Pathology & Oncology Research最新文献

Introduction/background: Gastric carcinomas (GC) are heterogeneous malignancies characterised by distinct histological and molecular subtypes. The microsatellite instability (MSI) molecular subtype, resulting from deficient DNA mismatch repair (dMMR), accounts for approximately 22% of global GC cases. Empirical evidence indicates differences in clinicopathological features, demographics, and treatment response in MSI GC compared to microsatellite stable (MSS) GC. MSI status has emerged as a potential biomarker for advanced GC, and this study aimed to determine the MSI prevalence of histopathologically confirmed GC cases at our centre.

Method and material: This was a retrospective cross-sectional analysis of GC cases from 2018 to 2022, which were retrieved from the laboratory information system. DNA from these cases was isolated and assessed for MSI using a pentaplex PCR panel and confirmatory IHC on MSI-H was performed. Samples with no allelic size variation in the 5 microsatellite markers were classified as microsatellite stable (MSS), variation in 1 marker as microsatellite instability low (MSI-L), and variation in 2 or more microsatellite markers as MSI-H.

Results: The study consisted of 64 cases with a MSI prevalence of 21.9% (n = 14) displaying a male predominance (n = 10; 71.4%) and a mean age of 62.7 years. Among these 14 MSI cases, 42.9% (n = 6) were classified as MSI-H with a mean age of 59.3 years. Half (n = 3) of these cases presented with upper gastrointestinal bleeding, with a majority of them diagnosed with moderately differentiated adenocarcinomas (66.7%). Microsatellite instability low was seen in 57.1% (n = 8) of the cases with a mean age of 65.3 years, and of these, patients presented with vomiting, epigastric pain and dysphagia with equal frequency at 25% (n = 2 respectively).

Conclusion: The frequency of MSI cases in this study is congruent with global trends, highlighting the importance of microsatellite status in GC for understanding clinicopathological differences between MSI and MSS patients. These findings support the potential of MSI status as a biomarker.

Objectives: To identify characteristic vascular features of focal nodular hyperplasia (FNH) on microvascular flow imaging (MVFI) and assess the utility of MVFI in FNH diagnosis.

Methods: This retrospective study included B-mode ultrasound (US) and MVFI scans of 41 FNHs, 21 hepatocellular carcinomas (HCCs), 20 metastases (METs), 10 hepatocellular adenomas (HCAs), and eight hemangiomas (HEMs) from 80 patients. Diagnoses were confirmed by contrast-enhanced imaging or histology. Two independent observers evaluated vascular patterns on MVFI. Interobserver agreement was calculated, and logistic regression models using either B-mode or MVFI features were developed to differentiate FNH from other focal liver lesions (FLLs).

Results: Interobserver agreement for MVFI patterns was substantial (κ = 0.641, p < 0.001). The spoke-wheel pattern (OR = 51.53 and 35.28) and central artery (OR = 4.96 and 1.95) were strongly associated with FNH. However, the spoke-wheel pattern also appeared in subsets of HCAs (20%-30%), HCCs (14%-19%), and METs (5%-15%). Rim vascularity was common but nonspecific. The MVFI-based model (AUC = 0.891, p < 0.001) outperformed the B-mode model (AUC = 0.814) in distinguishing FNH. For lesions ≥3 cm, MVFI accuracy was even higher (AUC = 0.944, p < 0.001).

Conclusion: MVFI enhances the diagnostic confidence of US for FNH, particularly in asymptomatic patients at low risk for malignancy. However, given the potential overlap with certain malignant FLLs, MVFI findings should be interpreted with caution.

