Search Results (72)

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is among the most clinically relevant and conceptually intricate precancerous lesions encountered in modern gastroenterology. First identified in the early 1980s as a “mucin-producing tumor,” IPMN has since undergone a profound redefinition: from an obscure and poorly classified entity to a well-established precursor of pancreatic ductal adenocarcinoma (PDAC), shaped by characteristic molecular alterations such as KRAS, GNAS, and RNF43 mutations. Over the past two decades, the reported incidence of IPMN has risen sharply, a trend largely attributable to the widespread use of high-resolution cross-sectional imaging rather than a genuine increase in disease prevalence. IPMNs are categorized anatomically into main-duct (MD-IPMN), branch-duct (BD-IPMN), and mixed-type forms and histologically into gastric, intestinal, pancreatobiliary, and oncocytic subtypes, each associated with distinct malignant potential and prognostic implications. International consensus guidelines (Sendai 2006; Fukuoka 2012; Fukuoka revision 2017; Kyoto 2024) have progressively refined strategies for risk stratification and surgical decision-making. Nevertheless, significant debate persists regarding optimal surveillance intervals, thresholds for resection, and the management of low-risk branch-duct lesions. This review offers a comprehensive and critically evaluated synthesis about IPMN, spanning its historical recognition, molecular pathogenesis, epidemiology, clinical manifestations, diagnostic evaluation, pathological features, differential diagnosis, surveillance paradigms, long-term complications, associated conditions, therapeutic options, and future directions. Particular attention is given to longstanding “myths” that have influenced clinical practice and to emerging “realities” grounded in contemporary molecular and clinical evidence. Our aim is to provide physicians with a clear and updated framework for navigating the complexities of IPMN management in current practice. Full article

Background/Objectives: Colorectal cancer commonly develops through an adenoma–carcinoma sequence, but the immune alterations accompanying this transition remain incompletely understood. Because we previously observed reduced γδ T cells, increased apoptosis, and frequent microsporidia infection in colorectal cancer, we investigated whether similar changes are already present in colonic adenomas. Methods: We studied 55 subjects, including 30 patients with colonic adenomas, 10 with colorectal cancer, and 15 healthy controls. Peripheral blood T-cell subsets and apoptosis were assessed by flow cytometry, tissue expression of IL-7, CD127, and CD132 was analyzed by RT-PCR, and microsporidia were detected in colonic tissues by immunofluorescence and real-time PCR. Results: γδ T cells were progressively reduced in colonic adenomas and further decreased in colorectal cancer, while apoptosis of both αβ and γδ T cells increased compared with healthy subjects. Tissue expression of CD132 was significantly downregulated in adenomas and colorectal cancer, whereas IL-7 expression was increased, particularly in adenomatous tissue, consistent with a compensatory mechanism attempting to preserve T-cell homeostasis despite reduced CD132 expression. Microsporidia prevalence rose from healthy controls to patients with colonic adenomas and colorectal cancer, and CD132 expression was more markedly reduced in microsporidia-positive colonic adenoma and cancer tissues. Conclusions: These findings indicate that altered IL-2 receptor-related signaling, γδ T-cell depletion, and increased apoptosis are already present at the adenoma stage and are associated with microsporidial infection. This pattern suggests a potential link between parasitic colonization and local immune dysfunction during colorectal tumorigenesis. Full article

This case highlights a novel genotype–phenotype correlation in the field of endocrinology. Specific endocrine and imaging assessment, in addition to next-generation sequencing (NGS), was performed on the Illumina MiSeq platform, using a TruSight One Sequencing Panel kit for genomic analysis of coding regions of 4813 genes. A 54-year-old female was confirmed with a papillary thyroid carcinoma after total thyroidectomy and underwent radioiodine ablative therapy. Three years later, a left femoral enchondroma of almost 3 cm was identified at computed tomography (CT) scan and magnetic resonance imaging (MRI). She experienced hypertension (in addition to obesity, dyslipidaemia and impaired glucose tolerance) and was later confirmed with ACTH-independent cortisol excess [lack of cortisol suppression at 1 mg dexamethasone testing of 13.9 (normal < 1.8 µg/dL)], noting bilateral adrenal tumors, of 4.7 cm (right), respectively, and of 1.6 cm (left) at CT. Right laparoscopic adrenalectomy was performed with post-operative adrenal insufficiency, requiring glucocorticoid replacement and stopping the anti-hypertensive medication. Pathology report confirmed an adrenocortical adenoma (a Ki67 proliferation index of 2%). Noting the unusual association of the mentioned conditions, NGS was performed in the peripheral blood and identified a heterozygote missense variant of the APC gene (c.5759G>A, p.Arg1920Gln), a heterozygote missense variant of the MSH6 gene (c.2092C>G, p.Gln698Glu), and an incidental additional finding: a heterozygote stop gain pathogenic variant of the CACNA1S gene (c.2707C>T, p.Arg903*). The first two are currently classified as variants of uncertain significance. Whether the co-presence of a triple mutation may change the clinical picture and the life-long outcomes across reciprocal influence is still an open matter. Further research will point out the clinical implications of this genotype–phenotype association, which, to our best knowledge, has not been previously reported. Full article

