Pathology & Oncology Research最新文献

Sarcomas with an EWSR1::POU2AF3(COLCA2) fusion are a very recently described entity of preferentially sinonasal origin and with undifferentiated round/spindle cell morphology. We established a novel cell line (PF1095) carrying a EWSR1::POU2AF3 fusion from the malignant pleural effusion of a 25-year-old sarcoma patient. The patient was first diagnosed with poorly differentiated neuroendocrine carcinoma based on tumor cell morphology and positivity to markers such as EMA, synaptophysin, and CD56. Later, the EWSR1 translocation was identified in the tumor cells with unknown partners and the patient received chemotherapy according to the Ewing 2008 protocol in combination with surgery and proton beam radiotherapy. At the time of cell line establishment, the disease progressed to pleural sarcomatosis with pleural effusion. In the cell line, we identified POU2AF3 as a fusion partner of EWSR1 and a TP53 frameshift deletion. Next, we determined the sensitivity of PF1095 cells to the currently approved chemotherapies in comparison to two conventional Ewing sarcoma lines (EW-7 and MHH-ES1) with the two most frequent EWSR::FLI1 fusions. Finally, we tested potential new combination therapies. We performed cell viability, proliferation, and cell cycle assays. We found that the proliferation rate of PF1095 cells was much slower than the EWSR1::FLI1 fusion lines and they also had a lower sensitivity to both irinotecan and doxorubicin treatment. Expression level of SLFN11, a predictor of sensitivity to DNA damaging agents, was also lower in PF1095 cells. Combination treatment with the PARP inhibitors olaparib and irinotecan or doxorubicin synergistically reduced cell viability and induced cell death and cell cycle arrest. This unique cell model provides an opportunity to test therapeutic approaches preclinically for this novel and aggressive sarcoma entity.

Introduction: Polycythemia indicates the pathological increase in the number of red blood cells and the rise of hematocrit values. Polyglobulia can be of primary or secondary origin, with the most common primary polycythemia being a myeloproliferative neoplasm, polycythemia vera. Polyglobulia patients may develop cardiovascular complications and thromboembolic events. The gold standard of first-line treatment in polycythemia vera is phlebotomy, which is indicated to keep the hematocrit value below 0.45. Until now the goal to be achieved in secondary polyglobulia has been similar. In secondary polyglobulia this rule of thumb needs to be re-evaluated as shown by the example of two patients suffering from different rare, genetically determined polyglobulias. In our article we present the case of these two patients and discuss the diagnostic and therapeutic principles to be applied in patients with rare, genetically determined polyglobulias.

Patients and methods: After completing the usual diagnostic algorithm for polyglobulia no cause could be identified in two of our male patients. Therefore, we set out to perform whole exome sequencing in both patients. Our analysis did not include copy number analysis.

Results: In Patient 1 the p.Ser179Pro variant in the VHL gene was detected in the homozygous state, which is classified as likely pathogenic according to the ACMG guidelines. Homozygous VHL mutations are implicated in Chuvash polycythemia. Segregation analysis was declined by the family. In Patient 2 the PKLR gene p.His306Gln variant was detected in the heterozygous form. The gene plays a role in pyruvate metabolism. Family screening did not detect this variant in healthy family members.

Discussion: We identified rare, possibly pathogenic genetic variants in two patients with polyglobulia and as a consequence of the genetic diagnosis we implemented individualized patient monitoring. We recommend the utilization of high-throughput genomic testing in cases with unexplained polyglobulia.

Background: Alectinib is effective in extending the survival of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) and generally has manageable side effects. However, intestinal ulcers and colitis are rare but serious adverse reactions linked to Alectinib, meriting further investigation into their causes.

