Special Issue "Molecular Pathology in Solid Tumors"

A special issue of Journal of Molecular Pathology (ISSN 2673-5261).

Deadline for manuscript submissions: closed (15 October 2021).

Special Issue Editors

Dr. Umberto Malapelle
E-Mail Website
Guest Editor
Department of Public Health, University Federico II of Naples, Naples, Italy
Interests: predictive molecular pathology in solid tumors; next generation technologies in molecular biology; liquid biopsies; predictive oncology
Special Issues and Collections in MDPI journals
Prof. Dr. Claudio Bellevicine
E-Mail Website
Guest Editor
Department of Public Health, University of Naples Federico II, Naples, Italy
Interests: thyroid cytopathology; thyroid carcinoma; anatomic pathology

Special Issue Information

Dear Colleagues,

This is the era of molecular pathology. Today, any aspect of modern medicine is indissolubly related to the pleiotropic world of molecular pathology. In this very exciting scenario, one of the main aims of this new discipline is to find the right way for the right patients, starting from an integrated morpho-molecular diagnosis, through the correct biomarker evaluation for treatment patient selection. In this setting, the implementation of next-generation technologies in association with the differential management of biological samples (e.g., tissue and body fluids) has become the key weapon to improve the clinical outcome of cancer patients.

Moreover, the application of molecular tests to the cytological diagnosis of several neoplasms such as that of the thyroid gland could improve the risk stratification of patients, allowing either a surgical or medical tailored treatment.

In this Special Issue, entitled “Molecular Pathology in Solid Tumors”, we would like to discuss new insights into Molecular Pathology, useful to improve the diagnosis and treatment of solid tumors, with a focus on predictive molecular tests in lung tumors and diagnostic molecular tests in thyroid nodules. Potential topics include but are not limited to the following:

1) Biomarker discovery;

2) Precision oncology;

3) Morpho-molecular diagnosis in solid tumors;

4) Molecular tests applied to the diagnosis of thyroid neoplasms;

5) Predictive molecular pathology for target treatment patient selections;

6) Application of next-generation technologies in diagnostic and predictive molecular pathology.

The following article types will be considered: Article, Review, Opinion, Perspective.

Dr. Umberto Malapelle
Dr. Claudio Bellevicine
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Molecular Pathology is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular pathology
  • solid tumors
  • next-generation technologies, target treatment

Published Papers (10 papers)

