Journal Description
Journal of Molecular Pathology
Journal of Molecular Pathology
is an international, peer-reviewed, open access journal on every topic related to modern histopathology and cytopathology, predictive pathology and molecular cytopathology, published quarterly online by MDPI.
- Open Access—free to download, share, and reuse content. Authors receive recognition for their contribution when the paper is reused.
- High Visibility: indexed within CAPlus / SciFinder, and many other databases.
- Rapid Publication: first decisions in 15 days; acceptance to publication in 3 days (median values for MDPI journals in the second half of 2021).
- Recognition of Reviewers: APC discount vouchers, optional signed peer review, and reviewer names published annually in the journal.
subject
Imprint Information
Open Access
ISSN: 2673-5261
Latest Articles
Use of the Biocartis Idylla™ Platform for the Detection of Epidermal Growth Factor Receptor, BRAF and KRAS Proto-Oncogene Mutations in Liquid-Based Cytology Specimens from Patients with Non-Small Cell Lung Carcinoma and Pancreatic Adenocarcinoma
J. Mol. Pathol. 2022, 3(2), 104-114; https://doi.org/10.3390/jmp3020010 - 14 May 2022
Abstract
The study aimed to demonstrate rapid and effective molecular testing on liquid-based cytology (LBC) samples for EGFR, KRAS and BRAF mutations using the Biocartis Idylla™. Rapid on-site evaluation (ROSE) LBC samples for patients with non-small cell lung carcinoma (NSCLC) or pancreatic ductal
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The study aimed to demonstrate rapid and effective molecular testing on liquid-based cytology (LBC) samples for EGFR, KRAS and BRAF mutations using the Biocartis Idylla™. Rapid on-site evaluation (ROSE) LBC samples for patients with non-small cell lung carcinoma (NSCLC) or pancreatic ductal adenocarcinoma (PDAC) were tested for EGFR, KRAS and BRAF mutations based on the relevance to tumour subtype. The quantification values (Cq values) and mutation detection status were compared between LBC samples and routine formalin-fixed paraffin-embedded (FFPE) clot samples. ROSE LBC samples (n = 54) showed a higher yield of well-preserved tumour and wild type (WT) DNA, demonstrated by lower quantification cycles, no false positives or false negatives, and a higher sensitivity for low allele frequency mutations when compared with FFPE clot samples. The Biocartis Idylla™ provides highly sensitive, reliable and rapid testing for LBC samples for the detection of EFGR and KRAS mutations. BRAF mutations were not detected in the participant cohort; however, all LBC WT BRAF results correlated with the results from the FFPE clot samples. Access to rapid molecular testing using LBC samples can detect the most frequent driver mutations closer to the time of diagnosis, enabling the selection of the most effective first-line targeted therapy sooner, reducing delays or side effects from suboptimal treatments, patient anxiety and costs to healthcare systems, whilst improving patient outcomes.
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(This article belongs to the Collection Feature Papers in Journal of Molecular Pathology)
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Open AccessReview
Micro-RNA in Cholangiocarcinoma: Implications for Diagnosis, Prognosis, and Therapy
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, , , , and
J. Mol. Pathol. 2022, 3(2), 88-103; https://doi.org/10.3390/jmp3020009 - 09 May 2022
Abstract
Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by
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Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by the following factors: late diagnosis, lack of effective therapeutic approaches, and resistance to conventional treatments. In the past few years, next-generation sequencing technologies has allowed us to study the genome, exome, and transcriptome of BDC deeper, revealing a previously underestimated class of RNA: the noncoding RNA (ncRNA). MicroRNAs (miRNAs) are small ncRNAs that play an important regulatory role in gene expression. The aberrant expression of miRNAs and their pivotal role as oncogenes or tumor suppressors in biliary carcinogenesis has been widely described in BDC. Due to their ability to regulate multiple gene networks, miRNAs are involved in all cancer hallmarks, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. Their use as diagnostic, prognostic, and predictive biomarkers has been widely explored in several human cancers, including BDC. Furthermore, miRNA-based therapeutic strategies are currently the subject of numerous clinical trials that are providing evidence of their efficacy as potent anticancer agents. In this review, we will provide a detailed update of miRNAs affecting BDC, discussing their regulatory function in processes underlying the molecular pathology of BDC. Finally, an overview of their potential use as biomarkers or therapeutic tools in BDC will be further addressed.