Case presentation: We report the case of a 62-year-old woman with NSCLC and brain metastases, who tested positive for ALK. She had been treated with Alectinib for nearly 4 years. The patient experienced diarrhea for 4 days, and a subsequent colonoscopy revealed pancolitis along with multiple ulcers in the terminal ileum and ileocecal valve. Given the severity of these symptoms, classified as a grade 3 adverse event by the Common Terminology Criteria for Adverse Events (CTCAE), Alectinib was discontinued. Treatment with oral enteric-coated Mesalazine tablets led to a resolution of the diarrhea and a significant improvement in the pancolitis and ulcers upon follow-up. The patient's anticancer therapy was subsequently switched to Ceritinib capsules. At follow-up, she demonstrated a stable tumor condition with no recurrence of intestinal ulcers or colitis.

Conclusion: To our knowledge, this is the first reported case of intestinal ulceration and colitis induced by Alectinib. Although such adverse events are exceedingly rare, they require vigilant monitoring in clinical practice. Decisions on continuing with Alectinib should consider the severity of side effects, classified by CTCAE grade. For managing these specific adverse events, oral Mesalazine enteric-coated tablets appear to be an effective treatment option.

Purpose: This study aims to evaluate whether survival outcomes for GIST patients have improved over the past decades and to identify the specific patient subgroups that have benefited from advances in treatment.

Patients and methods: A total of 4,127 GIST patients diagnosed between January 1980, and December 2019, were included in this study using data from the Surveillance, Epidemiology, and End Results (SEER)-9 Registries. Survival differences among GIST patients were analyzed across five time periods (1980-1999, 2000-2004, 2005-2009, 2010-2014, and 2015-2019) and within demographic, neoplastic, temporal, economic, and geographic categories using the log-rank test. Multivariable Cox regression models were employed to identify risk factors associated with GIST-specific survival. Associations between time periods and GIST-specific mortality (TSM) were examined using a multivariable Cox regression model.

Results: Survival outcomes for GIST patients significantly improved in the 2000-2009 period but showed no substantial improvement in the 2010-2019 period. After adjusting for age, gender, tumor location, ethnicity, tumor stage, median household income, and geographic area, the multivariable Cox regression models revealed that older age (≥65 years) (HR = 1.977, 95% CI = 1.470-2.657), tumors located outside the gastrointestinal tract (HR = 1.505, 95% CI = 1.267-1.786), regional lesions (HR = 2.225, 95% CI = 1.828-2.708), and distant lesions (HR = 5.177, 95% CI = 4.417-6.069) were independent risk factors for TSM (p < 0.05). After adjusting for time periods and age, gender, tumor location, tumor stage, median household income, patients in 2000-2004 (HR = 0.662, 95% CI = 0.523-0.839), 2005-2009 (HR = 0.431, 95% CI = 0.339-0.549), 2010-2014 (HR = 0.437, 95% CI = 0.341-0.561), and 2015-2019 (HR = 0.365, 95% CI = 0.273-0.489) had a significantly lower risk of TSM than patients in 1980-1999 (p < 0.05). Similarly, patients in 2005-2009 (HR = 0.661, 95% CI = 0.555-0.788), 2010-2014 (HR = 0.696, 95% CI = 0.578-0.838), and 2015-2019 (HR = 0.607, 95% CI = 0.476-0.773) also had a significantly lower risk of TSM than patients in 2000-2004 (p < 0.05). However, patients in 2010-2014 (HR = 1.042, 5% CI = 0.863-1.258) and 2015-2019 (HR = 0.945, 95% CI = 0.734-1.216) did not have a significantly lower risk of TSM compared to patients in 2005-2009 (p > 0.05).

Conclusion: GIST survival has significantly improved during the period 2000-2009 but showed no substantial improvement in 2010-2019, with the turning point for lower risk of TSM being 2005. Innovative strategies are needed to further improve survival outcomes for GIST patients, particularly for older patients and those with tumors originating outside the gastrointestinal tract.