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Research

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Article
Analysis of Copy Number Variations in Solid Tumors Using a Next Generation Sequencing Custom Panel
J. Mol. Pathol. 2021, 2(2), 123-134; https://doi.org/10.3390/jmp2020013 - 21 May 2021
Viewed by 603
Abstract
Somatic copy number variations (CNV; i.e., amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies. Although FISH is still considered the gold standard for CNV detection, the increasing [...] Read more.
Somatic copy number variations (CNV; i.e., amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies. Although FISH is still considered the gold standard for CNV detection, the increasing number of potentially druggable amplifications to be assessed makes a gene-by-gene approach time- and tissue-consuming. Here we investigated the potential of next generation sequencing (NGS) custom panels to simultaneously determine CNVs across FFPE solid tumor samples. DNA was purified from cell lines and FFPE samples and analyzed by NGS sequencing using a 20-gene custom panel in the GeneReader Platform®. CNVs were identified using an in-house algorithm based on the UMI read coverage. Retrospective validation of in-house algorithm to identify CNVs showed 97.1% concordance rate with the NGS custom panel. The prospective analysis was performed in a cohort of 243 FFPE samples from patients arriving at our hospital, which included 74 NSCLC tumors, 148 CRC tumors, and 21 other tumors. Of them, 33% presented CNVs by NGS and in 14 cases (5.9%) the CNV was the only alteration detected. We have identified CNV alterations in about one-third of our cohort, including FGFR1, CDK6, CDK4, EGFR, MET, ERBB2, BRAF, or KRAS. Our work highlights the need to include CNV testing as a part of routine NGS analysis in order to uncover clinically relevant gene amplifications that can guide the selection of therapies. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Article
Different Methods in HPV Genotyping of Anogenital and Oropharyngeal Lesions: Comparison between VisionArray® Technology, Next Generation Sequencing, and Hybrid Capture Assay
J. Mol. Pathol. 2021, 2(1), 29-41; https://doi.org/10.3390/jmp2010004 - 04 Mar 2021
Viewed by 677
Abstract
(1) Background: Human papillomaviruses (HPVs) are known to be related to the development of about 5% of all human cancers. The clinical relevance of HPV infection has been deeply investigated in carcinomas of the oropharyngeal area, uterine cervix, and anogenital area. To date, [...] Read more.
(1) Background: Human papillomaviruses (HPVs) are known to be related to the development of about 5% of all human cancers. The clinical relevance of HPV infection has been deeply investigated in carcinomas of the oropharyngeal area, uterine cervix, and anogenital area. To date, several different methods have been used for detecting HPV infection. The aim of the present study was to compare three different methods for the diagnosis of the presence of the HPV genome. (2) Methods: A total of 50 samples were analyzed. Twenty-five of them were tested using both next generation sequencing (NGS) and VisionArray® technology, the other 25 were tested using Hybrid Capture (HC) II assay and VisionArray® technology. (3) Results: A substantial agreement was obtained using NGS and VisionArray® (κ = 0.802), as well as between HC II and VisionArray® (κ = 0.606). In both analyses, the concordance increased if only high risk HPVs I(HR-HPVs) were considered as “positive”. (4) Conclusions: Our data highlighted the importance of technical choice in HPV characterization, which should be guided by the clinical aims, costs, starting material, and turnaround time for results. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Article
ROC Analysis Identifies Baseline and Dynamic NLR and dNLR Cut-Offs to Predict ICI Outcome in 402 Advanced NSCLC Patients
J. Mol. Pathol. 2020, 1(1), 19-31; https://doi.org/10.3390/jmp1010004 - 15 Sep 2020
Cited by 1 | Viewed by 1036
Abstract
Background: Neutrophil-to-Lymphocyte Ratio (NLR) and derived Neutrophils-to-(Leukocytes minus neutrophils) Ratio (dNLR) have been proposed as possible biomarkers of response to immune checkpoint inhibitors (ICI). However, in non-small cell lung cancer (NSCLC) studies, various NLR and/or dNLR cut-offs have been used, manly based on [...] Read more.
Background: Neutrophil-to-Lymphocyte Ratio (NLR) and derived Neutrophils-to-(Leukocytes minus neutrophils) Ratio (dNLR) have been proposed as possible biomarkers of response to immune checkpoint inhibitors (ICI). However, in non-small cell lung cancer (NSCLC) studies, various NLR and/or dNLR cut-offs have been used, manly based on previous reports on melanoma. Methods: In this Italian multicenter retrospective study, NLR, dNLR, platelet-to-lymphocyte ratio, albumin, and lactate dehydrogenase (LDH) were longitudinally assessed in patients with stage IV non-small cell lung cancer (NSCLC) treated with ICI. The primary objective was to evaluate if baseline parameters predicted response to ICI, using Receiver Operating Characteristic (ROC) curves. Secondary endpoint was to evaluate if dynamic changing of NLR and dNLR also predicted response. Results: Data of 402 patients were collected and analyzed. Among the baseline parameters considered, NLR and dNLR were the most appropriate biomarkers according to the ROC analyses, which also identified meaningful cut-offs (NLR = 2.46; dNLR = 1.61). Patients with low ratios reported a significantly improved outcome, in terms of overall survival (p = 0.0003 for NLR; p = 0.0002 for dNLR) and progression free survival (p = 0.0004 for NLR; p = 0.005 for dNLR). The role of NLR and dNLR as independent biomarkers of response was confirmed in the Cox regression model. When assessing NLR and dNLR dynamics from baseline to cycle 3, a decrease ≥1.04 for NLR and ≥0.41 for dNLR also predicted response. Conclusions in our cohort, we confirmed that NLR and dNLR, easily assessable on peripheral blood, can predict response at baseline and early after ICI initiation. For both baseline and dynamic assessment, we identified clinically meaningful cut-offs, using ROC curves. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Review