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(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Open AccessArticle
Molecular Diagnostics of Lung Cancer in Serous Effusion Samples
J. Mol. Pathol. 2022, 3(2), 78-87; https://doi.org/10.3390/jmp3020008 - 12 Apr 2022
Abstract
For molecular diagnostics of lung cancer samples, often only a small amount of material is available. The ever-increasing number of biomarker testing is in contrast to the amount of material obtained. In that case, cytological specimens, such as serous effusion samples, are one
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For molecular diagnostics of lung cancer samples, often only a small amount of material is available. The ever-increasing number of biomarker testing is in contrast to the amount of material obtained. In that case, cytological specimens, such as serous effusion samples, are one possible option. Effusion samples were prepared as sediment smears or cytospins or as a cell block if needed. Suitable tumor cells areas were marked by a cytopathologist and used for molecular diagnostics, including fast track analysis, parallel sequencing, and/or fluorescence in situ hybridization. In 62 cases of malignant effusion with cells of pulmonary adenocarcinoma, molecular diagnostics were carried out. A fast-track result with the high-resolution melting method for hotspot mutation of KRAS Exon 2 and EGFR exon 21 and fragment length analysis of EGFR exon 19 was available for 43 out of 47 samples (92%). Parallel sequencing was successful for 56 out of 60 samples (93.3%). In the same period, 108 FISH analyses were performed for MET amplification, followed by ROS1, RET, and ALK translocation analysis. If only a limited amount of tissue/biopsy is available, a malignant effusion is advisable to perform on the molecular diagnostics with a high success rate.
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(This article belongs to the Special Issue Molecular Cytopathology)
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Open AccessCase Report
Prometastatic CXCR4 and Histone Methyltransferase EZH2 Are Upregulated in SMARCB1/INI1-Deficient and TP53-Mutated Poorly Differentiated Chordoma
J. Mol. Pathol. 2022, 3(2), 68-77; https://doi.org/10.3390/jmp3020007 - 02 Apr 2022
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Background: Chordoma is a rare tumor most commonly arising in the sacrococcygeal region from notochord remnants. Usually, these tumors are locally invasive and recurrent, and they have a 5–43% ability to metastasize. A newly-described aggressive variant called poorly differentiated chordoma is different from
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Background: Chordoma is a rare tumor most commonly arising in the sacrococcygeal region from notochord remnants. Usually, these tumors are locally invasive and recurrent, and they have a 5–43% ability to metastasize. A newly-described aggressive variant called poorly differentiated chordoma is different from conventional chordoma in that it does not have the well-differentiated histologic appearance of conventional chordoma and also exhibits the loss of SMARCB1/INI1. Herein, we describe a case of poorly differentiated chordoma with SMARCB1/INI1 loss, a concurrent TP53 mutation, and Rb1 loss. Methods: The patient is a middle-aged man with a history of previously resected sacrococcygeal chordoma, who was found to have new hepatic, lung, and adrenal lesions. Results: Biopsy of the liver lesion showed sheets of malignant epithelioid cells with vacuolated cytoplasm, areas of necrosis, and up to five mitoses in one high-power field. No physaliferous cytologic features or matrix material was seen. After reviewing an extensive panel of immunohistochemical markers, the origin of the metastatic tumor could not be determined; the tumor was only positive for Cam5.2, EMA, and CD56. Brachyury was performed due to the patient’s previous history and was positive. Genomic testing showed a SMARCB1 mutation, TP53 mutation, and RB1 loss. Additional markers were performed, and the tumor showed a Ki-67 proliferation index of approximately 80%, mutant p53 protein, loss of INI1, and strong expression of both the histone methyl transferase EZH2 and the chemokine receptor CXCR4. Conclusions: Poorly differentiated chordoma is a highly aggressive variant of chordoma with few cases reported. This case of SMARCB1/INI-deficient, poorly differentiated chordoma also showed a concurrent TP53 mutation and loss of RB1, which resulted in malignant transformation with upregulation of both prometastatic CXCR4 and the histone methyltransferase EZH2, causing aggressive behavior and metastasis.
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Open AccessFeature PaperArticle
Evaluation of the TruSight Tumor 170 Assay and Its Value in Clinical Diagnostics
J. Mol. Pathol. 2022, 3(1), 53-67; https://doi.org/10.3390/jmp3010006 - 05 Feb 2022
Abstract
Background: Parallel sequencing technologies have become integrated into clinical practice. This study evaluated the TruSight Tumor 170 assay for the simultaneous detection of somatic gene mutations (SNPs and indels), gene fusions and CNVs, and its implementation into routine diagnostics. Methods: Forty-four formalin-fixed, paraffin-embedded
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Background: Parallel sequencing technologies have become integrated into clinical practice. This study evaluated the TruSight Tumor 170 assay for the simultaneous detection of somatic gene mutations (SNPs and indels), gene fusions and CNVs, and its implementation into routine diagnostics. Methods: Forty-four formalin-fixed, paraffin-embedded tissue samples analyzed previously with validated methods were evaluated with the TruSight Tumor 170 assay (Illumina). For data analysis the TruSight Tumor 170 app, the BaseSpace Variant Interpreter (Illumina), and the Molecular Health Guide Software (Molecular Health) were used. Results: All somatic gene mutations were identified when covered by the assay. Two high-level MET amplifications were detected by CNV analysis. Focal MET amplifications with a copy number below 10 were not reliably detected at the DNA-level. Twenty-one of 31 fusions and splice variants were confirmed with the assay on the RNA-level. The remaining eight aberrations were incorrect by previous methods. In two cases, no splicing was observed. Conclusions: The TruSight Tumor 170 gives reliable results even if low DNA and RNA concentrations are applied in comparison to other methods and can be used in a routine workflow to detect somatic gene mutations, gene fusions, and splice variants. However, we were not able to detect most focal gene amplifications/deletions.
