This article explores pigmented conjunctival lesions, emphasizing their clinical and histopathologic features. It highlights the diagnostic challenges posed by the overlapping clinical morphologies of benign, premalignant, and malignant melanocytic proliferations; biopsies of such lesions may be evaluated by dermatopathologists. This review discusses the distinct origins and molecular genetics of conjunctival melanocytic neoplasms, especially in sun-exposed areas like the bulbar conjunctiva, which share similarities with their cutaneous counterparts. Uveal melanoma, which is not the topic of this paper, is completely distinct molecular genetically and biologically. Understanding terminology used by ophthalmologists allows for more accurate communication regarding the managment and prognosis of patients with ocular melanocytic tumors.

Cutaneous vascular tumors (CVT) encompass a spectrum of benign, intermediate and malignant tumors. Classification and nomenclature of CVTs have been evolving based on emerging clinical and molecular/genetic data. Several benign and intermediate CVTs are newly identified and characterized and remain rare in the literature. Vascular tumors can be diagnostically challenging due to overlapping morphologic and immunohistochemical features, evolving terminology, and difficult to recognize vascular nature in a subset of tumors. Using an integrated approach, accurate diagnosis is feasible and essential for optimal patient management. In this review, we summarize select CVTs to update clinical, histologic, immunohistochemical, and molecular/genetic characteristics.

Anaplastic lymphoma kinase (ALK) rearrangements have emerged as a defining molecular alteration across a wide spectrum of cutaneous mesenchymal and melanocytic neoplasms with diverse clinical, histologic, immunophenotypic, and biologic features. This article describes several distinct ALK-rearranged cutaneous neoplasms: epithelioid fibrous histiocytoma, superficial ALK-rearranged myxoid spindle cell neoplasm, nonneural granular cell tumor, Spitz melanocytic neoplasms, and other emerging entities. ALK overexpression by immunohistochemistry and confirmatory molecular testing, when necessary, plays a critical diagnostic role. The expanding spectrum of ALK-rearranged cutaneous tumors underscores the value of an integrated diagnostic approach to ensure accurate diagnosis and guide clinical management.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive form of acute leukemia. BPDCN has a strong predilection for the skin and poses diagnostic challenges with clinical and histologic features that overlap with other conditions. BPDCN shows recurrent myeloid-associated mutations, complex chromosomal aberrancies, and copy-number changes with chromosomal losses involving tumor suppressors and cell cycle regulators. In patients with cutaneous BPDCN, the bone marrow frequently harbors mutationally related myeloid clones/neoplasms; BPDCN transforms from underlying premalignant hematopoietic clones with acquisition of additional progression events, and often occurs in association with ultraviolet damage in sun-exposed sites.

Neuroendocrine neoplasms are observed in multiple organs and are classified into well-differentiated neuroendocrine tumors/carcinoid or poorly differentiated high-grade neuroendocrine carcinoma. This present article aims to summarize the most important clinical, morphologic, immunohistochemical, and genetic features of skin tumors with neuroendocrine phenotype focusing on Merkel cell carcinoma, Wnt/betacatenin rosette-forming carcinoma, endocrine mucin-producing sweat gland carcinoma, and the related sweat gland carcinoma with neuroendocrine differentiation. We especially focused on diagnosis management of these tumor entities in current practice as well as differential diagnosis.

Novel fusion-associated cutaneous dermal tumors with melanocytic differentiation have recently been described, some of which demonstrate morphologic similarities to cutaneous clear cell sarcoma (CCS), Spitz tumors, or other mesenchymal neoplasms of unclear histogenesis. All of these novel fusion-associated tumors demonstrate upregulation in the microphthalmia-associated transcription factor pathway, which likely accounts for their melanocytic differentiation. Despite similarities to clear cell sarcoma (CSS), they appear to behave in a relatively more indolent fashion. This article summarizes the clinical, histologic, immunophenotypic, and molecular features of these cutaneous tumors and compares them to other diagnoses in the histologic differential. The available outcome and treatment data are summarized.

This article examines cutaneous neoplasms with NUTM1 gene fusions, focusing on poroma, porocarcinoma, and primary cutaneous NUT carcinoma. Diagnostic challenges include differentiating primary cutaneous NUT carcinoma from extracutaneous NUT carcinoma and porocarcinoma, for which immunohistochemistry (NUT, SOX10, YAP1) and molecular testing are essential.