Ki-67 proliferation indices (PIs) define the grading of GastroEnteroPancreatic NeuroEndocrine Neoplasms (GEPNENs) and are crucial for therapeutic decisions. The precise Ki-67 assessment relies on manual counting, which is time-consuming, hardly accessible during routine pathological signout and thus usually replaced by the easier eye-estimation/balling method prone to interobserver variability and differences originating from the hot-spot size, localisation and tumor heterogeneity. These discrepancies can significantly affect the final PI resulting in misgrading of GEPNENs with potential adverse patient outcomes. In the era of digital pathology more and more applications are available to overcome this problem. In our retrospective study of 60 surgically resected GEPNEN cases, we tested the equivalence of traditional clinical (C) grading, manual counting with a MarkerCounter (MC) application and automatic grading with tumor recognition PatternQuant application with subsequent NuclearQuant (NQ) PI-assessment within 3DHistechs digital pathology platform. We found almost perfect agreement between the various grading methods (Spearman rank-order correlations: C vs. MC: ρ = 0.912, C vs. NQ: ρ = 0.883, MC vs NQ: ρ = 0.953) without clinically significant misgradings. Also the numerical values of the PIs derived with the various methods showed close correlations (Linear regression: C vs. MC: r = 0.952, C vs. NQ: r = 0.925, MC vs NQ: r = 0.978). The automated PI-assessment involved a mean 5-fold more tumor cells, better approximating the global/total Ki-67 PI, which was earlier shown to deliver more robust prognostic power and decreased interobserver variability. Furthermore, G3 tumors differed from G2 and G1 tumors in their cytomorphological parameterers: high grade tumors had significantly larger and more polymorphic, less regular tumor cell nuclei, which parameters could be also utilized for grading and/or prognostication purposes. Our study applied a simple, quick, easy-to-use, Machine Learning-based method that could be incorporated into routine digital pathology signout alleviating pathologists' workload and increasing precision and recall rate.

Purpose: Valosin-containing protein (VCP/p97) is a key regulator of proteostasis and cellular stress response and has been linked to tumor progression and poor prognosis in various malignant diseases. However, data on its role in laryngeal squamous cell carcinoma (LSCC) are lacking.

Methods: In this retrospective single-center study, VCP/p97 protein expression was analyzed by immunohistochemistry in a cohort of 100 LSCC patients. Expression levels were semi-quantitatively assessed with H-Score, compared to normal tissue if possible and correlated with clinicopathological parameters. Survival analyses were evaluated by Cox regression.

Results: VCP/p97 was expressed in all tumors. Most LSCC (77.0%) showed a uniform staining pattern. 46 of these tumors (59.7%) exhibited a staining intensity of 2-3. Among the tumors with a non-homogeneous staining pattern (n = 23), two tumors showed a predominance to lower staining (staining intensity 1). In 13 samples a comparison to normal epithelium was possible. In these samples, 9 (69.2%) samples showed higher VCP/p97 expression compared to the normal epithelium and 4 (30.8%) showed lower expression. VCP/p97 H-Score was not significantly associated with tumor stage, grade, lymph node status or patient survival.

Conclusion: Although VCP/p97 expression is not prognostic in LSCC, its consistent expression may suggest a potential role as a molecular target. Further functional and translational studies are warranted to explore the therapeutic utility of VCP/p97 inhibition in LSCC.

Objective: To evaluate the technical performance and clinical integration of FoundationOne®CDx (F1CDx) for high-grade serous ovarian cancer (HGSOC), focusing on its role in guiding PARP inhibitor (PARPi) therapy recommendations in a tertiary oncology center.

Methods: We conducted a retrospective analysis of 178 F1CDx tests performed on 168 HGSOC patients with unknown BRCA mutation status between January 2019 and August 2024. Molecular findings, including BRCA1/2 mutations, homologous recombination deficiency (HRD) status, loss of heterozygosity (LOH) scores, and HRR-related gene alterations, were correlated with tumor board recommendations and decisions for PARPi therapy. Laboratory turnaround time (TAT), assay performance, and integration into clinical workflows were assessed.

Results: The F1CDx assay successfully generated comprehensive molecular profiles in 174 samples, with minimal limitations due to computational tumor content or inconclusive HRD readout. BRCA1/2 mutations were detected in 13.1% of patients, and 39.5% of tumors were HRD-positive (LOH ≥16%). In the internal cohort, 81.8% of patients received PARPi therapy recommendations, all directly informed by F1CDx results. PARPi selection differed by HRD status, with niraparib favored in HR-proficient and olaparib in HRD-positive tumors. The mean laboratory TAT was 8.4 days (standard deviation ±3.8), with 92.2% of tests completed within 14 days. No additional profiling was required for PARPi therapy recommendation, and no incidental findings beyond the scope of HRD testing were detected.

Conclusion: Molecular profiling with F1CDx proved to be a technically feasible, clinically impactful, and time-efficient assay, demonstrating its value in supporting molecular-guided PARPi therapy recommendations in the routine care of HGSOC patients.

Introduction: The antibody-drug conjugate (ADC) Sacituzumab-Govitecan (SG), a humanized anti-Trop2 monoclonal antibody linked to the cytotoxic topoisomerase I inhibitor SN38, achieved promising results in the treatment of various solid tumors. Treatment approaches with SG requires the expression of Trop2 within tumor cells. The present study explored immunohistochemical Trop2 expression in cervical carcinomas in correlation with histologic subtypes and p16 expression status.