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(This article belongs to the Collection Feature Papers in Journal of Molecular Pathology)
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Open AccessEditorial
Acknowledgment to Reviewers of Journal of Molecular Pathology in 2021
J. Mol. Pathol. 2022, 3(1), 52; https://doi.org/10.3390/jmp3010005 - 29 Jan 2022
Abstract
Rigorous peer-reviews are the basis of high-quality academic publishing [...]
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Open AccessArticle
Heterogeneity of Fecal Calprotectin Reflecting Generation of Neutrophil Extracellular Traps (NETs) in the Gut: New Immunoassays Are Available
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and
J. Mol. Pathol. 2022, 3(1), 38-51; https://doi.org/10.3390/jmp3010004 - 21 Jan 2022
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Background: We aimed at obtaining more information on the structure of fecal calprotectin (CP) as a basis for establishing improved quantitative assays and detection of Neutrophil Extracellular Traps (NETs) in stools. Commercial fecal CP assays produce different results, probably due to differences in
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Background: We aimed at obtaining more information on the structure of fecal calprotectin (CP) as a basis for establishing improved quantitative assays and detection of Neutrophil Extracellular Traps (NETs) in stools. Commercial fecal CP assays produce different results, probably due to differences in antibodies, extraction procedures, and standards used. In addition, the structure of fecal CP may be different from that in the standard so that rules for immunoassays are violated. We aimed at solving these problems by studying the structure of fecal CP and developing new antibodies and assay procedures including some for NETs in stools. Methods and Findings: Stool samples from children with abdominal symptoms were extracted by a conventional and a new procedure. Some extracts were run on anion exchange and size exclusion chromatography, and fractions were tested on ELISAs by use of ten new mouse monoclonal antibodies against the CP subunit S100A9. Hybrid ELISAs (named HELISA) were established using anti-DNA or anti-histones for coating of microwells, and enzyme labelled anti-CP was used for development. By ion exchange chromatography, five to ten fecal CP subfraction peaks differing in net electric charge were found, all of which contained the major chromatin components. The presence of DNA and histones followed calprotectin in the chromatographic fractions suggesting that NETs are generated in the gut lumen. The new CP monoclonals reacted very differently against the subfractions so that a mixture of them (called MiMo) must be used to obtain reliable assay values for fecal CP. A new method called FELISA was developed where standards and samples are applied directly in Nunc (Denmark) MaxiSorp plates, without any catching antibody. It takes advantage of the property of CP to bind strongly to the plastic in wells. This method has a higher sensitivity because it will detect CP molecules with only one antigenic epitope available. It will give more reliable estimates and more efficient selection of patients for complex diagnostic procedures. We also developed an alternative to the FELISA: a competitive ELISA where S100A9 coated in microwells will compete with CP in standards and samples for binding to a properly diluted HRP-anti-CP solution. In this method, the presence of other proteins in extraction or dilution buffers will not interfere. Using the HELISA, about 65% of the patients had detectable fecal NETs in concentrations between 150 and 1500 ng/mL; however, the values correlated poorly with CP values. Extraction of fecal samples with a simple buffer of TBS, and pH 5 with 5 mM EDTA, gave a yield of about 90%, while the yields of commercial kits are not specified or lie around 50%. A fecal CP standard will bring methods in accordance with the requirements for immunoassays that the structure of CP in the standard and sample must be the same. A mixture of fecal anion exchange fractions as a standard may be a solution to this problem. The principle worked in the first trial by giving the same values after storage of such a standard at 5C for four months. Conclusions: Fecal CP consists of at least five subfractions containing NETs or degradation products thereof. Commercial kits should not be accepted for clinical use unless it has been shown that they can detect all subfractions which may require the use of a mixture of monoclonals. The methods presented here can be used for such a quality control. The HELISA methods can be used for assays on NETs in stools and to study their possible pathogenic effects in the gut. Use of the FELISA and the S100A9 competitive method may give increased sensitivity, higher precision, and better selection of patients for more complex procedures.