Colorectal cancer (CRC) develops through both conventional adenoma–carcinoma and serrated neoplasia pathways, yet noninvasive screening still under-detects the advanced precursor lesions that enable true cancer prevention. Stool-based screening reduces CRC mortality, but its preventive impact remains constrained by limited detection of advanced precancerous lesions (APLs), including advanced adenomas and sessile serrated lesions. Next-generation multitarget stool DNA assays (mt-sDNA; e.g., Cologuard Plus) have established high sensitivity for CRC and specificity approaching 94%, leaving improved APL detection as the principal opportunity for innovation. This review presents a consensus framework for a multi-omic stool screening paradigm that integrates host epigenetic markers (DNA methylation) with gut microbiome features using artificial intelligence (AI). Multi-omics capture complementary layers of early tumor biology: epithelial shedding and field effects reflected in host methylation signals together with luminal ecological and inflammatory changes represented by microbial features. Evidence from cross-cohort microbiome studies indicates that microbial signatures provide an additive—rather than standalone—axis of information for CRC and its precursor lesions. Because microbiome-based models are highly susceptible to batch effects arising from collection devices, extraction chemistry, sequencing platforms, and bioinformatic pipelines, practical mitigation strategies are outlined, including harmonized pre-analytics, batch-aware study design, leakage-resistant validation, and computational harmonization. A translational roadmap linking analytical validity, locked-model development, and prospective colonoscopy-verified clinical validation is proposed, aligned with TRIPOD + AI, STARD, PROBAST-AI, SPIRIT-AI, CONSORT-AI, and DECIDE-AI reporting standards. Scenario modeling using BLUE-C prevalence estimates suggests that improving APL sensitivity from approximately 43% to 55–65% at ~94% specificity could translate to detecting roughly 13–23 additional advanced precancerous lesions per 1000 individuals screened, highlighting the potential prevention impact of a multi-omic approach. This framework aims to guide developers and clinical investigators toward next-generation stool tests capable of materially improving precursor-lesion detection while maintaining clinically acceptable specificity. Full article

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies. Accumulating genetic evidence supports a multistep model of tumor progression, in which early APC loss leads to chromosomal instability and adenoma formation, followed by activating mutations in KRAS that synergize with β-catenin signaling to promote tumor growth and invasion. Among the downstream effectors of these pathways, the Notch ligand Jagged1 has emerged as a critical mediator of CRC progression and chemoresistance. Jagged1 is not only a transcriptional target of the Wnt/β-catenin axis but also undergoes proteolytic cleavage via the KRAS/ERK/ADAM17 signaling cascade, generating a nuclear Jagged1 intracellular domain (Jag1-ICD) that drives reverse signaling. This dual functionality, activating canonical Notch signaling and initiating reverse nuclear signaling, positions Jagged1 as a key oncogenic driver in CRC. In this review, we first summarize the role of Jagged1 as an integral part of canonical Notch signaling. We then focus on the non-canonical Jagged1 reverse signaling function in cancer, with a particular emphasis on CRC. We underscore the dual role of Jagged1 in tumor biology and propose that it functions as a novel oncogene within the adenoma-to-carcinoma sequence, supporting CRC development and drug resistance via non-canonical mechanisms. Full article

