI. A better and early identification of pleural disease may be obtained, providing MRI as a possible tool that can differentiate malignant from benign pleural disease without using invasive procedures.

• Unusual Histology in Mesothelioma: A Report of Two Cases with a Brief Review. F. Bono, S. Ceola, C. Beretta, et al. 2022;12(2). PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is often difficult to diagnose due to its rarity and its unusual histopathological features that could lend to diagnostic pitfalls and misdiagnosis. The WHO histological classification of pleural tumors in 2021 recommended a pathologic grading system for malignant pleural mesothelioma. Architectural aspects and cytological features, with nuclear grading, bent on a neoplastic score with fundamental prognostic and diagnostic value. Unusual features must be correctly assigned in the grading system to avoid misdiagnosis, especially toward metastatic lesions or reactive pleural processes. In this paper, we present two cases as examples of unusual morphological and architectural features with a brief literature review.

• Assessment of Glutathione Peroxidase-1 (GPX1) Gene Expression as a Specific Diagnostic and Prognostic Biomarker in Malignant Pleural Mesothelioma. A.F. Gharib, M. Alaa Eldeen, A.S. Khalifa, et al. 2021;11(12). PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a malignant tumor of the mesothelial lining of the thorax. It has been related to frequent exposure to asbestos. Diagnosis of malignant pleural mesothelioma is considered a criticizing problem for clinicians. Early diagnosis and sufficient surgical excision of MPM are considered the cornerstone success factors for the management of early MPM. Glutathione peroxidase-1 (GPX1) is an intracellular protein found to be extensively distributed in all cells, and it belongs to the GPX group. In the current study, we included ninety-eight patients with MPM that underwent surgery at the Zagazig University Hospital in Egypt. We assessed GPX1 gene expression level as it was thought to be related to pathogenicity of cancer in a variety of malignant tumors. We observed a significant elevation in GPX1-mRNA levels in MPM relative to the nearby normal pleural tissues. It was found to be of important diagnostic specificity in the differentiation of MPM from normal tissues. Moreover, we studied the survival of patients in correlation to the GPX1 expression levels and we reported that median overall survival was about 16 months in patients with high GPX1 expression levels, while it was found to be about 40 months in low GPX1 levels.

• Combination of Plasma-Based Metabolomics and Machine Learning Algorithm Provides a Novel Diagnostic Strategy for Malignant Mesothelioma. N. Li, C. Yang, S. Zhou, et al. 2021;11(7). PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma (MM) is an aggressive and incurable carcinoma that is primarily caused by asbestos exposure. However, the current diagnostic tool for MM is still under-developed. Therefore, the aim of this study is to explore the diagnostic significance of a strategy that combined plasma-based metabolomics with machine learning algorithms for MM.

  Methods: Plasma samples collected from 25 MM patients and 32 healthy controls (HCs) were randomly divided into train set and test set, after which analyzation was performed by liquid chromatography-mass spectrometry-based metabolomics. Differential metabolites were screened out from the samples of the train set. Subsequently, metabolite-based diagnostic models, including receiver operating characteristic (ROC) curves and Random Forest model (RF), were established, and their prediction accuracies were calculated for the test set samples.

  Results: Twenty differential plasma metabolites were annotated in the train set; 10 of these metabolites were validated in the test set. The seven most prevalent diagnostic metabolites were taurocholic acid), 0.7142 (uracil), 0.7142 (biliverdin), 0.8571 (histidine), 0.5000 (tauroursodeoxycholic acid), 0.8571 (pyrroline hydroxycarboxylic acid), and 0.7857 (phenylalanine). Furthermore, RF based on 20 annotated metabolites showed a prediction accuracy of 0.9286, and its optimized version achieved 1.0000 in the test set. Moreover, the comparison between the samples of peritoneal MM (n = 8) and pleural MM (n = 17) illustrated a significant increase in levels of taurocholic acid and tauroursodeoxycholic acid, as well as an evident decrease in biliverdin.

  Conclusions: Our results revealed the potential diagnostic value of plasma-based metabolomics combined with machine learning for MM. Further research with large sample size is worthy conducting. Moreover, our data demonstrated dysregulated metabolism pathways in MM, which aids in better understanding of molecular mechanisms related to the initiation and development of MM.

