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Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 36265

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Dr. Moira Ragazzi

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Arcispedale Santa Maria Nuova—IRCCS, Reggio Emilia, Italy
Interests: breast cancer; thyroid cancer; fluorescence confocal microscopy; brain neoplasms; DNA mutations; immunohistochemistry
Special Issues, Collections and Topics in MDPI journals

Dr. Dario De Biase

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Co-Guest Editor

Department of Pharmacy and Biotechnology, University of Bologna, Viale Ercolani 4/2, S. Orsola Hospital, Bologna, Italy
Interests: next-generation sequencing; predictive markers in solid tumors; molecular pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular-tissue-based biomarkers are currently a fundamental part of cancer diagnosis. They may play a diagnostic role, as in the case of tumors of the central nervous system that are currently classified based on the presence of key genetic alterations according to the updated 4th edition of the World Health Organization’s Classification of Tumors of the Central Nervous System (WHO 2016). Molecular biomarkers may also have prognostic significance; examples include ki67 in neuroendocrine tumors and breast carcinoma, BRAF alterations, and Microsatellite Instability in colorectal cancer. Finally, they may have predictive value, guiding the clinical therapeutic choice, as in the case of hormone receptor expression and HER2 status in breast carcinoma or EGFR mutations and ALK rearrangements in non-small-cell lung cancer.

Our knowledge and the correct management of these biomarkers are the basis for good clinical practice. At the same time, it would be highly desirable to discover new markers that may be potential targets for therapy in order to improve cancer patients‘ care.

Our understanding of the different biomarkers in solid tumors has progressed significantly in recent years, bringing about a lot of benefits in this respect. However, continuous research is necessary in this field in order to provide better and more appropriate diagnosis and novel therapeutic approaches.

This Special Issue aims to present a collection of primary research and review articles that summarize the state of the art, deal with open questions, describe problems and solutions regarding the management and interpretation of currently available tests, and/or provide new insights into tissue-based biomarkers and their potential role in solid tumors.

Dr. Moira Ragazzi
Dr. Dario de Biase
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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

tissue-based biomarkers
immunomarkers
tumor markers
driving mutations
breast carcinomas
brain tumors
lung tumors
pancreatic tumors
thyroid tumors
colorectal carcinomas
melanoma
solid tumors
molecular techniques for solid tumors.

Published Papers (11 papers)

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Research

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13 pages, 2152 KiB

Open AccessCommunication

Imbalance of Mg Homeostasis as a Potential Biomarker in Colon Cancer

by Davide Schiroli, Chiara Marraccini, Eleonora Zanetti, Moira Ragazzi, Alessandra Gianoncelli, Eleonora Quartieri, Elisa Gasparini, Stefano Iotti, Roberto Baricchi and Lucia Merolle

Diagnostics 2021, 11(4), 727; https://doi.org/10.3390/diagnostics11040727 - 20 Apr 2021

Cited by 5 | Viewed by 1913

Abstract

Background: Increasing evidences support a correlation between magnesium (Mg) homeostasis and colorectal cancer (CRC). Nevertheless, the role of Mg and its transporters as diagnostic markers in CRC is still a matter of debate. In this study we combined X-ray Fluorescence Microscopy and databases information to investigate the possible correlation between Mg imbalance and CRC. Methods: CRC tissue samples and their non-tumoural counterpart from four patients were collected and analysed for total Mg level and distribution by X-Ray Fluorescence Microscopy. We also reviewed the scientific literature and the main tissue expression databases to collect data on Mg transporters expression in CRC. Results: We found a significantly higher content of total Mg in CRC samples when compared to non-tumoural tissues. Mg distribution was also impaired in CRC. Conversely, we evidenced an uncertain correlation between Mg transporters expression and colon malignancies. Discussion: Although further studies are necessary to determine the correlation between different cancer types and stages, this is the first report proposing the measurement of Mg tissue localisation as a marker in CRC. This study represents thus a proof-of-concept that paves the way for the design of a larger prospective investigation of Mg in CRC. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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16 pages, 1931 KiB

Open AccessArticle

GATA3 as an Adjunct Prognostic Factor in Breast Cancer Patients with Less Aggressive Disease: A Study with a Review of the Literature

by Patrizia Querzoli, Massimo Pedriali, Rosa Rinaldi, Paola Secchiero, Paolo Giorgi Rossi and Elisabetta Kuhn

