Search Results (1,550)

Objective: This study examined the frequency of entosis in solid tumors of various origins (colorectal cancer, breast cancer, and lung cancer) and its association with clinical and pathological characteristics. It also examined survival and copy number alterations (CNAs) in genes associated with stem cells. The aim was to assess the potential prognostic value of entotic events in tumors. Methods: A total of 238 patients were included: 96 with colorectal cancer (CRC), 45 with lung cancer (LC), and 97 with breast cancer (BC). Entotic cell-in-cell (CIC) structures were evaluated on hematoxylin–eosin–stained slides using Mackay’s criteria. A CIC frequency >0.1 per 20 high-power fields was considered positive. Clinicopathological parameters, overall survival (CRC), metastasis-free survival (LC and BC), and CNA profiles of stemness-related genes were analyzed. Amplifications of MAP1LC3A and other chromosomal loci were assessed. Results: CRC demonstrated the highest entosis rate, more than two-fold higher compared with BC and LC (p < 0.05). Entosis correlated with high tumor grade (G3) in CRC (p = 0.03). In LC, CIC-positive tumors were more frequent in patients with lymph-node metastases (p = 0.02), whereas in BC, the opposite trend was observed (p = 0.02). It was noted that in patients with stage III–IV LC, the frequency of entosis was significantly higher than in patients with stage I–II cancer (p = 0.03). CIC-positive status was associated with poorer overall survival in CRC (p = 0.03) and reduced metastasis-free survival in LC (p = 0.011). In breast cancer, no statistically significant survival differences were observed. Tumors harboring two or more stemness-gene amplifications showed significantly higher entosis frequency regardless of tumor site. A strong association was identified between entosis and MAP1LC3A amplification. Conclusions: Enosis is not a random morphological phenomenon but a process associated with unfavorable tumor characteristics, high malignancy, reduced survival, and amplification of stem cell-related genes. The results of this study confirm the working hypothesis that entosis may contribute to the emergence of aneuploid clones of tumor cells, including those containing amplifications of stem cell-associated genes. This positions entosis as a potential factor in tumor genetic heterogeneity, which is particularly important in the context of therapeutic selection pressure. The observed association between high entosis frequency and the presence of ≥2 stem cell gene amplifications, as well as its association with poor prognosis in colorectal and lung cancer, highlights its potential value as a prognostic indicator. Furthermore, MAP1LC3A amplification data may serve as a molecular marker of entotic activity and a potential therapeutic target. Full article

Background/Objectives: Penile squamous cell carcinoma (PSCC) is a rare malignancy with a potential major impact on survival. Prognostic assessment remains challenging, particularly in underrepresented eastern European populations, where region-specific evidence is lacking. This paper aimed to identify independent predictors of overall survival in surgically treated patients with PSCC from a Romanian high-volume tertiary center. Methods: This retrospective cohort study analyzed 60 patients who were surgically treated for PSCC between October 2020 and December 2024. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors. Results: The mean patient age was 62 ± 12 years. T-stage distribution showed 30% pT1, 35% pT2, 31.67% pT3, and 3.33% pT4, with 55% of patients presenting with nodal metastases. Univariate analyses demonstrated significant associations between lymphovascular invasion (p < 0.001), perineural invasion (p = 0.022), and positive surgical margins (p = 0.030) and risk of death. Multivariate analysis identified three independent prognostic factors: absence of histologically documented urethral invasion (HR 0.32; p = 0.027), T3–T4 disease (HR 8.26; p = 0.005 vs. T1), and N3 stage (HR 3.53; p = 0.030 vs. N0–N1). Patients without urethral invasion demonstrated significantly longer median overall survival (63 months vs. 11 months). The final three-variable prognostic model demonstrated good discrimination (C-index 0.78), providing a potential practical risk stratification tool. Conclusions: Urethral invasion, advanced T-stage, and N3 disease independently predict poor survival in surgically treated PSCC. The identification of urethral invasion as an independent prognostic factor warrants consideration in clinical practice. This is the first study of a Romanian cohort to provide critical data for risk-adapted treatment strategies in underrepresented eastern European populations. Full article