• Diagnostic Challenges in Epithelioid Pleural Mesothelioma: Case Series with Support from Electron Microscopy. F. Fortarezza, M. Della Barbera, F. Pezzuto, et al. 2021;11(5). Case report PubMed · Publisher · Free full text

  Abstract

  The histological diagnosis of pleural epithelioid mesothelioma can be difficult in the case of rare variants or in the definition of neoplasm origin in patients with previous or concomitant tumours. Currently, several immunohistochemical reactions are available in the surgical pathologist's armamentarium that allow us to obtain a more sensitive and specific diagnosis of malignant pleural mesothelioma. However, in some cases, the final interpretation remains inconclusive. Historically, ultrastructural examination has represented a useful tool for the definition of the mesothelial nature of neoplastic cells due to their peculiar morphological characteristics. The recent international guidelines for pathological diagnosis of pleural mesothelioma suggest the use of electron microscopy when the immunohistochemical reactions are equivocal or when further support of a diagnosis of mesothelioma is needed. This paper presents three cases of pleural epithelioid mesothelioma whose diagnoses were finally supported by ultrastructural examination.

• Pilot Study to Evaluate Serum Soluble Mesothelin-Related Peptide (SMRP) as Marker for Clinical Monitoring of Pleural Mesothelioma (PM): Correlation with Modified RECIST Score. F. Grosso, M. Mannucci, F. Ugo, et al. 2021;11(11). PubMed · Publisher · Free full text

  Abstract

  A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker for diagnosis of pleural mesothelioma (PM) and the most used for monitoring treatment. Radiological assessment of PM, based on modified RECIST (mRECIST) criteria, is challenging. This pilot study was designed to evaluate whether SMRP levels correlated over time with mRECIST score. Serial serum samples from PM patients were collected and SMRP levels were measured and compared with the mRECIST score obtained through centralized CT scans by blinded review. The within-patient SMRP-mRECIST relationship over time was estimated through a normal random-effects regression approach applied to the log-transformed mRECIST score. Overall, 58 PM patients were included (46 males and 12 females) with a median age at diagnosis of 67 years (min-max = 48-79), 44 (76%) with epithelioid and 14 (24%) with non-epithelioid histology. The total number of SMRP measurements and CT scans considered for analysis was 183. There was a statistically significant correlation between SMRP and mRECIST score in the 2 cohorts considered both separately and jointly. These results, although exploratory, suggest that SMRP measurement might be considered as an adjunct to monitor PM patients in order to delay CT scans time interval, thus warranting further investigation.

• Soluble High Mobility Group Box 1 (HMGB1) Is a Promising Biomarker for Prediction of Therapy Response and Prognosis in Advanced Lung Cancer Patients. N.A. Handke, A.B.A. Rupp, N. Trimpop, et al. 2021;11(2). PubMed · Publisher · Free full text

  Abstract

  Background: High mobility group box 1 protein (HMGB1) is known for its significant elevation in a multitude of tumors and benign diseases. In this study, we investigated the relevance of soluble HMGB1 for the prediction and monitoring of therapy response as well as the estimation of prognosis in advanced lung cancer.

  Materials And Methods: In a retrospective study, HMGB1 levels were assessed by an enzyme-linked immunosorbent assay (ELISA) in the sera of 96 patients with advanced lung cancer (79 non-small-cell lung carcinoma (NSCLC); 14 small cell lung carcinoma (SCLC), 3 Mesothelioma) prior to cycles 1, 2, and 3 of chemotherapy and correlated with radiological therapy response after 2 and 4 cycles as well as with overall survival. In addition, HMGB1 was compared with established tumor markers cytokeratin 19-fragments (CYFRA 21-1), carcinoembryonic antigen (CEA) and neuron specific enolase (NSE).

  Results: While pretherapeutic HMGB1 levels were not predictive or prognostically relevant in NSCLC patients, HMGB1 values prior to cycles 2 and 3 as well as kinetics from cycle 1 to 2 discriminated significantly between patients with good (remission and stable disease) and poor response (progression). Performance of HMGB1 in receiver operating characteristic (ROC) analyses of NSCLC patients, with areas under the curve (AUCs) of 0.690 at cycle 2 and 0.794 at cycle 3 as well as sensitivities of 34.4% and 37.5%, respectively, for progression at 90% specificity, was comparable with the best tumor-associated antigen CYFRA 21-1 (AUCs 0.719 and 0.799; sensitivities of 37.5% and 41.7%, respectively). Furthermore, high concentrations of HMGB1 at cycles 2 and 3 were associated with shorter overall survival in NSCLC patients.

  Conclusion: Soluble HMGB1 is a promising biomarker for prediction of therapy response and prognosis in advanced NSCLC patients.