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Open AccessReview
Molecular Testing and Treatment Strategies in RET-Rearranged NSCLC Patients: Stay on Target to Look Forward
J. Mol. Pathol. 2022, 3(1), 24-37; https://doi.org/10.3390/jmp3010003 - 18 Jan 2022
Abstract
RET alterations are recognized as key oncogenic drivers in different cancer types, including non-small cell lung cancer (NSCLC). Multikinase inhibitors (MKIs) with anti-RET activities resulted in variable efficacy with significant toxicities because of low target specificity. Selective RET kinase inhibitors, such as
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RET alterations are recognized as key oncogenic drivers in different cancer types, including non-small cell lung cancer (NSCLC). Multikinase inhibitors (MKIs) with anti-RET activities resulted in variable efficacy with significant toxicities because of low target specificity. Selective RET kinase inhibitors, such as pralsetinib and selepercatinib, demonstrated high efficacy and favorable tolerability in advanced RET-rearranged NSCLC patients, leading to their introduction in the clinical setting. Among the different approaches available for the identification of RET rearrangements, next-generation sequencing (NGS) assays present substantial advantages in terms of turnaround time and diagnostic accuracy, even if potentially limited by accessibility issues. The recent advent of novel effective targeted therapies raises several questions regarding the emergence of resistance mechanisms and the potential ways to prevent/overcome them. In this review, we discuss molecular testing and treatment strategies to manage RET fusion positive NSCLC patients with a focus on resistance mechanisms and future perspectives in this rapidly evolving scenario.
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(This article belongs to the Collection Feature Papers in Journal of Molecular Pathology)
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Open AccessBrief Report
Tissue Microarray from Cell Block Material (cbTMA)—An Additional Shot for Cytology in the Predictive Pathology Era: The PD-L1 Experience
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, , , , , and
J. Mol. Pathol. 2022, 3(1), 15-23; https://doi.org/10.3390/jmp3010002 - 12 Jan 2022
Abstract
Generally, predictive biomarker tests are clinically validated on histological formalin-fixed, paraffin-embedded (FFPE) samples. In addition to FFPE samples, cytological samples have also emerged as a useful approach to detect predictive biomarkers. However, as of today, despite the promising results reported in the recent
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Generally, predictive biomarker tests are clinically validated on histological formalin-fixed, paraffin-embedded (FFPE) samples. In addition to FFPE samples, cytological samples have also emerged as a useful approach to detect predictive biomarkers. However, as of today, despite the promising results reported in the recent literature, their full implementation in routine clinical practice is still lagging owing to a lack of standardized preparatory protocols, challenging assessments of cyto-histological correlation, and variable inter-observer agreement. The aim of this report was to explore the possibility of implementing a large-scale validation of predictive biomarker testing on cytological material. To this aim, we evaluated the technical feasibility of PD-L1 assessment on a cell block (CB)-derived tissue microarray (cbTMA). Consecutive and unselected CBs prepared from metastatic lymph node fine-needle cytology (FNC) samples were retrospectively collected and used for TMA construction. PD-L1 immunohistochemistry (IHC) was carried out on cbTMA sections with the companion diagnostic kit SP263 assay. TMA contained 33 CB-derived cores. A total of 20 sections were hematoxylin and eosin (H&E) stained. Overall, 29 (88%) samples were visible at least in one H&E-stained slide. Four cases out of five sections stained with the SP263 assay (4/29, 13.8%) showed PD-L1 positivity in neoplastic and/or immune cells; remarkably, no unspecific background was observed. Although our study was based on a limited and non-selected series, our findings do provide proof of concept for the use of cbTMA in predictive biomarker testing on cytological material in large-scale post-clinical trial validation studies, multicenter studies, and quality control programs.