Lymph node metastasis (LNM) is one of the most powerful prognostic determinants in head and neck squamous cell carcinoma (HNSCC). The extent and pattern of nodal involvement critically influence staging accuracy, therapeutic decision-making, and patient outcomes. However, the biological and clinical implications of nodal disease remain complex and continue to evolve. We aim to synthesize current clinical and translational evidence regarding the prognostic and therapeutic impact of LNM in HNSCC and to highlight emerging trends relevant to precision staging. A narrative review was conducted through a structured literature search in PubMed and Scopus (2008–2025), with emphasis on studies published in the last five years. Meta-analyses, large cohort studies, and evidence-based guidelines addressing prognostic factors, biological mechanisms, and management strategies were critically appraised. LNM is consistently associated with reduced overall and disease-free survival across major head and neck subsites. Key independent prognostic variables include the number of metastatic nodes, extranodal extension, and involved cervical levels. Recent advances, such as refinements in the AJCC 8th edition, sentinel lymph node mapping, high-resolution imaging, and molecular profiling, have improved early detection and refined risk stratification. LNM remains central to prognostic evaluation and treatment selection in HNSCC. Integrating biological insights with molecular diagnostics and advanced imaging will be essential to achieving precision staging and individualized therapeutic strategies. Full article

Background/Objectives: Accurate preoperative prediction of cervical lymph node metastasis (LNM) in head and neck squamous cell carcinoma (HNSCC) remains a major clinical challenge. This study aimed to develop a deep learning-based whole-slide image (WSI) model and an integrated nomogram to improve individualized LNM risk stratification. Methods: A total of 355 formalin-fixed paraffin-embedded (FFPE) WSIs and 282 frozen WSIs from the TCGA-HNSC cohort, along with 329 FFPE WSIs from an external institutional cohort, were retrospectively analyzed. Tumor regions were annotated and tiled into standardized patches. A dual-stage multiple instance learning framework was applied to generate WSI-level predictions. A pathological risk score (path-score) was derived and combined with clinical variables to construct a predictive nomogram. Results: The WSI-level model outperformed patch-level classifiers, with the logistic regression-based model achieving area under the curve (AUC) values of 0.821 in the internal validation cohort and 0.730 in the external cohort. The path-score was independently associated with LNM. The integrated nomogram further improved discrimination, yielding AUCs of 0.865 and 0.786 in the internal and external cohorts, respectively. Calibration and decision curve analyses demonstrated good agreement and meaningful clinical benefit. Conclusions: This deep learning-driven pathology nomogram provides a robust and clinically applicable tool for preoperative prediction of cervical lymph node metastasis in HNSCC. Full article

Background and Clinical Significance: Bladder cancer is common, with urothelial carcinoma (UC) comprising most cases in Western countries. Metastases usually involve pelvic structures, lymph nodes, and organs such as the liver, lungs, bones, and adrenal glands. Identifying unusual metastatic sites is critical for accurate diagnosis and treatment planning. Case Presentation: A 65-year-old man with a history of high-grade (G3) UC and carcinoma in situ, previously treated with TURBT, second-look resection, and SWOG-protocol BCG, presented with a new bladder lesion (pT1). Staging CT revealed extravesical spread and a 1.5 cm pancreatic body nodule. EUS-guided biopsy confirmed metastatic UC with concordant immunohistochemistry (GATA3+), excluding primary pancreatic cancer. The patient was referred for systemic therapy with immune checkpoint inhibitors and Enfortumab Vedotin. Conclusions: This case demonstrates the rare occurrence of pancreatic metastasis from bladder UC. EUS-guided biopsy with immunohistochemistry is essential to distinguish secondary lesions from primary pancreatic tumors. Accurate diagnosis is crucial to guide systemic therapy, particularly with emerging immunotherapy and antibody–drug conjugates. Full article

Bone metastasis is a devastating complication of advanced osteotropic malignancies, notably breast, prostate, lung carcinomas, and malignant melanoma, and remains a primary driver of mortality. Historical paradigms have conceptualized skeletal dissemination almost exclusively as a hematogenous process wherein circulating tumor cells colonize receptive bone marrow niches. However, this model fails to reconcile why lymph node metastasis consistently serves as a potent predictor of bone involvement even though therapeutic lymphadenectomy rarely prevents distant spread. This discordance suggests that lymph nodes function not merely as passive reservoirs but as active ‘evolutionary gateways’ that sculpt bone-tropic metastatic clones. In this review, we introduce the Lymphatic–Bone Axis, a framework integrating lymphatic biology into models of bone metastasis. We synthesize emerging evidence elucidating how the lymph node microenvironment primes tumor cells through CCR7-CXCR4 switching, induction of osteomimicry programs, and metabolic reprogramming that favors survival within the bone marrow. We also discuss preclinical data demonstrating direct intranodal intravasation via high endothelial venules (HEVs), providing a rapid route into the systemic circulation that bypasses the thoracic duct. Beyond consolidating current knowledge, we outline a research agenda for dissecting this axis, including longitudinal single-cell transcriptomic mapping and functional assessments of lymph node-derived tumor cells. Finally, we consider translational implications, highlighting why bone-targeted agents alone may prove insufficient once cells are conditioned within lymphatic niches. By mechanistically linking lymphatic priming to skeletal colonization, this review informs the rational design of multimodal therapeutic approaches that jointly target lymphatic transit and the bone microenvironment. Full article