Tumor necrosis factor alpha (TNF-α) is a pleiotropic cytokine that can both facilitate tumor progression and directly mediate tumor cell killing. This dual role creates a conundrum in which TNF can be either beneficial or detrimental for a tumor, depending on the context. Herein, we describe the history of the cytokine, the cases in which TNF-α has been considered as a cancer immunotherapy, and the toxicities that can manifest from its use. We also add context to its activity, particularly in T cells (via the engagement of TNF receptors) as well as the epigenetic and immunoregulatory pathways that are elicited. Furthermore, we highlight the fundamental differences in the transcriptional and translational regulation of this cytokine, which plays a significant role in the context of malignancy and potential success of immunotherapies. This review aims to provide insight and background on molecular switches, cellular context, and TNF receptor dynamics that determine the role of TNF-α as both tumor suppressor and promoter in different models, which is essential for deriving maximal benefit from TNF therapies.

Anti-EGFR rechallenge emerged as a potential therapeutic option for patients with chemorefractory metastatic colorectal cancer (mCRC) that maintained a circulating tumor DNA (ctDNA) RAS/BRAF wild type (WT) status. However, its efficacy compared to standard of care (SoC) in randomized controlled trials (RCTs) remains uncertain. In our systematic review and meta-analysis, we investigated the outcomes of anti-EGFR rechallenge versus SoC for patients with pretreated ctDNA RAS/BRAF WT mCRC. This study followed the PRISMA guidelines, and a systematic search of PubMed and ASCO/ESMO meeting abstracts was conducted in October 2025 for relevant RCTs. Pooled odds ratios (OR) for disease control rate (DCR) and objective response rate (ORR), and hazard ratios (HR) for survival outcomes were calculated. We identified three phase II randomized trials with 320 patients. Anti-EGFR rechallenge significantly improved DCR (OR = 3.39, 95 % CI 2.13-5.39), ORR (OR = 5.13, 95 % CI 2.30-11.41) and progression free survival (HR 0.674; 95 % CI, 0.499-0.909; p = 0.009) compared to SoC. No overall survival benefit was detected (HR 0.895; 95 % CI 0.736-1.087; p = 0.263). These findings support the use of anti-EGFR rechallenge strategy aslater-line treatment when tumor shrinkage is a clinical priority. Further evidence from prospective trials is required.

ADP-ribosylation is a versatile post-translational modification that governs fundamental processes, including DNA repair, transcription, and stress adaptation. Its homeostasis relies on the dynamic interplay between poly(ADP-ribose) polymerases (PARPs), which assemble mono- or poly-ADP-ribose (PAR) chains on target macromolecules, and ADP-ribosyl hydrolases, which dismantle them. Disruption of this balance leads to the accumulation of toxic PAR and cell death, revealing vulnerabilities that can be therapeutically exploited. PARP inhibitors (PARPis) have revolutionised the treatment of homologous recombination-deficient cancers via synthetic lethality. Yet, emerging resistance limits their long-term efficacy, underscoring the need for novel targets within ADP-ribose signalling. The poly(ADP-ribose) glycohydrolase (PARG), the principal enzyme involved in hydrolysing PAR, has emerged as a compelling candidate: its inhibition amplifies replication stress, drives mitotic catastrophe, and selectively kills cancer cells, particularly those reliant on PAR turnover for survival. Elevated PARG expression correlates with aggressive tumours and poor prognosis, positioning it as both a prognostic biomarker and therapeutic target. This review integrates recent structural and biochemical insights into PARG, highlighting the mechanisms of PAR reversal, regulatory control, and potential synthetic lethal interactions. We also discuss the discovery and development of selective PARG inhibitors, which promise to expand the therapeutic landscape, overcome PARPis resistance, and exploit vulnerabilities in replication-stressed cancers. By bridging mechanistic understanding with translational potential, targeting PARG represents a frontier in precision cancer therapy.

Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of myeloid malignancies characterized by clonality, cytopenia, bone marrow dysplasia, and a variable risk of progression to acute myeloid leukemia (AML). With few therapeutic advances beyond the introduction of hypomethylating agents twenty years ago, MDS remains associated with poor overall survival, limited curative options, and frequent relapse or resistance to available treatments. Breakthroughs in genomic and single-cell technologies have transformed our understanding of MDS pathogenesis, revealing that disease initiation and progression follow stereotyped evolutionary trajectories driven by distinct constellations of somatic mutations and modulated by both endogenous and exogenous factors. In this review, we synthesize current knowledge of the genetic landscape of MDS and dissect the clonal path of the disease from precursor states to AML transformation. We further discuss how germline predisposition, bone marrow microenvironmental remodeling, and exposure to environmental or genotoxic stressors impact the selection, expansion, and transformation potential of the hematopoietic clone. Finally, we outline how these insights have underpinned a conceptual shift toward a molecular taxonomy of myeloid neoplasms, redefining diagnostic boundaries between MDS and AML, improving prognostic stratification, and enabling a biology-driven framework for personalized treatment of MDS.

