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Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors

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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 (28 February 2026) | Viewed by 14838

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Dr. Maurizio Martini

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Department of Human Pathology of Adults and Developmental Age “Gaetano Barresi,” Division of Pathology, University of Messina, 98125 Messina, Italy
Interests: hematopathology; glial and central nervous system cancer; gastrointestinal tumor; lung cancer; thyroid cancer; genitourinary cancer
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Special Issue Information

Dear Colleagues,

The Special Issue focuses on the latest developments in molecular pathology and imaging technologies and their application in precision oncology. Modern cancer diagnosis and treatment planning increasingly rely on a multi-faceted approach that integrates traditional histopathology with a deeper understanding of molecular biomarkers and advanced imaging techniques. This approach allows for a more detailed classification of tumors and the development of personalized treatment strategies. The Special Issue aims to bring together cutting-edge research on new methods for tumor classification, predictive biomarker evaluation, and the use of digital pathology and artificial intelligence in cancer diagnosis and treatment. We invite submissions on a wide range of topics, including the use of multi-omics data, advanced imaging modalities, and the intersection of these technologies to improve diagnostic accuracy, predict treatment response, and monitor disease progression.

Dr. Maurizio Martini
Guest Editor

Gabriele Ricciardi
Guest Editor Assistant

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 submissions that pass pre-check are 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 250 words) can be sent to the Editorial Office for assessment.

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. Diagnostics is an international peer-reviewed open access semimonthly 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 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

molecular pathology
molecular imaging
precision oncology
biomarkers
digital pathology
artificial intelligence

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Published Papers (8 papers)

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Research

Jump to: Review, Other

21 pages, 14084 KB

Open AccessArticle

Integrative Bulk and Single-Nucleus Analyses Nominate COL5A2 as a CAF/ECM-Associated Marker Associated with PDAC Progression

by Kuan-Ting Lu, Tsung-Ming Chang, Chi-Jen Chang and Ju-Fang Liu

Diagnostics 2026, 16(8), 1205; https://doi.org/10.3390/diagnostics16081205 - 17 Apr 2026

Viewed by 193

Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic microenvironment; however, reproducible stromal-associated biomarkers linked to disease progression remain limited. This study therefore aimed to identify and validate a biologically relevant stromal/extracellular matrix (ECM)-associated candidate biomarker for PDAC. Methods: Three GEO bulk transcriptomic PDAC cohorts (GSE15471, GSE16515, and GSE62452) were integrated for differential expression, functional enrichment, protein–protein interaction, and hub-gene analyses. Candidates identified as a promising biomarker were further evaluated using the following: public proteomic and survival resources; head-to-head receiver operating characteristic (ROC) comparisons against COL1A1, COL3A1, and COL5A1; a progression cohort (GSE43288); and single-nucleus RNA sequencing data (GSE202051). Results: Among 206 shared differentially expressed genes, COL5A2 was the only consensus hub retained across multiple network-ranking methods. COL5A2 protein expression was found to be elevated in tumor tissue and associated with worse overall and disease-free survival. In ROC analyses, COL5A2 exhibited stable tumor-versus-non-tumor discrimination across GSE15471, GSE16515, and GSE62452 (AUC = 0.932, 0.760, and 0.782, respectively) and significantly outperformed COL3A1 in two cohorts. In GSE43288, COL5A2 expression increased along the normal–pancreatic intraepithelial neoplasia–PDAC axis and remained positively associated with ECM and cancer-associated fibroblast (CAF) signature scores after adjustment for disease group. Reanalysis of GSE202051 restricted to the original 18 untreated PDAC specimens revealed that COL5A2 expression was concentrated in fibroblast-lineage compartments, with CAFs accounting for the largest overall contribution and myCAFs demonstrating the strongest per-specimen expression enrichment. Conclusions: COL5A2 is a reproducible stromal/ECM-associated candidate biomarker linked to PDAC progression, with predominant expression in fibroblast/CAF compartments. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