Diagnostics 2021, 11(4), 604; https://doi.org/10.3390/diagnostics11040604 - 28 Mar 2021

Cited by 11 | Viewed by 2623

Abstract

Background: GATA binding protein 3 (GATA3) expression is positively correlated with estrogen receptor (ER) expression, but its prognostic value as an independent factor remains unclear. Thus, we undertook the current study to evaluate the expression of GATA3 and its prognostic value in a large series of breast carcinomas (BCs) with long-term follow-up. Methods: A total of 702 consecutive primary invasive BCs resected between 1989 and 1993 in our institution were arranged in tissue microarrays, immunostained for ER, progesterone receptor (PR), ki-67, HER2, p53, and GATA3, and scored. Clinico-pathological data were retrospectively collected. Results: GATA3 was evaluable in 608 (87%) of the 702 cases; it was positive in 413 (68%) cases and negative in 195 (32%) cases. GATA3 positivity was significantly associated with lower grade (p < 0.0001), size (p = 0.0463), stage (p = 0.0049), ER+ (p < 0.0001), PR+ (p < 0.0001), HER2− (p = 0.0175), and p53 wild-type pattern (p < 0.0001). The median follow-up was 183 months, GATA3 positivity was associated with better overall survival (HR 0.70, p = 0.001), and its prognostic value was retained in a multivariate analysis. The association with better overall survival was stronger in patients with grade 1–2, pT1–2, pN0, stage I–II, ER+, PR+, ki-67 < 20%, HER2−, a wild-type p53 immunohistochemical pattern, and in luminal B BC. Conclusions: Our findings indicate that GATA3 is a positive prognostic marker in BC patients, especially in patients with biologically less aggressive BC. Incorporating GATA3 immunohistochemistry into routine practice could help further stratify BC patients for their risk. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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10 pages, 3283 KiB

Open AccessArticle

Interpretation According to Clone-Specific PD-L1 Cutoffs Reveals Better Concordance in Muscle-Invasive Urothelial Carcinoma

by Tzu-Hao Huang, Wei Cheng and Yeh-Han Wang

Diagnostics 2021, 11(3), 448; https://doi.org/10.3390/diagnostics11030448 - 05 Mar 2021

Cited by 3 | Viewed by 1546

Abstract

Because immune checkpoint inhibitors have been approved for treating advanced urothelial carcinoma (UC), programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been widely used as companion or complementary diagnostic tests for predicting treatment outcomes. Because different clones, scoring algorithms, and cutoffs have been used for interpretation, this study investigated the variation, correlation, and concordance of four validated PD-L1 clones (SP142, SP263, 22C3, and 28-8) and proposed a practical solution for the harmonization of PD-L1 IHC. A tissue microarray, including 46 muscle-invasive UCs, was constructed for PD-L1 testing with the four clones. Tumor cell (TC) and immune cell (IC) expression was analyzed. SP142 had significantly low TC expression, whereas SP263, 22C3, and 28-8 exhibited a moderate correlation (rho ≥ 0.6), with almost perfect concordance (intraclass correlation coefficient > 0.8) in TC expression. Fair to moderate correlation and concordance were observed in IC expression in most pairwise comparisons of clones. Substantial concordance (kappa > 0.6) was noted when high PD-L1 expression was defined by applying clone-specific cutoffs to each clone. Our findings imply that a universal cutoff value is not feasible for UC; we propose that PD-L1 IHC assays for UC should be interpreted according to a clone-specific scoring algorithm and cutoff value. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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11 pages, 2510 KiB

Open AccessArticle

Distinct Somatic Alteration Features Identified by Gene Panel Sequencing in Korean Triple-Negative Breast Cancer with High Ki67 Expression

by Woo Young Sun, Jina Lee, Bong Kyun Kim, Jong Ok Kim and Joonhong Park

Diagnostics 2021, 11(3), 416; https://doi.org/10.3390/diagnostics11030416 - 01 Mar 2021