Material and methods: Using an immunoreactive score (IRS), immunohistochemical Trop2 expression in surgically treated cervical carcinoma specimens was evaluated by comparing squamous cell carcinomas and adenocarcinomas, and the expression status of p16 as a surrogate marker for high-risk HPV infection.

Results: A total of 101 cases were included in this study. Of these 75% were squamous cell carcinomas, and 25% were adenocarcinomas, and 5% showed negative immunoexpression for p16, indicating HPV-independent carcinoma. All tumors showed at least weak Trop2 expression. There were no differences in the mean Trop2 IRS-scores comparing histological subtype [squamous: 8.5 (3-9) vs. adeno: 6 (1-9); p = 0.8] and p16 expression status [positive: 9 (6-9) vs. negative: 8 (6-9; p = 0.6]. No differences in Trop2 expression were observed when post-surgical tumor stage, pelvic lymph node status and peritumoral stromal remodelling (desmoplastic response and peritumoral infiltrating lymphocytes) were analysed.

Conclusion: Regardless of the histologic tumor type and p16 expression status, cervical carcinomas show high Trop2 expression and, therefore, may represent a promising therapeutic target. Clinical trials exploring Trop2 directed ADCs such as Sacituzumab-Govitecan are warranted in this cancer type, including the prognostically poor HPV-independent (p16 negative) tumors, mainly adenocarcinomas.

Significance: Regardless of the histologic tumor type and p16-expression status, cervical carcinomas show high Trop2 expression, which may therefore represent a promising therapeutic target in these tumors.

Objective: Histopathological growth patterns (HGPs) were identified as prognostic factors for colorectal adenocarcinomas; however, they have been examined in a consecutive setting with controversial results. Our study aimed to examine HGPs' association with clinicopathological factors in a retrospective, consecutive, single-center, cohort study.

Methods: Our study comprised the data of patients who were treated for liver metastases from 2011 to 2023. In all cases, general clinicopathological data were registered. The histological slides of all metastatic foci were individually evaluated. Statistical analyses were carried out by using the Kruskal-Wallis and Fisher's exact test. P-values less than 0.05 were considered significant.

Results: Altogether 336 liver metastases from 205 patients have been included in our retrospective, consecutive, single-center, cohort study. The male-to-female ratio was 116:89, and the average age of patients was 68 years (median: 69.5; range: 27-93). Most examined cases were of colorectal origin (n = 164). Replacement pattern was found to be the most common (n = 99). The 163 colorectal adenocarcinoma metastasis cases reflected a similar order of magnitude of replacement type (n = 78) and desmoplastic (n = 68) HGPs. The majority (70%) of neuroendocrine tumours (n = 10) showed pushing HGP, while 3 of 5 non-epithelial tumours were associated with replacement-type HGP. A significant association was found between HGPs and histological subtype (p < 0.001), grade (p = 0.002), the presence of venous spread (p = 0.02), and the largest diameter of liver metastasis (p = 0.023).

Conclusion: Even though our study highlights the HGPs' association with several clinicopathological parameters that might influence prognosis, their role in the treatment process of colorectal or other carcinomas remains controversial.

Objective: We analyzed changes in intratumoral CD8⁺ and CD4⁺ T-cell subpopulations following neoadjuvant chemoimmunotherapy in non-small cell lung cancer. We then assessed whether these alterations favored better outcomes and explored their association with the tumor microenvironment.

Methods: Paired pre- and post-treatment samples from 32 patients with non-small cell lung cancer who underwent neoadjuvant chemoimmunotherapy at Shandong Cancer Hospital (January 2021-June 2023) were analyzed retrospectively. A quantitative analysis of tumor cells and their microenvironment was performed using a tissue microarray and a multiplex immunofluorescence technique. The analysis was based on the number of cells per thousand nucleated cells. Patients exhibiting a major pathologic response were classified as responders. The delta parameter (post-treatment minus pre-treatment) was utilized to assess changes in these indicators, and associations with treatment response were identified using the Wilcoxon Signed-Rank test and logistic regression analyses.