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21 pages, 78949 KB

Open AccessEditor’s ChoiceArticle

FGF2 as a Potential Tumor Suppressor in Lung Adenocarcinoma

by Shih-Sen Lin, Hsin-Ying Lu, Tsung-Ming Chang, Ying-Sui Sun and Ju-Fang Liu

Diagnostics 2026, 16(2), 250; https://doi.org/10.3390/diagnostics16020250 - 13 Jan 2026

Viewed by 722

Abstract

Background/Objectives: Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer (NSCLC), is frequently diagnosed at advanced stages with distant metastasis, underscoring the need for effective prognostic biomarkers. Fibroblast growth factor 2 (FGF2), a multifunctional regulator, has shown to play contradictory roles in cancer progression. Methods: We analyzed three independent Gene Expression Omnibus (GEO) datasets (GSE19804, GSE18842, and GSE19188) to identify consistently dysregulated genes in LUAD. Functional enrichment (GO, KEGG, and cancer hallmark analysis), protein–protein interaction (PPI) network construction, and hub gene prioritization were performed using public bioinformatic tools. Survival analyses were conducted via the Kaplan–Meier Plotter. The expression of FGF2 was validated across multiple platforms, including TCGA, CPTAC, TNMplot, LCE, and the Human Protein Atlas. Functional assays (Transwell migration and wound healing) demonstrated that exogenous FGF2 significantly suppressed LUAD cell motility in vitro. Results: A total of 949 differentially expressed genes (DEGs) were commonly identified across datasets, with enrichment in cell adhesion and metastasis-related pathways. Among the 11 hub genes identified, FGF2 was consistently downregulated in LUAD tissues across all datasets and stages. Higher FGF2 expression was associated with longer overall and progression-free survival. In vitro, FGF2 treatment significantly suppressed the migration and wound healing abilities of LUAD cell lines. Conclusions: FGF2 is downregulated in LUAD and inversely associated with metastatic progression and poor prognosis. The observed reduction in cancer cell motility upon FGF2 treatment in vitro, together with its expression pattern, supports a potential tumor-suppressive role and suggests that FGF2 may serve as a candidate non-invasive biomarker for monitoring LUAD metastasis. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

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Review

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15 pages, 476 KB

Open AccessReview

The Value of Circulating Tumor HPV DNA in Head and Neck Squamous Cell Cancer: A Review

by Rüveyda Dok, Sandra Nuyts, Fernando Lopez, Carol Bradford, Arlene A. Forastiere, Primož Strojan, Abbas Agaimy, Göran Stenman, Fernanda V. Mariano, Ilmo Leivo, Karthik N. Rao, Michelle Williams, Avraham Eisbruch, Nabil F. Saba and Alfio Ferlito

Diagnostics 2025, 15(21), 2708; https://doi.org/10.3390/diagnostics15212708 - 26 Oct 2025

Cited by 1 | Viewed by 3298

Abstract

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) represent a distinct subgroup of head and neck squamous cell carcinoma (HNSCC) characterized by better prognosis and increased radiosensitivity compared to HPV-negative OPSCC. However, current diagnostic and monitoring methods, including tissue biopsies and imaging, are insufficient for precise risk stratification and early detection of recurrence, leading to challenges in treatment de-escalation and surveillance strategies. Circulating tumor HPV DNA (ctHPV-DNA) has emerged as a promising minimally invasive biomarker that offers tumor-specific detection and monitoring capabilities, potentially transforming the management of HPV-related OPSCC through early disease detection, treatment response assessment, recurrence surveillance stratification, and disease monitoring. Despite encouraging results from early clinical studies, current use is limited to trial settings. Large-scale prospective studies are needed to validate its clinical utility and determine whether early ctHPV-DNA testing can improve patient outcome while reducing treatment related morbidity. This review outlines the biological rationale, technological approaches, and current clinical evidence for ctHPV-DNA in HPV-related OPSCC, emphasizing its potential role in treatment monitoring and surveillance. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