Background: In cancer surgery, resection of the primary tumor and regional lymph nodes (LNs) is critical. Adequate LN examination is essential to detect metastasis, which determines the cancer stage. Fluorescence emission allows for visual differentiation and rapid monitoring of LNs. Methods: Cancer tissue is stained with a fluorescent dye (indocyanine green, ICG) to identify LNs. Fluorescence is induced from the stained LNs using LED light, and a photosensor coupled with a speaker detects the fluorescence signal and triggers an audible alarm. Filters are applied to prevent false alarms. Results: Upon LN detection, an alarm is emitted from the speaker, and the results are recorded using the LED and a digital multimeter (DMM). In clinical trials, ICG is injected to induce LN fluorescence staining, followed by LED irradiation to induce the fluorescent wavelength and verify LN imaging. Discussion: In clinical trials, ICG stains both LNs and blood vessels, which may lead to false positives. To address this limitation, artificial intelligence algorithms can be trained to specifically identify LNs. Conclusions: Detection of fluorescence wavelengths via photosensors allows for rapid identification of LNs, confirmed through an audible alarm, thereby reducing surgical time. This method shows potential for broad application in cancer surgery. Full article

Background: Clear cell renal cell carcinoma (ccRCC) constitutes 75–80% of all renal cell carcinomas and exhibits aggressive behavior with high metastatic potential. Common metastatic sites include lungs, bones, lymph nodes, and liver, while urinary bladder involvement is exceedingly rare. Early detection of atypical metastases is critical for risk stratification, surgical planning, and systemic therapy selection. Methods: We report a 69-year-old male presenting with recurrent, painless gross hematuria and dysuria. Contrast-enhanced computed tomography revealed a left renal mass with bilateral pulmonary nodules, regional lymphadenopathy, and a bladder lesion. The patient underwent transurethral resection (TUR) of the bladder lesion, followed by robot-assisted left nephro-adrenalectomy with para-aortic lymphadenectomy. Histopathology and immunohistochemistry (PAX8+, CD10+, CAIX+, CK7−, GATA3−) confirmed ccRCC with synchronous bladder metastasis. Postoperatively, combined immune checkpoint inhibitor (ICI) therapy and tyrosine kinase inhibitors (TKIs) were initiated. Results: TUR provided symptomatic relief and diagnostic confirmation. Robot-assisted surgery enabled precise, oncologically safe excision of the primary tumor and regional metastases with minimal blood loss and no perioperative complications. Pathological staging was pT3aN1M1, ISUP grade 2, with lymphovascular invasion, confirming advanced disease requiring systemic therapy. Early initiation of ICI plus TKI therapy targeted residual micrometastases to potentially prolong survival. Conclusions: This case highlights the rare occurrence of ccRCC with synchronous bladder metastasis and underscores the importance of comprehensive imaging, detailed morphologic and immunohistochemical evaluation, and a multidisciplinary approach. Robot-assisted cytoreductive surgery combined with modern systemic therapy represents an effective strategy for advanced ccRCC, emphasizing the need for individualized treatment and long-term follow-up in atypical metastatic scenarios. Full article

Isolated pelvic nodal metastasis from carcinoma of unknown primary origin (CUP) is rare. Evaluation should prioritize gynecological and anorectal sites based on pelvic lymphatic drainage. Although spontaneous regression of these primary lesions is exceptional, regressed lesions can present as CUP, necessitating diagnostic caution. Here, we report the case of a 40-year-old woman with a solitary, intensely fluorodeoxyglucose F-18 avid left obturator lymph node and a subtle endocervical abnormality on pelvic magnetic resonance imaging. Loop electrosurgical excision revealed a Nabothian cyst only. Excisional nodal biopsy by polymerase chain reaction revealed metastatic squamous cell carcinoma with diffuse block-type p16 and human papillomavirus (HPV) 16. Considering the potential for a primary cervical tumor along the obturator drainage pathway, the patient underwent hysterectomy with pelvic lymph node dissection. No residual invasive carcinoma was found; however, HPV16 was detected in the cervix with a low-grade squamous intraepithelial lesion, supporting a regressed cervical focus. She received adjuvant cisplatin-based chemoradiotherapy and has remained disease-free for 56 months. This case highlights the diagnostic value of integrating lymphatic anatomy with the molecular profile of HPV. Cervical squamous cell carcinoma rarely regresses and presents solely as an isolated nodal disease. Full article