• A Single Liver Metastasis from Pleural Biphasic Mesothelioma. A. Marzullo, G. Serio, F. Pezzuto, et al. 2020;10(8). PubMed · Publisher · Free full text

  Abstract

  Virtually any malignancy can metastasize to the liver. Large solitary metastases are rare and can be difficult to distinguish from primary tumors. Malignant mesothelioma is often considered as a locally invasive cancer but tumor dissemination to extra-thoracic sites is possible, and the liver can be involved. Herein, we present a rare case of pleural mesothelioma with a solitary large liver metastasis diagnosed postmortem in a ninety-two-year-old man with 35 years of exposure to asbestos. Results of immunohistochemical staining of the pleural and liver tumor were similar, both positive for low-molecular weight keratins, calretinin, vimentin, and podoplanin, and negative for Claudin-4, TTF1, CEA, BerEP4, CK7, CK19, CK20, BAP1, Hep Par1, p40, and WT1. Fluorescent in-situ hybridization (FISH) for p16/CDKN2A was also performed and a homozygous deletion was detected in both tumors, supporting the diagnosis of mesothelioma. Reporting this case, we would like to point out that extra-thoracic dissemination from pleural mesothelioma, even if exceptional, can occur. In cases where differential diagnoses are challenging, the value of ancillary techniques and a practical approach to diagnostic work-up is of primary importance.

• Chromatographic Detection of 8-Hydroxy-2'-Deoxyguanosine in Leukocytes of Asbestos Exposed Workers for Assessing Past and Recent Carcinogen Exposures. F. Cellai, S. Bonassi, A. Cristaudo, et al. 2020;10(4). PubMed · Publisher · Free full text

  Abstract

  Asbestos fibers include a group of silicate minerals that occur in the environment and are widely employed in occupational settings. Asbestos exposure has been associated to various chronic diseases; such as pulmonary fibrosis; mesothelioma; and lung cancer; often characterized by a long period of latency. Underlying mechanisms that are behind the carcinogenic effect of asbestos have not been fully clarified. Therefore; we have conducted an epidemiological study to evaluate the relationship between 8-hydroxy-2'-deoxyguanosine (8-oxodG), one of the most reliable biomarkers of oxidative stress and oxidative DNA damage; and asbestos exposure in the peripheral blood of residents in Tuscany and Liguria regions; Italy; stratified by occupational exposure to this carcinogen. Levels of 8-oxodG were expressed such as relative adduct labeling (RAL); the frequency of 8-oxodG per 105 deoxyguanosine was significantly higher among exposed workers with respect to the controls; i.e., 3.0 ± 0.2 Standard Error (SE) in asbestos workers versus a value of 1.3 ± 0.1 (SE) in unexposed controls (p < 0.001). When the relationship with occupational history was investigated; significant higher levels of 8-oxodG were measured in current and former asbestos workers vs. healthy controls; 3.1 ± 0.3 (SE) and 2.9 ± 0.2 (SE), respectively. After stratification for occupational history; a significant 194% excess of adducts was found in workers with 10 or more years of past asbestos exposure (p < 0.001). 8-oxodG can be used for medical surveillance programs of cohorts of workers with past and recent exposures to carcinogens for the identification of subjects requiring a more intense clinical surveillance.

• Prognostic Value of Ki67 Percentage, WT-1 Expression and p16/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study. F. Pezzuto, G. Serio, F. Fortarezza, et al. 2020;10(6). PubMed · Publisher · Free full text

  Abstract

  Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignant neoplasm with a poor survival. Although some advances in knowledge have been obtained for the pleural form, much less is known about DMPM. Advantages in terms of prognosis are still limited and strong efforts need to be made. The aim of our study was to correlate several histological and molecular factors with survival in a large cohort of 45 DMPMs. We evaluated histotype, nuclear grade, mitotic count, necrosis, inflammation, desmoplastic reaction, Ki67 percentage, WT-1 expression, p16 protein by immunohistochemistry and CDKN2A deletion by FISH. Our results showed that epithelioid histotype, nuclear grade 2, mitotic count ≤5 x mm2, absence of desmoplasia and p16/CDKN2A deletion, low Ki67 value, and high WT-1 expression were correlated with the most prolonged survival (p = 0.0001). Moreover, p16 loss in immunohistochemistry reflected CDKN2A deletion detected with FISH, and both were correlated with the worst survival (p = 0.0001). At multivariate analysis, Ki67 value, WT-1 expression and p16/CDKN2A deletion emerged as independent prognostic factors (p = 0.01, p = 0.0001 and p = 0.01, respectively). These parameters are easy to analyse at the time of DMPM diagnosis and may support better patient stratification, prediction of treatment effectiveness and therapeutic optimization.

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