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22 pages, 384 KB

Open AccessReview

Molecular Diagnostics and Personalized Therapeutics in Differentiated Thyroid Carcinoma: A Clinically Oriented Review

by Andrés Coca-Pelaz, Juan Pablo Rodrigo, Mark Zafereo, Iain Nixon, Pia Pace-Asciak, Gregory W. Randolph, Carlos Suárez and Alfio Ferlito

Diagnostics 2025, 15(19), 2493; https://doi.org/10.3390/diagnostics15192493 - 30 Sep 2025

Cited by 2 | Viewed by 3092

Abstract

Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy and typically has a favorable prognosis. However, a subset of patients experience aggressive disease, recurrence, or treatment resistance, underscoring the need for more precise diagnostic and therapeutic strategies. Advances in molecular profiling have improved the management of thyroid cancer by enabling risk-adapted treatment and targeted interventions. This narrative review offers a clinically focused synthesis of the current role of molecular diagnostics and personalized therapeutics in DTC. We examine key genetic alterations and their diagnostic, prognostic, and therapeutic implications, and discuss how molecular markers enhance traditional risk stratification systems, informing surgical decisions, radioactive iodine (RAI) use, and surveillance. The growing role of targeted therapies, such as tyrosine kinase inhibitors and agents against specific oncogenic drivers, is reviewed, particularly for RAI-refractory DTC. We also address real-world challenges in implementing precision medicine, including access, cost, and standardization. Future directions, such as liquid biopsy, artificial intelligence, and multi-omic integration, are explored as tools to achieve fully personalized care. This review aims to bridge the gap between molecular discovery and clinical application, offering practical insights for endocrinologists, surgeons, oncologists, and multidisciplinary teams managing DTC. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

Other

Jump to: Research, Review

24 pages, 17012 KB

Open AccessSystematic Review

Prognostic Value of Primary Total Glossectomy in Tongue Cancer: A Systematic Review and Meta-Analysis of Survival Outcomes

by M. P. Sreeram, Prajwal Dange, Karthik N. Rao, Luiz P. Kowalski, Remco de Bree, Orlando Guntinas-Lichius and Alfio Ferlito

Diagnostics 2025, 15(22), 2847; https://doi.org/10.3390/diagnostics15222847 - 10 Nov 2025

Viewed by 1742

Abstract

Background/Objectives: Total glossectomy (TG) is among the most radical operations in head and neck oncology. While it can achieve local control in advanced oral tongue squamous cell carcinoma, survival and functional outcomes are inconsistently reported, and pooled estimates remain limited. This study aimed to systematically evaluate survival, functional recovery, and prognostic factors following primary TG. Methods: We conducted a proportional meta-analysis of studies reporting outcomes after primary TG for oral tongue squamous cell carcinoma. Studies combining TG with laryngectomy, salvage settings, or second primary tumors were excluded. Two reviewers independently screened, extracted data, and assessed quality with the Newcastle–Ottawa Scale. Pooled 1-, 3-, and 5-year overall survival (OS) with 95% confidence intervals (CIs) was calculated using a random-effects model. Heterogeneity was quantified (Q, τ², I²), and robustness was assessed with sensitivity analyses. Disease-free survival (DFS) and functional outcomes (swallowing, airway, speech) were narratively summarized due to inconsistent reporting. Results: Ten studies (1992–2022) comprising 261 patients met the criteria. Pooled OS was 81% (95% CI, 71–90) at 1 year, 55% (95% CI, 41–68) at 3 years, and 47% (95% CI, 27–67) at 5 years, with rising heterogeneity (I² up to 89%). The post-2000 series showed improved 5-year OS (63%). Adverse prognostic factors included advanced T stage, nodal disease (N+), and positive margins. Functional recovery varied: 15–30% remained gastrostomy-dependent and 20–25% aspirated, while reconstruction and structured rehabilitation improved outcomes. Conclusions: Survival after TG declines beyond the first year, with under half surviving at 5 years, though modern outcomes appear better. Significant functional morbidity underscores the need for multidisciplinary care. Future biomarker-driven studies should refine patient selection and prognostic assessment. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