Clonal hematopoiesis (CH) is increasingly recognized not only as a predisposing factor for overt hematologic malignancies but also as a contributor to cardiovascular, metabolic, and other age-associated degenerative and inflammatory disorders. These associations likely arise from complex heterotypic interactions between clonally affected and non-clonal immune cells, leading to systemic immune dysregulation and chronic inflammation that affects multiple organ systems, most prominently the cardiovascular system. Somatic mutations typically linked to myeloid neoplasms disturb the inflammatory homeostasis of hematopoietic and immune compartments, resulting in a persistently heightened inflammatory state and exaggerated responses under stress conditions. Pattern-recognition receptors (PRRs) of the innate immune system detect pathogen- or damage-associated molecular patterns and activate supramolecular organizing centers (SMOCs) and downstream signaling cascades-including the inflammasome, myddosome, trifosome, necroptosome, and the TGF-β pathway-that drive the production of pro-inflammatory cytokines such as IL-1β, TNF-α, IFN-I, and IL-6. Recent studies have begun to elucidate the mechanisms by which CH-associated mutations confer clonal advantage and dysregulate inflammatory signaling, bridging hematologic and degenerative diseases. A better understanding of these mechanistic links may facilitate the development of targeted therapies aimed at curbing clonal evolution and mitigating inflammation-driven comorbidities. In this review, we summarize the current knowledge on CH, its impact on immune dysregulation, and emerging therapeutic opportunities.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer with a poor prognosis, and its molecular mechanisms remain unclear. Our previous research identified the signal sequence receptor subunit delta (SSR4) of the TRAP complex as a potential ESCC biomarker. The TRAP complex, composed of SSR1, SSR2, SSR3, and SSR4, is essential for protein translocation, folding, and quality control, crucial for cellular balance. While individual TRAP subunits have been studied, a comprehensive understanding of their roles in human diseases is lacking.

The study of breast cancer is complicated by the heterogeneity inherent within the disease. Numerous models have been developed to study the initiation, progression, and treatment of breast cancer. These include carcinogen induced mouse models, genetically engineered mouse models, and patient derived xenografts. The relevance of these mouse models to humans must be precisely defined for appropriate understanding of disease mechanisms to derive intervening treatments. Sequencing projects such as The Cancer Genome Atlas Project (TCGA) and Catalogue Of Somatic Mutations In Cancer (COSMIC) were pivotal developments in understanding driving events in human cancers. These studies have revealed that in addition to activation of strong oncogenes, or loss of tumor suppressors, that secondary events are necessary for tumor development and progression. These techniques should also be applied to mouse models of human breast cancer. For all the available models studied and reviewed here, whole genome sequencing (WGS) in conjunction with gene expression analysis has revealed conserved events between human and mouse model systems. This identification of conserved, critical events driving breast cancer has led to novel targets based on breast cancer subtype, ultimately resulting in new therapeutic opportunities. The combination of sequencing and choice of the appropriate mouse model can provide a powerful tool in developing appropriate pre-clinical models of breast cancer.

Acromegaly is a rare, insidious disease associated with significant morbidity and mortality usually caused by a growth hormone (GH)-secreting pituitary tumor. Somatic mutations in GNAS are common in these tumors, yet their diagnostic, prognostic, and therapeutic implications are less clear.

Keratin 6A (KRT6A) is an epithelial-specific type II keratin localized within cytoskeletal intermediate filaments and functions in cooperation with KRT16/17 to maintain epidermal homeostasis and tissue repair. Accumulating evidence highlights its multifaceted roles in cancer. Aberrant KRT6A expression promotes cell cycle progression, epithelial-mesenchymal transition, migration, and invasion, thereby driving tumor initiation and metastasis, although tumor-suppressive effects have been observed in specific contexts. Mechanistically, KRT6A regulates adhesion, cytoskeletal remodeling, and critical signaling pathways, thereby reshaping tumor immunity and metabolism to facilitate immune evasion and metabolic dysregulation. Elevated KRT6A expression is strongly associated with resistance to chemotherapy, targeted therapy, and radiotherapy. Therapeutic approaches targeting KRT6A include nucleic acid-based interventions, protein degradation strategies, inhibition of upstream regulatory pathways, and combinatorial regimens to overcome drug resistance. Clinically, KRT6A has emerged as both a diagnostic and prognostic biomarker, supporting treatment monitoring and enhancing predictive models for risk stratification and individualized outcome evaluation. Beyond oncology, mutations in KRT6A underlie pachyonychia congenita, and its dysregulation contributes to epidermal hyperproliferative disorders such as psoriasis. Overall, systematic elucidation of the structure-function-pathway-clinical axis of KRT6A offers new opportunities for precision medicine and supports its potential as a therapeutic target in cancer management.