Sessile serrated lesions (SSLs) are well-known precursors of colorectal cancer in the general population, but their role in inflammatory bowel disease (IBD) is less clear. This narrative review summarizes what is known about the prevalence, molecular features, endoscopic detection, malignant potential, and management of SSLs in patients with IBD, highlighting where evidence supports action nowadays and where prospective studies are urgently needed. IBD-associated colorectal cancer has long been considered a consequence of the inflammation–dysplasia–carcinoma sequence, distinct from the conventional adenoma–carcinoma pathway. Increasing evidence, however, suggests that the serrated pathway, typically characterized by SSLs and traditional serrated adenomas (TSAs), may also contribute to IBD-related oncogenesis. This review synthesizes histopathological, molecular, endoscopic, and clinical data on SSLs in patients with IBD, with contextual reference to TSAs, sessile serrated lesions with dysplasia, and serrated epithelial change only when relevant to their interpretation or risk stratification. SSLs are now more frequently identified in IBD surveillance, especially in ulcerative colitis and the proximal colon, although prevalence estimates remain heterogeneous due to evolving definitions and significant interobserver variability. Molecular studies indicate that IBD-associated serrated lesions often harbor BRAF mutations but display a lower CpG island methylator phenotype than their sporadic counterparts, suggesting an inflammation-modified biology. While most hyperplastic polyps and non-dysplastic SSLs appear to pose limited neoplastic risk, dysplastic serrated lesions carry a markedly higher likelihood of synchronous or metachronous advanced neoplasia. Advances in high-definition endoscopy and chromoendoscopy improve the detection of these subtle, mucus-capped, flat lesions, while endoscopic resection is nowadays feasible in expert hands. Future priorities should include prospective multicenter cohorts integrating molecular profiling to refine surveillance strategies. Full article

Genomic studies have provided key insights into the molecular pathogenesis of differentiated thyroid carcinoma (DTC), including the role of genes involved in the homologous recombination (HR) related to DNA repair and genomic stability. This research aimed to investigate the genetic landscape of HR genes in thyroid pathology, associated with recurrence risk and clinical prognosis. The study involved six individuals with thyroid conditions, including two patients diagnosed with papillary thyroid carcinoma (PTC) and four individuals with benign thyroid disease. The research material consisted of tumor samples collected during surgical procedures. Protein interactions were analyzed using the STRING database (string-db.org). Homologous recombination genes were sequenced using the HRR Panel vr1.0 on the MiSeq™ Sequencing System. Bioinformatics analysis revealed a relationship between BRAF mutations and HR gene defects in PTC. Mutations in BRCA1, BRCA2, and FANCA genes, typically associated with thyroid tumors, were identified in the tissue of papillary thyroid cancer (PTC). A statistically significant correlation was found between the FANCA gene mutation (rs7195066) and the recurrent course of the PTC. The preliminary findings suggest a potential role for non-pathogenic BARD1 mutations in follicular adenoma. No significant association was found between genes involved in homologous recombination repair and the incidence of papillary thyroid carcinoma, suggesting that these genes may not play a major role in the development of this type of thyroid cancer. Full article

Fusobacterium nucleatum (Fn) has been increasingly recognized as a crucial mediator of colorectal cancer (CRC) biology, particularly in microsatellite-stable (MSS) tumors, where immune checkpoint inhibitors (ICIs) have shown limited efficacy. Rather than representing a passive microbial passenger, Fn actively shapes tumor behavior by adhering to epithelial cells, activating oncogenic signaling, and promoting epithelial–mesenchymal transition (EMT). At the same time, it remodels the tumor microenvironment, driving immune suppression through inhibitory receptor engagement, accumulation of myeloid-derived cells, and metabolic reprogramming of tumor-associated macrophages. These mechanisms converge to impair cytotoxic immunity and contribute to both intrinsic and acquired resistance to ICIs. Beyond immune escape, Fn interferes with conventional chemotherapy by sustaining autophagy and blocking ferroptosis, thereby linking microbial colonization to multidrug resistance. Most of these mechanisms derive from preclinical in vitro and in vivo models, where causal relationships can be inferred. In contrast, human data are mainly observational and provide correlative evidence without proving causality. No interventional clinical studies directly targeting Fn have yet been conducted. Its enrichment across the adenoma–carcinoma sequence and consistent detection in both tumor and fecal samples highlight its potential as a biomarker for early detection and patient stratification. Importantly, multidimensional stool assays that integrate microbial, genetic, and epigenetic markers are emerging as promising non-invasive tools for CRC screening. Therapeutic strategies targeting Fn are also under exploration, ranging from antibiotics and bacteriophages to multifunctional nanodrugs, dietary modulation, and natural microbiota-derived products. These approaches may not only reduce microbial burden but also restore immune competence and enhance the efficacy of immunotherapy in MSS CRC. Altogether, current evidence positions Fn at the intersection of microbial dysbiosis, tumor progression, and therapy resistance. A deeper understanding of its pathogenic role may support the integration of microbial profiling into precision oncology frameworks, paving the way for innovative diagnostic and therapeutic strategies in CRC. Full article