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25 pages, 1537 KB

Open AccessSystematic Review

Bayesian Monte Carlo Simulation Based on Systematic Review for Personalized Risk Stratification of Contralateral Lymph Node Metastasis in Oral Squamous Cell Carcinoma

by Karthik N. Rao, M. P. Sreeram, Prajwal Dange, Andres Coca Pelaz, Cesare Piazza, Remco de Bree, Fernando Lopez, Orlando Guntinas-Lichius, Luiz Paulo Kowalski, Kevin T. Robbins, Primož Strojan, Carlos Suárez, Akihiro Homma, Robert Takes, Juan Pablo Rodrigo, Marc Hamoir, Avraham Eisbruch, Francisco Civantos, Anna Luíza Damaceno Araújo, Alessandra Rinaldo, Małgorzata Wierzbicka and Alfio Ferlito Show full author list Hide full author list

Diagnostics 2025, 15(21), 2668; https://doi.org/10.3390/diagnostics15212668 - 22 Oct 2025

Cited by 1 | Viewed by 1468

Abstract

Background: Contralateral lymph node metastasis (CLNM) in oral squamous cell carcinoma (OSCC) represents a major clinical challenge, in patients with a clinically contralateral node-negative neck. Individualized risk stratification is crucial to guide decisions on elective contralateral neck dissection. This study aimed to synthesize existing evidence and apply Bayesian Monte Carlo Simulation (MCS) to estimate CLNM probability across various clinic-pathological scenarios. Methods: A systematic search of PubMed, PubMed Central, and Embase (2000–2024) identified 26 eligible studies. Effect sizes for seven key risk factors—midline-crossing tumours, extranodal extension (ENE), ≥2 ipsilateral lymph nodes, depth of invasion (DOI) >10 mm, perineural invasion and lymphovascular invasion (PNI-LVI), poor differentiation, and floor of mouth subsite—were computed and incorporated into a Bayesian logistic model. Using the No-U-Turn Sampler (NUTS) in RStan, 100,000 virtual patient profiles were simulated to generate posterior probabilities of CLNM. Results: The baseline CLNM risk for lateralized tumours without additional risk factors was 4.2%. Single risk factors increased probability substantially: midline-crossing tumours (31.7%), ENE (27.4%), and ≥2 ipsilateral nodes (24.9%). Combinations of risk factors amplified the risk non-linearly: the presence of a midline-crossing tumour, ENE, and ≥2 ipsilateral nodes yielded a 76.8% CLNM probability, and the presence of all seven risk factors increased it to 93.7%. Risk tiers were classified from minimal (<20%) to very high (>50%) to guide clinical decision-making. Conclusions: This MCS-based model reveals that CLNM risk increases multiplicatively with the presence of various high-risk features. The simulation supports bilateral neck management in high-risk patients and observation in low-risk cases. Prospective validation is needed to integrate this model into routine clinical practice and to guide patient-specific surgical planning. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

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23 pages, 3084 KB

Open AccessEditor’s ChoiceSystematic Review

Patterns of Lateral Lymph Node Involvement by Neck Level in cNIb Differentiated Thyroid Carcinoma: A Systematic Review and Meta-Analysis

by Dana M. Hartl, Karthik N. Rao, Andrés Coca Pelaz, Alessandra Rinaldo, Mark E. Zafereo, Greg W. Randolph, Iain J. Nixon, Marc Hamoir, K. Thomas Robbins, Luiz P. Kowalski, Pia Pace Asciak, Badr Soudi, Juan P. Rodrigo and Alfio Ferlito

Diagnostics 2025, 15(20), 2613; https://doi.org/10.3390/diagnostics15202613 - 16 Oct 2025