Background: Occult lymph node metastasis (OLNM) and depth of invasion (DOI) are key determinants of elective neck dissection in clinically node-negative oral tongue squamous cell carcinoma (OTSCC), yet accurate preoperative risk stratification remains challenging. This study evaluated the diagnostic performance of artificial intelligence (AI)-based predictive models for OLNM and DOI in OTSCC. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines. A structured search of PubMed identified twelve eligible studies, nine of which provided extractable 2 × 2 contingency data for inclusion in the primary bivariate meta-analysis. One additional study modeling DOI-derived pT stage was synthesized narratively. Pooled sensitivity and specificity were estimated using a bivariate random-effects model. Heterogeneity, threshold effects, and publication bias (Deeks’ test) were assessed. Methodological quality was evaluated using QUADAS-2 supplemented by an AI-specific methodological appraisal. Results: Across nine studies included in the primary meta-analysis, pooled sensitivity was 0.679 (95% CI: 0.604–0.745) and pooled specificity was 0.762 (95% CI: 0.705–0.811), with a summary AUC of 0.786. Heterogeneity was moderate for sensitivity (I² = 41.8%) and low for specificity (I² = 23.4%), with no significant threshold effect (ρ = −0.117, p = 0.776). No significant publication bias was detected (p = 0.596). Subgroup analyses showed comparable performance between OLNM-specific and general LNM models, whereas deep learning or hybrid approaches demonstrated higher accuracy than traditional machine learning methods. Notably, only one out of nine primary studies incorporated true external validation. Conclusions: AI-based models demonstrate moderate discriminative performance for predicting LNM and DOI in OTSCC and may serve as adjunctive tools in preoperative risk stratification rather than standalone decision-makers. However, the near absence of external validation, limited calibration reporting, and lack of clinician-comparator analyses substantially constrain current clinical translation. Future research should prioritize multi-center prospective validation, systematic calibration and decision-curve analyses, and adherence to TRIPOD-AI and CLAIM reporting standards. Full article

Lymph node (LN) dissection is a necessary part of every oncologic surgery in order to provide important information for staging, predicting prognosis and improving survival. To do this, surgical oncologists strive to localize and dissect every pathologically positive LN while avoiding the increased morbidity of removing true negative LNs. The goal is to develop an imaging method to distinguish positive and negative LNs, but a specific biomarker is missing. Thus, our aim is to identify a reliable imaging marker for identifying LNs with lung cancer cells. After screening many epithelial markers, we identified E-cadherin, a membrane protein normally expressed in epithelial cells, including in the lung. To follow up on our potential target, we performed immunofluorescence staining on 48 human LNs with a conjugated anti-E-cadherin monoclonal antibody. Fluorescence was significantly higher in LNs with metastasis, as shown in 48 positive LNs from patients with resected primary lung cancer. There was high fluorescence in both hilar and mediastinal LNs, and in all primary tumor histologies. E-cadherin may be useful for the surgical oncologist for targeted imaging technologies for selecting positive LNs from lung cancer. Full article

Background: The use of [⁶⁸Ga]Ga-PSMA-PET/CT for prostate cancer (PCa) staging is limited by cost and availability. This study evaluates whether radiomic features from contrast-enhanced (CE) CT can predict PSMA-positive lymph nodes (LNs) as a surrogate for metastasis. Methods: A retrospective study of 447 patients included 2537 segmented LNs (425 PET-positive, 2112 PET-negative). Two uroradiologists assessed 417 LNs on CE-CT using a four-point Likert scale. Radiomic features were extracted, selected using four algorithms, and analyzed with six model-building methods. Model performance was compared to radiologist ratings. Results: Radiomic models achieved an accuracy of 0.77–0.85, sensitivity of 0.85–0.91, and specificity of 0.74–0.85. Compared to radiologists, models had higher NPV (0.97–0.98 vs. 0.96) and sensitivity (0.85–0.91 vs. 0.76), but radiologists had superior accuracy (0.95 vs. 0.77–0.85) and specificity (0.97–0.98 vs. 0.74–0.85). In a subanalysis of LNs rated as probably benign or malignant, expert radiologists outperformed the algorithm with greater specificity and PPV (p < 0.005). A density threshold of >27 HU predicted PSMA-positive LNs with 0.79 accuracy, 0.87 sensitivity, and 0.78 specificity. Conclusions: While radiomics did not outperform expert radiologists, the single first-order parameter CT density >27 HU was predictive of PSMA-positive LNs. Clinical Relevance Statement: Radiomic models did not outperform expert uroradiologists. However, in high-volume or resource-limited settings lacking access to [⁶⁸Ga]Ga-PSMA-PET/CT, they may help improve LN assessment in PCa patients with CT alone. Full article