Background/Objectives: The Wnt signaling pathway is pivotal in the adenoma–carcinoma sequence; however, its role in small bowel adenocarcinoma (SBA) remains insufficiently characterized. We analyzed the clinicopathological significance of Wnt pathway-related gene mutations and the expression of downstream or associated proteins in SBA. Methods: Immunohistochemical staining for β-catenin, cyclin D1, c-Myc, E-cadherin, and Wnt5a was performed in 75 primary SBA surgical specimens. Targeted next-generation sequencing was conducted in 48 of these cases. Results: The genomic alterations in the Wnt pathway were identified as APC (14.6%) and CTNNB1 (8.3%), with no overlap between the two mutations. Aberrant (reduced membranous and/or nuclear) expression of β-catenin was observed in 37% of cases. Cyclin D1 and c-Myc were expressed in 60% and 41% of cases, respectively. Aberrant expression of β-catenin and/or Wnt5a was present in 60% of cases and was correlated with cyclin D1 and c-Myc expression. Mutations in APC and CTNNB1 were found in intestinal- and gastrointestinal-type SBAs, but were absent in gastric-type SBA. In intestinal-type SBA, the mutation frequency of APC and CTNNB1 was 39%, closely aligning with the 45% aberrant expression of β-catenin. Aberrant expression of β-catenin and/or Wnt5a, a ligand of the noncanonical Wnt pathway, was detected in 60% of cases and showed a correlation with both cyclin D1 and c-Myc expression. Conclusions: These findings suggest that both canonical and noncanonical Wnt pathway-related proteins are involved in SBA carcinogenesis and progression. Notably, the canonical Wnt pathway appears to play a predominant role in intestinal-type SBA. Full article

Accounting for 15–30% of colorectal cancer cases, the serrated pathway remains poorly characterized compared to the adenoma–carcinoma sequence. It involves sessile serrated lesions as precursors and is characterized by BRAF mutations (BRAF^V600E), CpG island hypermethylation, and microsatellite instability (MSI). Using label-free proteomics, we compared normal tissue margins from patients with diverticular disease, sessile serrated lesions, low-grade adenomas, and high-grade adenomas. We identified S100A14 as significantly overexpressed in sessile serrated lesions compared to low-grade adenomas, high-grade adenomas, and normal tissues. This overexpression was confirmed by immunohistochemical scoring in an independent cohort. Gene expression analyses of public datasets showed higher S100A14 expression in BRAF^V600E-mutated and MSI-H colorectal cancers compared to microsatellite stable BRAF^wt tumors. This finding was confirmed by immunohistochemical scoring in an independent colorectal cancer cohort. Furthermore, single-cell RNA sequencing analysis from the Human Colon Cancer Atlas revealed that S100A14 expression in tumor cells positively correlated with the abundance of tumoral CD8⁺ cytotoxic T cells, particularly the CD8⁺ CXCL13⁺ subset, known for its association with a favorable response to immunotherapy. Collectively, our results demonstrate for the first time that S100A14 is a potential biomarker of serrated neoplasia and further suggests its potential role in predicting immunotherapy responses in colorectal cancer. Full article

Background/Objectives: The methylation of the hypermethylated oncological region (THOR) of human telomerase reverse transcriptase (hTERT) may forecast tumour aggressiveness. This pilot study aimed to evaluate THOR methylation as a potential biomarker for recurrence/malignant transformation in salivary gland pleomorphic adenomas (PA). Methods: THOR methylation was assessed by quantitative pyrosequencing in 96 parotid tissue samples (benign and malignant), including non-neoplastic parotid tissue, PA, recurrent PA (rPA), and carcinomas, along with their adjacent tissues. TERT promoter mutations (TPMs) were analysed by Sanger sequencing. Results: THOR methylation significantly differed across the seven groups. Malignant tissues showed higher THOR methylation than non-neoplastic tissues, whereas benign tumours showed no significant difference from non-neoplastic tissue. THOR methylation in rPA was closer to carcinoma than to normal tissue, similar in rPA and tissues adjacent to rPA, and higher in tissues adjacent to carcinomas than in non-neoplastic tissues. A subset of PA-adjacent tissues showed epigenetic alterations, suggesting an increased risk of recurrence or malignant transformation (5–15%). No TPMs were detected. Conclusions: THOR methylation may add information to differentiate normal from carcinogenic tissues and, as such, may be included in a biomarkers panel. Epigenetic alterations in PA-adjacent tissues with normal histology highlight the need for improved diagnostic markers. Full article