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(This article belongs to the Special Issue Molecular Cytopathology)
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Open AccessReview
The Multifaceted Profile of Thyroid Disease in the Background of DICER1 Germline and Somatic Mutations: Then, Now and Future Perspectives
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, , , , , and
J. Mol. Pathol. 2022, 3(1), 1-14; https://doi.org/10.3390/jmp3010001 - 11 Jan 2022
Abstract
DICER1 protein is a member of the ribonuclease (RNAse) III family with a key role in the biogenesis of microRNAs (miRNA) and in microRNA processing, potentially affecting gene regulation at the post-transcriptional level. The role of DICER1 and its relevance to thyroid cellular
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DICER1 protein is a member of the ribonuclease (RNAse) III family with a key role in the biogenesis of microRNAs (miRNA) and in microRNA processing, potentially affecting gene regulation at the post-transcriptional level. The role of DICER1 and its relevance to thyroid cellular processes and tumorigenesis have only recently been explored, following the acknowledgement that DICER1 germline and somatic changes can contribute not only to non-toxic multinodule goiter (MNG) lesions detected in individuals of affected families but also to a series of childhood tumours, including thyroid neoplasms, which can be identified from early infancy up until the decade of 40s. In a context of DICER1 germline gene mutation, thyroid lesions have recently been given importance, and they may represent either an index event within a syndromic context or the isolated event that may trigger a deeper and broader genomic analysis screening of individuals and their relatives, thereby preventing the consequences of a late diagnosis of malignancy. Within the syndromic context MNG is typically the most observed lesion. On the other hand, in a DICER1 somatic mutation context, malignant tumours are more common. In this review we describe the role of DICER protein, the genomic events that affect the DICER1 gene and their link to tumorigenesis as well as the frequency and pattern of benign and malignant thyroid lesions and the regulation of DICER1 within the thyroidal environment.
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(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Open AccessCase Report
Fine-Needle Aspiration Is Suitable for Breast Cancer BRCA Molecular Assessment: A Case Report
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, , , , , , , and
J. Mol. Pathol. 2021, 2(4), 319-324; https://doi.org/10.3390/jmp2040028 - 03 Dec 2021
Abstract
Breast cancer is the most common cause of cancer-related deaths in the female population worldwide. To the best of our knowledge, breast cancer (BRCA)1/2 gene mutations have not been described yet on breast cancer cytological specimens. Here we describe the
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Breast cancer is the most common cause of cancer-related deaths in the female population worldwide. To the best of our knowledge, breast cancer (BRCA)1/2 gene mutations have not been described yet on breast cancer cytological specimens. Here we describe the case of a 38-year old woman with a family and personal history for breast cancer, who underwent a fine needle aspiration (FNA) procedure for a novel 30 mm lesion located in the external quadrants of the contralateral (left) breast. Cytological findings and ancillary immunostaining confirmed the diagnosis of a triple negative NST carcinoma. BRCA1/2 molecular assessment was carried out on DNA extracted from cytological (November 2020), biopsy (December 2014) and surgical resection (July 2015) specimens, as well as on the resection of a benign fibroadenoma, by using a next generation sequencing approach. Molecular analysis showed a pathogenic BRCA1 insertion (c.5266dupC; p.Q1756PfsTer74) in the cytological specimen (allelic fraction 92.0%), biopsy (allelic fraction 84.2%), surgical resection (allelic fraction 87.8%) and fibroadenoma (58.9%), demonstrating a germinal BRCA mutated status.
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(This article belongs to the Special Issue Molecular Cytopathology)
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Open AccessOpinion
From Information Overload to Actionable Insights: Digital Solutions for Interpreting Cancer Variants from Genomic Testing
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and
J. Mol. Pathol. 2021, 2(4), 312-318; https://doi.org/10.3390/jmp2040027 - 21 Nov 2021
Abstract
Given the increase in genomic testing in routine clinical use, there is a growing need for digital technology solutions to assist pathologists, oncologists, and researchers in translating variant calls into actionable knowledge to personalize patient management plans. In this article, we discuss the
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Given the increase in genomic testing in routine clinical use, there is a growing need for digital technology solutions to assist pathologists, oncologists, and researchers in translating variant calls into actionable knowledge to personalize patient management plans. In this article, we discuss the challenges facing molecular geneticists and medical oncologists in working with test results from next-generation sequencing for somatic oncology, and propose key considerations for implementing a decision support software to aid the interpretation of clinically important variants. In addition, we review results from an example decision support software, NAVIFY Mutation Profiler. NAVIFY Mutation Profiler is a cloud-based software that provides curation, annotation, interpretation, and reporting of somatic variants identified by next-generation sequencing. The software reports a tiered classification based on consensus recommendations from AMP, ASCO, CAP, and ACMG. Studies with NAVIFY Mutation Profiler demonstrated that the software provided timely updates and accurate curation, as well as interpretation of variant combinations, demonstrating that decision support tools can help advance implementation of precision oncology.