Inflammatory mammary carcinoma (IMC) is an aggressive mammary carcinoma phenotype characterized by tumor emboli within superficial dermal lymphatic vessels and early metastasis. A captive Bengal tiger (Panthera tigris tigris) presented with large abdominal mammary masses and regional lymphadenopathy; contrast-enhanced computed tomography also revealed a pulmonary nodule. Postmortem examination and histopathology confirmed mammary carcinoma with dermal lymphatic tumor emboli and metastases to regional lymph nodes and the lung. Tumor emboli were cytokeratin positive, supporting epithelial origin and an IMC diagnosis, and neoplastic cells were immunopositive for cytokeratin with concurrent vimentin immunoreactivity. This case highlights the clinicopathologic basis of IMC and the diagnostic importance of including full-thickness skin and adjacent subcutis in the sampling plan. Full article

Introduction: Thyroglobulin antibodies (Tg-Abs) are often thought to be associated with thyroid autoimmunity, and as such, a link with thyroid cancer has been found in some, but not all, studies. Tg-Abs are also found in non-autoimmune thyroid-follicular destruction. Given these contradictory results, we designed the present study. Methods: We reviewed data from patients undergoing thyroidectomy for different indications in multiple centers across Greece and the US over 10 years. We compared the incidence of thyroid cancer and its features of tumor aggressiveness among patients with positive (≥30 IU/mL) and negative (<30 IU/mL) Tg-Abs titers and the Tg-Abs titers among patients with cancer, benign disease, and those with and without features of tumor aggressiveness. Furthermore, we performed multivariate and multiple regression analyses to identify if these effects were independently statistically significant. Results: We reviewed n = 9463 consecutive thyroidectomies and included n = 2873 subjects in the present work: n = 1537 with thyroid cancer and n = 1336 with benign disease. The incidence of thyroid cancer was significantly higher in preoperative Tg-Abs+ subjects, n = 273/638 (57.2%), compared with Tg-Abs− subjects, n = 1063/2235 (52.4%), OR 1.21, p < 0.05. Tumor size was larger, and capsular invasion and lymph node involvement were significantly more common in Tg-Abs+ subjects. Mean Tg-Abs were higher in subjects with tumors with extrathyroidal extension, capsular invasion, and lymph node involvement. On regression, Tg-Abs positivity was not associated with thyroid cancer incidence or aggressiveness, though, with the important exception of lymph node involvement (p < 0.001). Conclusions: Elevated preoperative thyroglobulin-antibody titers do not seem to affect the likelihood of developing thyroid cancer, even though they seem to be a surrogate for lymph node metastasis (as opposed to thyroid peroxidase antibodies, TPO-Abs). Further work is needed to clarify the interplay of this immune response on thyroid cancer metastatic behavior. Full article

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune cell dysfunction and poor prognosis. CD44, a cell surface glycoprotein with multiple splice variants, has been implicated in tumor progression, but its compartment-specific roles in PDAC remain unclear. CD44 standard and variant isoform expression was analyzed in patient-derived lymph nodes (LNs) by quantitative PCR. Immune cell-specific CD44 expression was assessed by flow cytometry in LNs and peripheral blood. Soluble and exosome-associated CD44 (exo-CD44) were measured in plasma. Clinical associations and survival analyses were performed. Transcriptomic, immune infiltration, immune checkpoint, and drug sensitivity analyses were conducted using TCGA-PAAD and pharmacogenomic datasets. CD44 standard isoform expression was unchanged in PDAC LNs, whereas multiple CD44 variant isoforms (v4–v10) were significantly reduced and associated with metastatic disease and poor survival, particularly CD44v5, v6, v7, and v10. CD44 expression was enriched in CD45⁺ immune cells, with highest levels in CD4⁺ T cells in both LNs and blood. Soluble CD44 levels showed no clinical associations. In contrast, exo-CD44 levels were reduced overall in PDAC but increased in patients with distant metastasis, positive resection margins, systemic inflammation, and reduced survival. High CD44 expression was associated with advanced disease, immune cell infiltration, immune checkpoint gene expression, reduced sensitivity to gemcitabine, paclitaxel, rapamycin, and FMK, and distinct CTLA4/PD-L1 checkpoint profiles. CD44 exhibits compartment-specific regulation in PDAC, linking immune remodeling, exosome signaling, and therapeutic resistance to adverse clinical outcome. Full article