Results: Of the 32 patients, 59.38% were classified as responders. Across all patients, neoadjuvant chemoimmunotherapy significantly reduced the densities of dysfunctional CD8⁺ resident memory T cells and cytotoxic and dysfunctional CD8⁺ bystander T cells, while conventional CD4⁺ T cells increased significantly. Similar trends were observed in the response group. In the non-response group, only cytotoxic CD8⁺ bystander T cells were reduced in number. Logistic regression analysis revealed that a high delta conventional CD4⁺ T cells is more favorable for MPR (OR = 0.13, p = 0.038), exhibiting a similar trend to changes in HIF-1α (p = 0.049).

Conclusion: Alterations in specific CD8⁺ and CD4⁺ T-cell subpopulations during neoadjuvant chemoimmunotherapy may favor better outcomes and are potentially associated with tumor hypoxia. These findings provide a new perspective on developing strategies to improve treatment sensitivity in non-small cell lung cancer.

Testicular germ cell tumors (TGCTs), though typically responsive to therapy, may rarely develop somatic-type malignancy (STM), a transformation associated with poor prognosis and chemoresistance. This study presents two cases of postpubertal-type teratoma with intestinal-type adenocarcinoma as STM, offering insights into their clinical, histopathological, immunophenotypic, and molecular profiles. The first patient, a 63-year-old male, presented with pulmonary and retroperitoneal metastases and underwent orchiectomy, revealing an intratesticular intestinal-type adenocarcinoma. Molecular testing confirmed 12p overrepresentation and pathogenic mutations in CTNNB1, STK11, and MDM2. The second patient, initially diagnosed at age 35 with a mixed TGCT, developed STM as a late recurrence 16 years post-orchiectomy, manifesting as a retroperitoneal mass with vertebral invasion. Histology again confirmed intestinal-type adenocarcinoma, and molecular testing revealed amplification of ERBB2, KRAS, along with mutations in TP53 and PIK3CA. Both cases were managed with capecitabine-oxaliplatin plus bevacizumab, followed by maintenance therapy, achieving disease stabilization for at least 9 months. These cases illustrate the diagnostic and therapeutic complexities of STM, particularly with adenocarcinoma morphology that may mimic primary gastrointestinal neoplasms. Accurate diagnosis required exclusion of alternate primary sites and demonstration of chromosome 12 aberrations using FISH and next-generation sequencing. Our findings emphasize the importance of long-term follow-up in TGCT patients, particularly those with teratomatous elements, and highlight the value of cytogenetic and molecular profiling in confirming STM and identifying potential therapeutic targets. Given the rarity of STM, especially in metastatic or recurrent settings, there is an urgent need for standardized diagnostic protocols and evidence-based treatment strategies. These cases support the use of tumor-specific chemotherapy regimens guided by the histological and molecular characteristics of STM.

Cancer is a deadly disease affecting millions of people worldwide. Circulating tumor cells (CTCs) represent a critical link between primary malignancies and metastasis, acting as key players in cancer dissemination, progression, and recurrence. Although rare, CTCs offer a valuable, non-invasive window into tumor biology and the evolution of disease in patients. CTCs can exist as single cells in the circulation, but some are shed and travel in larger groups, referred to as CTC clusters. These clusters possess a greater oncogenic potential compared to individual CTCs. In this review, we aim to provide insight into the dynamic biological processes underlying CTC generation, biology, and survival, with a focus on epithelial-to-mesenchymal transition (EMT) and beyond like cancer stem cells (CSCs), cellular plasticity, and senescence. A crucial aspect of CTC biology is EMT, a process that imparts cancer cells with increased motility, invasiveness, resistance to apoptosis, and the ability to intravasate and evade the immune system. Beyond EMT the cancer cells show further plasticity, allowing epithelial tumor cells to adopt mesenchymal or hybrid phenotypes, which enables adaptation to a changing microenvironment and enhances therapy resistance. Moreover, a subset of cancer cells can acquire stem cell-like properties, including self-renewal and tumor-initiating capacity. EMT, along with processes such as dedifferentiation, contributes to the generation of cancer stem cells. In recent years, studies have also highlighted the complex and paradoxical role of senescence in CTC biology. While senescence typically results in permanent cell cycle arrest, in cancer cells it may be reversible and can promote tumor cell dormancy, immune evasion, and metastatic reactivation. By exploring the connections between CTCs, EMT, CSCs, plasticity, and senescence, we aim to shed light on the unique biology of CTCs, their metastatic potential, and their contributions to tumor heterogeneity. We hope that a better understanding of these processes will help advance the development of novel biomarkers and therapeutic targets for solid tumors beyond EMT.