Background and Clinical Significance: The concurrent presence of a thyrotropin-secreting hypophyseal adenoma (TSHoma) with a thyroid malignancy, such as papillary thyroid carcinoma (PTC), is exceptionally rare and significantly complicates clinical diagnosis and management. This rare combination raises difficult decisions regarding the treatment sequence and carries the risk of exacerbating either or both conditions. Case report: We present the case of a 59-year-old female patient exhibiting persistent hyperthyroid symptoms with unusually normal TSH levels despite elevated thyroid hormone concentrations. Initial diagnostic imaging revealed a hypophyseal macroadenoma and a diffuse nodular goiter. After the macroadenoma diagnosis, the patient initially refused surgical intervention, and subsequent dopamine agonist therapy proved ineffective. Eight years later, during a routine follow-up, a thyroid ultrasound revealed a diffuse nodular goiter classified as EU-TIRADS 5, and papillary thyroid carcinoma was confirmed through fine needle aspiration biopsy. A total thyroidectomy and subsequent radioactive iodine therapy were performed. However, persistently elevated postoperative TSH levels remained despite high-dose levothyroxine therapy. Due to the increased risk of malignancy recurrence associated with elevated TSH levels, the patient consented to macroadenoma surgery. A successful transsphenoidal macroadenomectomy stabilized the patient’s condition, allowing for the normalization of TSH levels. Conclusions: This case underscores the importance of accurate differential diagnosis and highlights the challenges in managing TSH levels in patients with coexisting thyroid malignancies. With there being no clear guidelines for managing the combination of these conditions, decisions regarding treatment priority should consider the patient’s preferences, the risk of malignancy recurrence or progression, neurological symptoms, and the aggressiveness of the thyroid tumor. Full article

Ampullary adenomas are rare outgrowths at the ampulla of Vater that may progress into cancer via the adenoma-to-carcinoma sequence, particularly in individuals with hereditary polyposis syndrome. Many are diagnosed incidentally or once the lesion becomes large enough to cause obstruction. Traditionally managed surgically with high morbidity and mortality, advances in imaging and therapy have made endoscopic ampullectomy the first-line treatment for noninvasive lesions. Despite its high success rate and favorable safety profile, complications such as pancreatitis, ductal stenosis, bleeding, recurrence, and perforation can occur. Recommendations for optimal endoscopic techniques and surveillance intervals are largely based on expert opinion in interventional endoscopy and findings from small-scale studies. This review provides an updated framework for the diagnosis and management of ampullary adenomas. Full article

Background: While intratumoral microbiota have been identified in various cancers, their presence and clinical significance in lacrimal gland tumors remain largely unexplored. This study investigates the existence, composition, and potential clinical significance of intratumoral bacteria in lacrimal gland tumors. Methods: High-throughput 16S rDNA sequencing was performed on tumor DNA extracted from 89 paraffin-embedded tissues from patients with lacrimal gland tumors. Diversity analysis and LEfSe differential analysis were conducted to identify tumor-type-specific bacterial taxa. LASSO regression and the Cox proportional hazards models were used to analyze the relationship between intratumoral microbiota and prognosis. Results: Significant differences in the β diversity of intratumoral microbiota were observed across adenoid cystic carcinoma (ACC), carcinoma ex pleomorphic adenoma (CXPA), pleomorphic adenoma (PA), and IgG4-related disease (IgG4-RD) patients. After FDR correction, Garicola, Prevotella, Polaribacter, and Helicobacter were notably enriched in the tumors of ACC, CXPA, PA, and IgG4-RD patients, respectively. Importantly, patients with malignant lacrimal gland tumors who experienced relapse, distant metastasis, or death had significantly higher α diversity within their tumors. Furthermore, specific genera, such as Roseburia and Alloprevotella, were particularly associated with poorer prognosis in patients with malignant lacrimal gland tumors. Conclusions: This study provides a comprehensive analysis of microbial profiles in lacrimal gland tumors, highlighting distinct microbial characteristics across tumor types. Our findings suggest that intratumoral bacterial diversity and specific genera may serve as potential prognostic markers for malignant lacrimal gland tumors. Full article

Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations—one germline and one somatic—and analyze the broader prevalence and significance of FLCN in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline FLCN mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic FLCN inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic FLCN mutation in an oncocytic poorly differentiated thyroid carcinoma, which exhibited extensive angioinvasion, high proliferative activity, and concurrent TP53 and RB1 mutations. The tumor progressed with metastatic disease despite multimodal treatment. Thyroid carcinomas revealed FLCN alterations in 1.1% of cases. Pathogenic mutations were rare but associated with oncocytic morphology, while homozygous deletions occurred more frequently in genomically unstable tumors, including anaplastic thyroid carcinoma. These findings suggest FLCN mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of FLCN coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including FLCN in genetic testing could improve tumor detection and characterization, particularly in BHD patients who may benefit from routine thyroid screening. Further studies are needed to clarify FLCN’s role in thyroid cancer pathogenesis. Full article