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(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
Open AccessCase Report
Progression of Well-Differentiated Papillary Mesothelial Tumour to Mesothelioma in a Patient with Ehlers Danlos Syndrome
J. Mol. Pathol. 2021, 2(4), 306-311; https://doi.org/10.3390/jmp2040026 - 29 Oct 2021
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Well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumour (WDPMT) in the current WHO classification because all mesotheliomas are now regarded as malignant. WDPMT is now defined as a non-invasive papillary mesothelial proliferation, with retained labelling for BAP1-desirable. The current WHO classification
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Well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumour (WDPMT) in the current WHO classification because all mesotheliomas are now regarded as malignant. WDPMT is now defined as a non-invasive papillary mesothelial proliferation, with retained labelling for BAP1-desirable. The current WHO classification also includes mesothelioma in situ (MIS), which is defined as pre-invasive flat or papillary proliferation of mesothelial cells with a loss of BAP1 or MTAP. WDPMT has been variably defined in the past but was thought to occur more commonly in women and pursue a more indolent course than mesothelioma, but its progression to invasive disease has occasionally been reported. Here, we report a case of a 68-year-old woman with a history of asbestos exposure and an underlying diagnosis of Ehlers Danlos syndrome who was diagnosed with symptomatic WDPMT of the peritoneum that progressed to mesothelioma within two years. On retrospective analysis, the WDPMT showed a loss of BAP1. We suggest that a loss of BAP1 in WDPMT should be reported, since these lesions may show aggressive behaviour, and that they may best be regarded as similar to mesothelioma in situ.
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Open AccessArticle
Conventional Transbronchial Needle Aspiration (cTBNA) and EBUS-Guided Transbronchial Needle Aspiration (EBUS-TBNA): A Retrospective Study on the Comparison of the Two Methods for Diagnostic Adequacy in Molecular Analysis
by
, , , , , , , , , and
J. Mol. Pathol. 2021, 2(4), 296-305; https://doi.org/10.3390/jmp2040025 - 09 Oct 2021
Cited by 1
Abstract
Introduction: In recent years, there has been a growing development of molecularly targeted therapies for various types of solid tumors—in particular, in non-small-cell lung cancer (NSCLC). This has required the need for greater quantities of tissue that is able to support ancillary studies,
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Introduction: In recent years, there has been a growing development of molecularly targeted therapies for various types of solid tumors—in particular, in non-small-cell lung cancer (NSCLC). This has required the need for greater quantities of tissue that is able to support ancillary studies, alongside cyto-histological diagnoses for the assessment of molecular targets. Conventional TBNA (cTBNA) and EBUS-guided TBNA (EBUS-TBNA) have shown a high diagnostic yield for malignant mediastinal and/or hilar lymph node enlargement and peribronchial masses; however, few studies have compared these two procedures. We retrospectively compared TBNA patients (EBUS-TBNA and cTBNA) in order to determine the diagnostic yield and material adequacy for subsequent ancillary analyses. Materials and Methods: We retrospectively evaluated 318 patients with clinical suspicion of lung cancer or with disease recurrence. All of the patients underwent TBNA (either EBUS-TBNA or cTBNA) on enlarged mediastinal and/or hilar lymph nodes and peribronchial masses between January 2017 and June 2021 at the University Hospital of Pisa, Italy. After a definitive diagnosis, molecular analyses and an evaluation of PD-L1 expression were performed in the cases of adenocarcinoma, squamous cell carcinoma, and NSCLC, not otherwise specified (NOS). Results: EBUS-TBNA was performed in 199 patients and cTBNA was performed in 119 patients with 374 and 142 lymph nodes, respectively. The overall diagnostic yield for positive diagnoses was 59% (diagnostic rate of 61% in EBUS-TBNA, and 55% in cTBNA). Adenocarcinoma (ADC) was the most frequent diagnosis in both methods. EBUS-TBNA diagnostic adequacy was 72% for molecular analysis, while it was 55.5% for cTBNA, showing a statistical trend (p = 0.08) towards the significance of EBUS. The average percentage of neoplastic cells was also statistically different between the two methods (p = 0.05), reaching 51.19 ± 22.14 in EBUS-TBNA and 45.25 ± 22.84 in cTBNA. With regard to the PD-L1 protein expression, the percentage of positivity was similar in both procedures (86% in EBUS-TBNA, 85% in cTBNA). Conclusions: Conventional TBNA (cTBNA) and EBUS-guided TBNA (EBUS-TBNA) are minimally invasive diagnostic methods that are associated with a high diagnostic yield. However, EBUS-TBNA has an improved diagnostic adequacy for molecular analysis compared to cTBNA, and is associated with a higher average percentage of neoplastic cells.