Bladder cancer kills nearly 170,000 people worldwide each year. Over the past 4 decades, the systematic treatment of metastatic and locally advanced bladder cancer has mainly consisted of platinum-based chemotherapy. In the last 10 years, the development of next-generation sequencing have led to rapid characterization of whole-genome sequencing of bladder cancer, which gives us a better understanding of the pathogenesis of bladder cancer. Based on indications of high mutation burden, and microsatellite instability-high/deficient mismatch repair, immune checkpoint inhibitors have been studied in metastatic and locally advanced bladder cancer as well as bladder-sparing, and shows a good response in these specific indications. Besides, clinically significant expressed molecular targets are used to develop cancer targeted drugs, such as fibroblast growth factor receptor inhibitors and antibody-drug coupling agents. The exploration of molecular characteristics and subtypes of bladder cancer and the development of new drugs and treatment strategy have also stimulated more clinical studies of bladder cancer. Here, we review advances in the treatment of bladder cancer and clinical practice of next-generation sequencing, highlight important advances in immunotherapy for bladder cancer, preliminarily summarize molecular features of bladder cancer for clinical practice, and came up with direction for future treatment development.

Truncated‑cadherin (T‑cadherin) is a distinct glycosylphosphatidylinositol‑anchored atypical cadherin that differs from classical cadherins since it does not have transmembrane and intracellular domains. It primarily functions as a dual receptor, serving as a physiological receptor for low‑density lipoprotein (LDL) and a specific receptor for high‑molecular‑weight (HMW) adiponectin. Upon binding to LDL, T‑cadherin activates calcium signaling, thereby promoting cell proliferation and migration and contributing to the development of atherosclerotic plaques. Conversely, its interaction with HMW adiponectin mediates cardiovascular protective effects through various mechanisms, such as increased exosome secretion, reduced intracellular ceramide accumulation, improved insulin sensitivity and anti‑inflammatory actions. T‑cadherin is predominantly expressed in cardiovascular tissues, such as endothelial cells, smooth muscle cells, pericytes and cardiomyocytes. Genetic polymorphisms in cadherin‑13, the gene encoding T‑cadherin, are notably associated with the risk of hypertension, type 2 diabetes and end‑stage renal disease. In cancer, T‑cadherin generally has tumor‑suppressive effects, particularly in gastric, ovarian and breast cancers. This function is often compromised by promoter region hypermethylation, which leads to gene silencing and subsequently inhibits key signaling pathways, such as the PI3K/Akt, Wnt/β‑catenin and epithelial‑mesenchymal transition pathways. The present review provided a comprehensive overview of the molecular mechanisms, regulation of expression and potential clinical importance of T‑cadherin as a diagnostic biomarker and therapeutic target for cardiovascular diseases, including atherosclerosis, hypertension and heart failure, metabolic disorders, such as diabetes, and various cancers. Further research is required to fully elucidate the signal transduction pathways and competitive dynamics of T‑cadherin ligand binding.

Globally, colorectal cancer (CRC) ranks third in terms of incidence, while it is the second leading cause of cancer‑related mortality. The high incidence and mortality rates of CRC pose a considerable challenge to global human health. Currently, surgical treatment and chemotherapy, which exert unsatisfactory clinical benefits in patients with CRC, are posing major issues in clinical practice, including recurrence, drug resistance and drug toxicity. Therefore, novel treatment approaches for CRC are urgently needed. Emerging evidence has suggested that exosomes carry out a key role in the occurrence and development of CRC, thus attracting considerable attention from researchers. However, exosomes act in a source‑dependent manner as exosomes from different sources can exhibit distinct roles in the onset and progression of CRC. The present review systematically summarizes the molecular mechanisms underlying the effects of exosomes from different sources on promoting or inhibiting CRC. Additionally, the potential of exosomes in the diagnosis and treatment of CRC are also discussed, thus providing a foundation for the future application of exosomes in managing CRC.

Lung cancer remains the leading cause of cancer-related mortality worldwide, highlighting the urgent need for earlier detection within real-world screening and patient management pathways. Recent advances in multi-omics technologies have created new opportunities for identifying biomarkers associated with early-stage lung cancer, particularly in high-risk populations under clinical surveillance.