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Review
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
Viewed by 914
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Review
Modern Challenges for Early-Phase Clinical Trial Design and Biomarker Discovery in Metastatic Non-Small-Cell Lung Cancer
J. Mol. Pathol. 2021, 2(3), 207-222; https://doi.org/10.3390/jmp2030018 - 23 Jun 2021
Viewed by 535
Abstract
Oncology research has changed extensively due to the possibility to categorize each cancer type into smaller subgroups based on histology and particularly on different genetic alterations due to their heterogeneity. The consequences of this heterogeneity are particularly evident in the management of metastatic [...] Read more.
Oncology research has changed extensively due to the possibility to categorize each cancer type into smaller subgroups based on histology and particularly on different genetic alterations due to their heterogeneity. The consequences of this heterogeneity are particularly evident in the management of metastatic non-small-cell lung cancer (NSCLC). This review will discuss the benefits and challenges of incorporating precision medicine into early- through late-phase metastatic NSCLC clinical trials, discussing examples of drug development programs in oncogene- and non-oncogene-addicted NSCLC. The experiences of clinical development of crizotinib, gefitinib and osimertinib are depicted showing that when a targeted drug is administrated in a study population not selected by any biomarker, trials could produce negative results. However, the early detection of biomarker-driven biology helps to obtain a greater benefit for a selected population and can reduce the required time for drug approval. Early clinical development programs involving nivolumab, pembrolizumab and avelumab, immune checkpoint inhibitors, taught us that, beyond safety and activity, the optimal selection of patients should be based on pre-specified biomarkers. Overall, the identification of predictive biomarkers is one of the greatest challenges of NSCLC research that should be optimized with solid methodological trial designs to maximize the clinical outcomes. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Review
Emerging Biomarkers for the Selection of Advanced NSCLC-Affected Immunotherapy Patients
J. Mol. Pathol. 2021, 2(2), 197-206; https://doi.org/10.3390/jmp2020017 - 10 Jun 2021
Viewed by 650
Abstract
Immunotherapy in the form of ICIs has revolutionized advanced NSCLC treatment algorithms, with ICI-containing combination treatments being the latest addition to approved regimens. However, PD-L1 still represents the only routinely assessed and validated biomarker apart from genetic drivers testing, impairing our capacity to [...] Read more.
Immunotherapy in the form of ICIs has revolutionized advanced NSCLC treatment algorithms, with ICI-containing combination treatments being the latest addition to approved regimens. However, PD-L1 still represents the only routinely assessed and validated biomarker apart from genetic drivers testing, impairing our capacity to personalize and guide treatment. Therefore, this paper aims to analyze the most promising emerging predictive biomarkers that could help us in the near future to select patients more effectively. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
Review
Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma
J. Mol. Pathol. 2021, 2(2), 173-196; https://doi.org/10.3390/jmp2020016 - 04 Jun 2021
Cited by 2 | Viewed by 1021
Abstract
The molecular pathways which promote lung cancer cell features have been broadly explored, leading to significant improvement in prognostic and diagnostic strategies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment approach for patients with metastatic non-small cell [...] Read more.
The molecular pathways which promote lung cancer cell features have been broadly explored, leading to significant improvement in prognostic and diagnostic strategies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment approach for patients with metastatic non-small cell lung cancer (NSCLC). Latest investigations by using next-generation sequencing (NGS) have shown that other oncogenic driver mutations, believed mutually exclusive for decades, could coexist in EGFR-mutated NSCLC patients. However, the exact clinical and pathological role of concomitant genomic aberrations needs to be investigated. In this systematic review, we aimed to summarize the recent data on the oncogenic role of concurrent genomic alterations, by specifically evaluating the characteristics, the pathological significance, and their potential impact on the treatment approach. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Review
PIK3CA Mutation Assessment in HR+/HER2− Metastatic Breast Cancer: Overview for Oncology Clinical Practice
J. Mol. Pathol. 2021, 2(1), 42-54; https://doi.org/10.3390/jmp2010005 - 11 Mar 2021
Cited by 1 | Viewed by 843
Abstract
Activation of the PI3K–AKT–mTOR pathway occurs in several human cancers, including hormone receptor (HR)-positive breast cancer (BC) where is associated with resistance to endocrine therapy and disease progression. In BC, the most common PI3K–AKT–mTOR pathway alteration is represented by PIK3CA oncogenic mutations. These [...] Read more.
Activation of the PI3K–AKT–mTOR pathway occurs in several human cancers, including hormone receptor (HR)-positive breast cancer (BC) where is associated with resistance to endocrine therapy and disease progression. In BC, the most common PI3K–AKT–mTOR pathway alteration is represented by PIK3CA oncogenic mutations. These mutations can occur throughout several domains of the p110α catalytic subunit, but the majority are found in the helical and kinase domains (exon 9 and 20) that represent the “hotspots”. Considering the central role of the PI3K–AKT–mTOR pathway in HR-positive BC, several inhibitors (both pan-PI3K and isoform-specific) have been developed and tested in clinical trials. Recently, the PI3Kα-selective inhibitor alpelisib was the first PI3K inhibitor approved for clinical use in HR-positive metastatic BC based on the results of the phase III SOLAR-1 trial. Several methods to assess PIK3CA mutational status in tumor samples have been developed and validated, including real-time polymerase chain reaction (PCR), digital droplet PCR (ddPCR), BEAMing assays, Sanger sequencing, and next-generation sequencing (NGS) panels. Several new challenges will be expected once alpelisib is widely available in a clinical setting, including the harmonization of testing procedures for the detection of PI3K–AKT–mTOR pathway alterations. Herein, we provide an overview on PI3K–AKT–mTOR pathway alterations in HR-positive BC, discuss their role in determining prognosis and resistance to endocrine therapy and highlight practical considerations about diagnostic methods for the detection of PI3K–AKT–mTOR pathway activation status. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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Review
A Comparison Between First-, Second- and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small-Cell Lung Cancer and Brain Metastases
J. Mol. Pathol. 2021, 2(1), 1-10; https://doi.org/10.3390/jmp2010001 - 12 Jan 2021
Cited by 1 | Viewed by 1054
Abstract
Patients with non-small-cell lung cancer (NSCLC), harboring Epidermal Growth Factor Receptor (EGFR) mutations, are more susceptible to brain metastases (BM). Comparisons of the efficacy of different-generation EGFR-tyrosine kinase inhibitors (TKI) on BMs from NSCLC are currently limited. We identified studies comparing different EGFR-TKIs [...] Read more.
Patients with non-small-cell lung cancer (NSCLC), harboring Epidermal Growth Factor Receptor (EGFR) mutations, are more susceptible to brain metastases (BM). Comparisons of the efficacy of different-generation EGFR-tyrosine kinase inhibitors (TKI) on BMs from NSCLC are currently limited. We identified studies comparing different EGFR-TKIs for NSCLC through Pubmed literature search and selected those with neurological outcome data. By two retrospective analyses, Erlotinib showed longer neurological time-to-progression (30 months vs. 15.8 months, P = 0.024) and reduced the risk of central nervous system (CNS) progression (Hazard Ratio (HR) 0.25; 95% CI, 0.08–0.81; P = 0.021) compared to Gefitinib. In a phase 2b randomized trial, 16% of patients with BMs had a similar Progression Free Survival (PFS) (HR 0.76, 95% CI 0.41–1.44) or Overall Survival (OS) (HR 1.16, 95% CI 0.61–2.21) with Afatinib versus Gefitinib; a lower risk of developing subsequent BMs with Afatinib than Gefitinib (HR 0.49; 95% CI 0.34–0.71; P < 0.001) was reported by a retrospective study. A randomized phase 3 trial proved that patients with BMs treated with Osimertinib had longer PFS (HR 0.47, 95% CI 0.30–0.74) and OS (HR 0.79, 95% CI 0.61–1.01) than with Gefitinib, and lower incidence of CNS progression (6% vs. 15%, respectively). Although there is limited evidence, differences in CNS activity may exist between EGFR-TKIs. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