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(This article belongs to the Special Issue Molecular Cytopathology)
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Open AccessReview
Clinical and Molecular Features of Anti-CENP-B Autoantibodies
J. Mol. Pathol. 2021, 2(4), 281-295; https://doi.org/10.3390/jmp2040024 - 29 Sep 2021
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Centromeric proteins are the foundation for assembling the kinetochore, a macromolecular complex that is essential for accurate chromosome segregation during mitosis. Anti-centromere antibodies (ACAs) are polyclonal autoantibodies targeting centromeric proteins (CENP-A, CENP-B, CENP-C), predominantly CENP-B, and are highly associated with rheumatologic disease (lcSSc/CREST
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Centromeric proteins are the foundation for assembling the kinetochore, a macromolecular complex that is essential for accurate chromosome segregation during mitosis. Anti-centromere antibodies (ACAs) are polyclonal autoantibodies targeting centromeric proteins (CENP-A, CENP-B, CENP-C), predominantly CENP-B, and are highly associated with rheumatologic disease (lcSSc/CREST syndrome). CENP-B autoantibodies have also been reported in cancer patients without symptoms of rheumatologic disease. The rise of oncoimmunotherapy stimulates inquiry into how and why anti-CENP-B autoantibodies are formed. In this review, we describe the clinical correlations between anti-CENP-B autoantibodies, rheumatologic disease, and cancer; the molecular features of CENP-B; possible explanations for autoantigenicity; and, finally, a possible mechanism for induction of autoantibody formation.
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Open AccessCommentary
Precision Prevention: The 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors
by
J. Mol. Pathol. 2021, 2(3), 274-280; https://doi.org/10.3390/jmp2030023 - 09 Sep 2021
Abstract
The approach to cervical cancer prevention has evolved significantly over the past two decades. HPV immunization has decreased the specificity of screening modalities and HPV-based testing has been replacing our previously successful morphology-only approach. Additionally, there is much more emphasis on providing precision
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The approach to cervical cancer prevention has evolved significantly over the past two decades. HPV immunization has decreased the specificity of screening modalities and HPV-based testing has been replacing our previously successful morphology-only approach. Additionally, there is much more emphasis on providing precision prevention, rather than the previously used “one-fits-all” management strategies. A number of new biomarkers are entering clinical practice and being integrated into cervical cancer screening and management in order to enable a more personalized assessment of the risk for precancer/cancer for an individual patient. The 2019 ASCCP Risk-Based Management Consensus Guidelines expand on the concept of “equal management for equal risk”. They consider a patient’s history in addition to current test results to provide recommendations for increased surveillance/treatment in patients at higher risk for CIN3+ while minimizing interventions for lower-risk patients who have new versus persistent HPV infection. Clinical management decisions are based on immediate risk and 5-year risk estimates for CIN3+, which are determined by referencing an extensive risk table compiled by the National Cancer Institute (NCI). The course of action for a given patient is recommended by comparison of the risk in the risk database, to the predetermined clinical action thresholds. These guidelines address the need for simplification and offer some stability for the provider while being conducive to the incorporation of anticipated continued technologic advances in methods for cervical cancer prevention. Their enduring nature will allow for changes needed based on risk reduction as HPV vaccination uptake increases and vaccinated women reach screening age. Similarly, the design allows for the addition of new tests into the risk assessment calculations after their approval by applicable regulatory agencies and review/consensus approval by the ASCCP new technology and enduring guidelines workgroups. As cytopathologists, we must be familiar with the scientific advancements in primary and secondary prevention, evolving screening and management guidelines, and participate actively in the multidisciplinary approach for the prevention of cervical cancer.
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(This article belongs to the Special Issue Selected Highlights of the 9th Molecular Cytopathology Meeting)
Open AccessReview
Liquid Biopsy for Biomarker Testing in Non-Small Cell Lung Cancer: A European Perspective
J. Mol. Pathol. 2021, 2(3), 255-273; https://doi.org/10.3390/jmp2030022 - 18 Aug 2021
Cited by 4
Abstract
The development of targeted therapies has improved survival rates for patients with advanced non-small cell lung cancer (NSCLC). However, tissue biopsy is unfeasible or inadequate in many patients, limiting biomarker testing and access to targeted therapies. The increasing numbers of established and emerging
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The development of targeted therapies has improved survival rates for patients with advanced non-small cell lung cancer (NSCLC). However, tissue biopsy is unfeasible or inadequate in many patients, limiting biomarker testing and access to targeted therapies. The increasing numbers of established and emerging biomarkers with available targeted treatments highlights the challenges associated with sequential single-gene testing and limited tissue availability. Multiplex next-generation sequencing (NGS) offers an attractive alternative and represents a logical next step, and in cases where the tumour is inaccessible, tissue biopsy yields insufficient tumour content, or when the patient’s performance status does not allow a tissue biopsy, liquid biopsy can provide valuable material for molecular diagnosis. Here, we explore the role of liquid biopsy (i.e., circulating cell-free DNA analysis) in Europe. Liquid biopsies could be used as a complementary approach to increase rates of molecular diagnosis, with the ultimate aim of improving patient access to appropriate targeted therapies. Expert opinion is also provided on potential future applications of liquid biopsy in NSCLC, including for cancer prevention, detection of early stage and minimum residual disease, monitoring of response to therapy, selection of patients for immunotherapy, and monitoring of tumour evolution to enable optimal adaptation/combination of drug therapies.