Viewed by 2027

Abstract

Background/Objectives: The optimal extent of lateral lymph node dissection in cN1b differentiated thyroid cancer remains controversial. This systematic review aimed to assess the frequency of lymph node involvement across neck levels I to V. Materials and Methods: A systematic review was conducted following PRISMA guidelines. PubMed was searched for studies on lateral neck dissection in differentiated thyroid cancer. Included studies reported level-specified metastatic rates. Data on patient numbers and metastatic events were extracted. A random-effects meta-analysis with Freeman–Tukey double arcsine transformation was performed for each neck level to calculate pooled prevalence proportions and 95% confidence intervals. Heterogeneity was assessed using the I² statistic. Results: Meta-analysis of 57 studies revealed that level III (68%, 95% CI: 63–73) and level IV (66%, 95% CI: 61–70) had the highest metastatic prevalence, followed by level IIA (46%, 95% CI: 37–56). Level V demonstrated an overall prevalence of 22% (95% CI: 18–26), with sublevel VB (19%, 95% CI: 11–28) significantly higher than VA (4%, 95% CI: 1–9). Level I (6%, 95% CI: 2–11) and sublevel IIB (14%, 95% CI: 9–20) showed the lowest risk. Significant heterogeneity (I² 71–94%) was observed across all levels. Conclusions: Our findings support sparing level I, and sublevels IIB and VA during lateral neck dissection. Current guidelines recommend systematic dissection of IIA, III, IV, and VB, although VB involvement was found to be only 19% in our study. Future personalization of the extent of neck dissection, based on individual risk factors, may be key to optimizing oncologic and functional outcomes. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

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17 pages, 2174 KB

Open AccessCase Report

Fourth Ventricle Epidermoid Cyst: Case Report of Precision Telovelar Microsurgery, Functional Preservation, and Lifelong Surveillance

by Daniel Costea, Nicolaie Dobrin, Catalina-Ioana Tataru, Corneliu Toader, Răzvan-Adrian Covache-Busuioc, Matei Șerban, Octavian Munteanu and Ionut Bogdan Diaconescu

Diagnostics 2025, 15(20), 2600; https://doi.org/10.3390/diagnostics15202600 - 15 Oct 2025

Cited by 5 | Viewed by 1638

Abstract

Background and Clinical Significance: Fourth ventricular epidermoid cysts are among the least frequently encountered intracranial tumors (less than 1%). Their slow growth pattern along cisternal and subarachnoid spaces, and their close proximity to neurovascular structures (brainstem–cerebellar), create difficulty for surgical treatment. Total removal is often complicated by the capsule’s adherence to eloquent structures and requires a thoughtful surgical approach of weighing radical resection versus neurologic/function preservation. This case description provides an example of using careful clinical–radiological correlation and anatomy-dissecting microsurgery as a method of permanent decompression and neurologic recovery with low operative risk. Case Presentation: A 57-year-old female presented with impaired stability of gait, gaze-evoked nystagmus, appendicular ataxia, minimal ipsilateral hypotonia, and mild bulbar dyscoordination. Imaging (MRI, MRA) revealed a large, lobulated mass that was lobulated and avascular centered in the left cerebellar hemisphere, with an extension into the vermis and cisterna magna, and partial filling of the fourth ventricle with classic epidermoid imaging. Resection was performed via a midline suboccipital telovelar approach with microsurgery, relying on native arachnoid planes and quadrant opportunities of decompression, while preserving critical neurovascular structures. A thin rim of capsule intimately adherent to the floor of the ventricle was intentionally left to minimize irreversible cranial nerve injury. Histology showed keratinizing stratified squamous epithelium with laminated keratin and cholesterol clefts. Following resection, truncal stability, limb coordination, and ocular pursuit improved without additional deficits. Initial and 3-month postoperative MRI showed total decompression, re-established CSF pathways, and no recurrence. Conclusions: This case demonstrates that maximal safe resection (with function preservation) through natural anatomy corridors can achieve excellent neurologic results in fourth ventricular epidermoids. Lifelong MRI surveillance will be needed due to the srisk of delayed recurrence even after near-total resection. Full article

(This article belongs to the Special Issue Advances in Molecular Pathology and Imaging for Precision Diagnosis and Treatment of Tumors)

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