Other

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Opinion
Mismatch Repair Status Characterization in Oncologic Pathology: Taking Stock of the Real-World Possibilities
J. Mol. Pathol. 2021, 2(2), 93-100; https://doi.org/10.3390/jmp2020009 - 01 Apr 2021
Cited by 2 | Viewed by 937
Abstract
The mismatch repair (MMR) system has a key role in supporting the DNA polymerase proofreading function and in maintaining genome stability. Alterations in the MMR genes are driving events of tumorigenesis, tumor progression, and resistance to therapy. These genetic scars may occur in [...] Read more.
The mismatch repair (MMR) system has a key role in supporting the DNA polymerase proofreading function and in maintaining genome stability. Alterations in the MMR genes are driving events of tumorigenesis, tumor progression, and resistance to therapy. These genetic scars may occur in either hereditary or sporadic settings, with different frequencies across tumor types. Appropriate characterization of the MMR status is a crucial task in oncologic pathology because it allows for both the tailored clinical management of cancer patients and surveillance of individuals at risk. The currently available MMR testing methods have specific strengths and weaknesses, and their application across different tumor types would require a tailored approach. This article highlights the indications and challenges in MMR status assessment for molecular pathologists, focusing on the possible strategies to overcome analytical and pre-analytical issues. Full article
(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)
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