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(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Open AccessFeature PaperReview
Liquid Biopsy Analysis in Clinical Practice: Focus on Lung Cancer
by
, , , , , , , , and
J. Mol. Pathol. 2021, 2(3), 241-254; https://doi.org/10.3390/jmp2030021 - 16 Jul 2021
Cited by 2
Abstract
Lung cancer is the leading cause of cancer death worldwide. Despite the emergence of highly effective targeted therapies, up to 30% of advanced stage non-small cell lung cancer (NSCLC) patients do not undergo tissue molecular testing because of scarce tissue availability. Liquid biopsy,
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Lung cancer is the leading cause of cancer death worldwide. Despite the emergence of highly effective targeted therapies, up to 30% of advanced stage non-small cell lung cancer (NSCLC) patients do not undergo tissue molecular testing because of scarce tissue availability. Liquid biopsy, on the other hand, offers these patients a valuable opportunity to receive the best treatment options in a timely manner. Indeed, besides being much faster and less invasive than conventional tissue-based analysis, it can also yield specific information about the genetic make-up and evolution of patients’ tumors. However, several issues, including lack of standardized protocols for sample collection, processing, and interpretation, still need to be addressed before liquid biopsy can be fully incorporated into routine oncology practice. Here, we reviewed the most important challenges hindering the implementation of liquid biopsy in oncology practice, as well as the great advantages of this approach for the treatment of NSCLC patients.
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(This article belongs to the Special Issue Selected Highlights of the 9th Molecular Cytopathology Meeting)
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Open AccessFeature PaperReview
Molecular Testing of Thyroid Fine-Needle Aspiration: Local Issues and Solutions. An Interventional Cytopathologist Perspective
by
, , , , , and
J. Mol. Pathol. 2021, 2(3), 233-240; https://doi.org/10.3390/jmp2030020 - 13 Jul 2021
Cited by 1
Abstract
Molecular testing has acquired a relevant role for diagnostic and prognostic stratification of indeterminate thyroid nodules. Besides the available commercial solutions marketed in the United States, various local testing strategies have been developed in the last decade. In this setting, the modern interventional
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Molecular testing has acquired a relevant role for diagnostic and prognostic stratification of indeterminate thyroid nodules. Besides the available commercial solutions marketed in the United States, various local testing strategies have been developed in the last decade. In this setting, the modern interventional cytopathologist, the physician who performs the both aspirate and the morphologic interpretation plays a key role in the correct handling of fine-needle aspiration (FNA) samples not only for microscopy but also for molecular techniques. This review summarizes experiences with local approaches to the molecular testing of thyroid FNA, highlighting the role of the modern interventional cytopathologist.
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(This article belongs to the Special Issue Selected Highlights of the 9th Molecular Cytopathology Meeting)
Open AccessArticle
Prognostic Significance of JMJD3 Expression in Pleural Mesotheliomas
J. Mol. Pathol. 2021, 2(3), 223-232; https://doi.org/10.3390/jmp2030019 - 03 Jul 2021
Abstract
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Pleural mesothelioma is a disease associated with asbestos exposure and patients often have poor prognosis. Biomarkers that can stratify tumours more efficiently are much sought after to enable more personalized treatment options and predict prognosis. Jumonji domain-containing protein D3 (JMJD3) has variable expression
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Pleural mesothelioma is a disease associated with asbestos exposure and patients often have poor prognosis. Biomarkers that can stratify tumours more efficiently are much sought after to enable more personalized treatment options and predict prognosis. Jumonji domain-containing protein D3 (JMJD3) has variable expression in a range of tumours. However, there has been much discordance in the immunohistochemical labelling of JMJD3 between cancers at different sites and ambiguity exists regarding its functional significance. Recent evidence suggests that although nuclear expression of JMJD3 has a demethylase role in most cancers, there are also demethylase-independent actions of JMJD3 that need to be explored including its cytoplasmic expression. We analysed JMJD3 labelling in 99 pleural mesothelioma tissues and correlated nuclear and cytoplasmic expression with survival outcomes. We found that low nuclear and high cytoplasmic expression were associated with poor survival outcomes in our cohort (p = 0.014 and p = 0.041, respectively). Additionally, we found that low nuclear expression of JMJD3 was frequent in the sarcomatoid subtype (p < 0.001). Finally, we showed that cytoplasmic labelling is an independent prognostic marker of poor survival. Our cohort only contained a small number of tumours with high cytoplasmic expression of JMJD3, and a larger cohort study may provide clearer stratification.
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