Cited by 1 | Viewed by 1971

Abstract

This study aimed to clarify the genetic difference between Korean triple-negative breast cancer (TNBC) and other breast cancer (BC) subtypes. TNBC was defined as the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) amplification. DNA panel of the Ion Torrent Oncomine Comprehensive Assay (OCA) v3 was performed to identify somatic alteration in 48 specimens. In a total of 102 alterations (37 nonsense, 35 missense, 8 frameshift and 22 amplifications), 30 nucleotide alterations (24 nonsense, 1 missense, and 5 frameshift) were newly identified. The eight most commonly altered genes were PIK3CA, TP53, ERBB2, BRCA2, FANCD2, AKT1, BRCA1, and FANCA. TNBC had significantly lower mutation frequency in PIK3CA (TNBC vs. hormone receptor-positive and HER2-negative BC [HRPBC], p = 0.009), but higher mutation frequency in TP53 (TNBC vs. HRPBC, p = 0.036; TNBC vs. hormone receptor-positive and HER2- positive BC [HHPBC], p = 0.004). TNBC showed frequently higher Ki-67 expression than any positive BC (p = 0.004) due to HRPBC (p < 0.001). TNBC with high Ki-67/unmutated PIK3CA/mutated TP53 appears at a younger age (52.2 ± 7.6 years), compared to other subtypes (63.7 ± 11.0 years). TNBC with high Ki-67/unmutated PIK3CA/mutated TP53 may be related to relatively early onset BC. These findings demonstrate the genomic heterogeneity between TNBC and other BC subtypes and could present a new approach for molecular targeted therapy in TNBC patients. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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10 pages, 1129 KiB

Open AccessArticle

PD-L1 Expression Is an Independent Marker for Lymph Node Metastasis in Middle Eastern Endometrial Cancer

by Abdul K. Siraj, Sandeep Kumar Parvathareddy, Padmanaban Annaiyappanaidu, Nabil Siraj, Maha Al-Rasheed, Ismail A. Al-Badawi, Fouad Al-Dayel and Khawla S. Al-Kuraya

Diagnostics 2021, 11(3), 394; https://doi.org/10.3390/diagnostics11030394 - 25 Feb 2021

Cited by 3 | Viewed by 1538

Abstract

Programmed death ligand 1 (PD-L1) expression in endometrial cancer (EC) tumor cells have been reported in several studies with inconsistent results. Furthermore, there is scarcity of data on the prevalence and prognostic significance of PD-L1 expression in EC from Middle Eastern ethnicity. We aimed to assess PD-L1 expression in a large cohort of Middle Eastern EC and to correlate this with clinico-pathological factors, as well as mismatch repair (MMR) protein status and patients’ outcome. PD-L1 expression was investigated using immunohistochemistry on tissue microarray in an unselected cohort of 440 EC. Kaplan–Meier and logistic regression analysis were used to compare the outcome and prognostic factors. PD-L1 expression in tumor tissue was detected in 18.9% (83/440) EC cases with no impact on survival. When stratified for MMR protein status, PD-L1 expression was similar for both MMR deficient and MMR proficient ECs. However, the expression of PD-L1 in tumor cells was significantly associated with type II (non-endometrioid) histology (p = 0.0005) and lymph node metastasis (p = 0.0172). Multivariate analysis showed PD-L1 expression to be an independent risk factor for lymph node metastasis (odds ratio: 2.94; 95% CI: 1.26–6.84; p = 0.0123). In conclusion, PD-L1 was strongly associated with non-endometrioid EC and was an independent prognostic marker of lymph node metastasis. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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11 pages, 892 KiB

Open AccessArticle

Suitability of Bronchoscopic Biopsy Tissue Samples for Next-Generation Sequencing

by Shuji Murakami, Tomoyuki Yokose, Daiji Nemoto, Masaki Suzuki, Ryou Usui, Yoshiro Nakahara, Tetsuro Kondo, Terufumi Kato and Haruhiro Saito

Diagnostics 2021, 11(3), 391; https://doi.org/10.3390/diagnostics11030391 - 25 Feb 2021

Cited by 20 | Viewed by 2644

Abstract

A sufficiently large tissue sample is required to perform next-generation sequencing (NGS) with a high success rate, but the majority of patients with advanced non-small-cell lung cancer (NSCLC) are diagnosed with small biopsy specimens. Biopsy samples were collected from 184 patients with bronchoscopically diagnosed NSCLC. The tissue surface area, tumor cell count, and tumor content rate of each biopsy sample were evaluated. The impact of the cut-off criteria for the tissue surface area (≥1 mm²) and tumor content rate (≥30%) on the success rate of the Oncomine Dx Target Test (ODxTT) was evaluated. The mean tissue surface area of the transbronchial biopsies was 1.23 ± 0.85 mm² when small endobronchial ultrasonography with a guide sheath (EBUS-GS) was used, 2.16 ± 1.49 mm² with large EBUS-GS, and 1.81 ± 0.75 mm² with endobronchial biopsy (EBB). The proportion of samples with a tissue surface area of ≥1 mm² was 48.8% for small EBUS-GS, 79.2% for large EBUS-GS, and 78.6% for EBB. Sixty-nine patients underwent ODxTT. The success rate of DNA sequencing was 84.1% and that of RNA sequencing was 92.7% over all patients. The success rate of DNA (RNA) sequencing was 57.1% (71.4%) for small EBUS-GS (n = 14), 93.4% (96.9%) for large EBUS-GS (n = 32), 62.5% (100%) for EBB (n = 8), and 100% (100%) for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (n = 15). Regardless of the device used, a tissue surface area of ≥ 1 mm² is adequate for samples to be tested with NGS. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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10 pages, 938 KiB

Open AccessArticle

IDH1 Non-Canonical Mutations and Survival in Patients with Glioma

by Enrico Franceschi, Dario De Biase, Vincenzo Di Nunno, Annalisa Pession, Alicia Tosoni, Lidia Gatto, Giovanni Tallini, Michela Visani, Raffaele Lodi, Stefania Bartolini and Alba Ariela Brandes

Diagnostics 2021, 11(2), 342; https://doi.org/10.3390/diagnostics11020342 - 19 Feb 2021

Cited by 16 | Viewed by 2197

Abstract

Background: Non-canonical mutations of the isocitrate dehydrogenase (IDH) genes have been described in about 20–25% and 5–12% of patients with WHO grade II and III gliomas, respectively. To date, the prognostic value of these rare mutations is still a topic of debate. Methods: We selected patients with WHO grade II and III gliomas and IDH1 mutations with available tissue samples for next-generation sequencing. The clinical outcomes and baseline behaviors of patients with canonical IDH1 R132H and non-canonical IDH1 mutations were compared. Results: We evaluated 433 patients harboring IDH1 mutations. Three hundred and ninety patients (90.1%) had a canonical IDH1 R132H mutation while 43 patients (9.9%) had a non-canonical IDH1 mutation. Compared to those with the IDH1 canonical mutation, patients with non-canonical mutations were younger (p < 0.001) and less frequently presented the 1p19q codeletion (p = 0.017). Multivariate analysis confirmed that the extension of surgery (p = 0.003), the presence of the 1p19q codeletion (p = 0.001), and the presence of a non-canonical mutation (p = 0.041) were variables correlated with improved overall survival. Conclusion: the presence of non-canonical IDH1 mutations could be associated with improved survival among patients with IDH1 mutated grade II–III glioma. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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15 pages, 828 KiB

Open AccessArticle

Managing Deviating EQA Results: A Survey to Assess the Corrective and Preventive Actions of Medical Laboratories Testing for Oncological Biomarkers

by Cleo Keppens, Ed Schuuring and Elisabeth MC Dequeker

Diagnostics 2020, 10(10), 837; https://doi.org/10.3390/diagnostics10100837 - 18 Oct 2020

Cited by 3 | Viewed by 2442

Abstract

Laboratories testing predictive biomarkers in lung and colorectal cancer are advised to participate in external quality assessment (EQA) schemes. This study aimed to investigate which corrective actions were taken by laboratories if predetermined performance criteria were not met, to ultimately improve current test practices. EQA participants from the European Society of Pathology between 2014 and 2018 for lung and colorectal cancer were contacted, if they had at least one analysis error or test failure in the provided cases, to complete a survey. For 72.4% of 514 deviating EQA results, an appropriate action was performed, most often including staff training (15.2%) and protocol revisions (14.6%). Main assigned persons were the molecular biologist (40.0%) and pathologist (46.5%). A change in test method or the use of complex techniques, such as next-generation sequencing, required more training and the involvement of dedicated personnel to reduce future test failures. The majority of participants adhered to ISO 15189 and implemented suitable actions by designated staff, not limited to accredited laboratories. However, for 27.6% of cases (by 20 laboratories) no corrective action was taken, especially for pre-analytic problems and complex techniques. The surveys were feasible to request information on results follow-up and further recommendations were provided. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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Review

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16 pages, 3154 KiB

Open AccessReview

What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors

by Antonio De Leo, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, Daniela Turchetti, Claudio Zamagni, Anna Myriam Perrone, Pierandrea De Iaco, Giovanni Tallini and Dario de Biase

Diagnostics 2021, 11(4), 697; https://doi.org/10.3390/diagnostics11040697 - 14 Apr 2021

Cited by 53 | Viewed by 9752

Abstract

Ovarian carcinomas represent a heterogeneous group of neoplasms consisting of separate entities with distinct risk factors, precursor lesions, pathogenesis, patterns of spread, molecular profiles, clinical course, response to chemotherapy, and outcomes. The histologic subtype and the related molecular features are essential for individualized clinical decision-making. The fifth edition of the World Health Organization classification of tumors of the female genital tract divides ovarian carcinomas into at least five main and distinct types of ovarian carcinomas: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma. Molecular pathology has improved the knowledge of genomic landscape of ovarian carcinomas identifying peculiar alterations for every histologic subtype. It is well-known that high-grade and low-grade serous carcinomas are separate entities with entirely different morphologic and molecular characteristics. TP53 and BRCA mutations are typical of high-grade serous carcinoma, whereas BRAF and KRAS mutations frequently occur in low-grade serous carcinoma. Endometrioid and clear cell carcinomas are frequently associated with endometriosis. Endometrioid tumors are characterized by β-catenin alterations, microsatellite instability, and PTEN and POLE mutations, while ARID1A mutations occur in both endometrioid and clear cell carcinomas. Mucinous carcinomas are uncommon tumors associated with copy-number loss of CDKN2A and KRAS alterations and metastasis from other sites should always be considered in the differential diagnosis. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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15 pages, 657 KiB

Open AccessReview

The Role of the Pathologist in the Next-Generation Era of Tumor Molecular Characterization

by Valentina Angerilli, Francesca Galuppini, Fabio Pagni, Nicola Fusco, Umberto Malapelle and Matteo Fassan

Diagnostics 2021, 11(2), 339; https://doi.org/10.3390/diagnostics11020339 - 18 Feb 2021

Cited by 46 | Viewed by 5107

Abstract

Current pathology practice is being shaped by the increasing complexity of modern medicine, in particular of precision oncology, and major technological advances. In the “next-generation technologies era”, the pathologist has become the person responsible for the integration and interpretation of morphologic and molecular information and for the delivery of critical answers to diagnostic, prognostic and predictive queries, acquiring a prominent position in the molecular tumor boards. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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17 pages, 3643 KiB

Open AccessReview

Immunohistochemical Biomarkers as a Surrogate of Molecular Analysis in Ovarian Carcinomas: A Review of the Literature

by Giacomo Santandrea, Simonetta Piana, Riccardo Valli, Magda Zanelli, Elisa Gasparini, Antonio De Leo, Vincenzo Dario Mandato and Andrea Palicelli

Diagnostics 2021, 11(2), 199; https://doi.org/10.3390/diagnostics11020199 - 29 Jan 2021

Cited by 23 | Viewed by 3548

Abstract

The term “ovarian carcinoma” encompasses at least five different malignant neoplasms: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, mucinous carcinoma, and clear cell carcinoma. These five histotypes demonstrated distinctive histological, molecular, and clinical features. The rise of novel target therapies and of a tailored oncological approach has demanded an integrated multidisciplinary approach in the setting of ovarian carcinoma. The need to implement a molecular-based classification in the worldwide diagnostic and therapeutic setting of ovarian cancer demanded a search for easy-to-use and cost-effective molecular-surrogate biomarkers, relying particularly on immunohistochemical analysis. The present review focuses on the role of immunohistochemistry as a surrogate of molecular analysis in the everyday diagnostic approach to ovarian carcinomas. Full article

(This article belongs to the Special Issue Tissue-Based Biomarkers of Solid Tumors in the Routine Clinical Setting)

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