Giant cell tumour of bone (GCTB) is viewed as a benign, locally aggressive primary bone tumour with metastatic potential. Current management is surgery with bone curettage or resection and systemic therapy with denosumab. Diagnosis is confirmed histologically prior to surgery, with staging for pulmonary disease, as pulmonary metastases (PM) reportedly occur in <8%. This study aimed to assess incidence, surveillance and management of PM in patients with GCTB, with histopathological review. A retrospective audit of the Oxford bone tumour registry was performed from January 2014 - October 2023. Inclusion criterion was histological confirmation of GCTB. Exclusion criteria were incomplete medical, imaging or histology records, or referral for secondary MDT opinion for diagnosis. From an initial group of 126 GCTB patients, 83 patients met the full selection criteria. Pulmonary metastases were identified in 11 patients. Three with PM were excluded on histopathological review as being giant cell rich osteosarcoma rather than metastatic GCTB. This left 8 (9.6%) patients, one had PM at presentation and seven at follow-up between 2 and 42 months. Two were histologically confirmed after cardiothoracic surgery and biopsy, six radiologically diagnosed. Three (37.5%) patients with PM have died (between 1 and 12 months after confirmed PM), five are alive with stable disease. Seven (87.5%) of patients with pulmonary disease were treated with denosumab/chemotherapy (three before, four after pulmonary diagnosis). Five (62.5%) with pulmonary disease had recurrence of local disease requiring further surgery. Local recurrence was an independent risk factor for PM on statistical analysis. GCTB may present with PM, but more commonly, metastasis occurs after surgery, presenting on surveillance and can progress. There were no distinct differences in histopathological appearance between patients with GCTB that developed PM and those that did not, therefore morphological features of the tumour cannot be currently used to predict tumour behaviour. PM can behave aggressively, necessitating identifying histological markers to recognise patients at risk of metastatic GCTB, for example, through mRNA single cell analysis. We propose GCTB patients with PM receive regular chest surveillance with PET scan and/or CT to monitor disease progression, and a multi-centre audit of GCTB outcome undertaken to further define optimal clinical management.

The establishment of positive and negative controls in immunohistochemistry (IHC) screening for anaplastic lymphoma kinase (ALK) rearrangements is essential in the treatment of lung adenocarcinoma. However, positive control of patient tissue is rare and comes with ethical issues. A novel automated solution for ALK IHC quality control management was investigated by comparison with the established D5F3 antibody on the VENTANA system in 87 lung adenocarcinoma specimens with known ALK status re-analyzed by fluorescence in situ hybridization. The BP6165 concentrated antibody on the LYNX480 PLUS platform demonstrated excellent sensitivity and specificity (98.30% and 100%, respectively) in 87 biopsy specimens. The ALK controls in liquid form (CLFs) applied in an automated way showed a more regular circular shape and better cell distribution than those applied manually. In addition, the novel controls can show changes in the same pattern as tissue controls under different antibody concentrations and antigen retrieval conditions. The automated solution for ALK IHC quality control management provides a convenient solution without the consumption of scarce tissue for IHC testing in day-to-day pathology practice. The availability of standardized protocols for the detection of ALK rearrangements using the BP6165 concentrated antibody on the LYNX480 PLUS platform will expand the number of laboratories that can reliably and consistently determine the eligibility of patients with lung adenocarcinoma for treatment with ALK tyrosine kinase inhibitors.

Introduction: Breast cancer is a leading cause of morbidity and mortality among women. Advances in molecular biology have improved detection and treatment, but conventional histopathological factors remain crucial for prognosis. Tumour budding, defined as clusters of less than 5 tumour cells detached from the main tumour, has been linked to poor prognosis in several cancers. This study explores the association between intra-tumoral budding (ITB) and peripheral tumour budding (PTB) with known prognostic factors in Invasive Breast Carcinoma of no special type (IBC NST).

Materials and methods: This retrospective study analysed 70 cases of IBC NST diagnosed at Kasturba Medical College, Manipal, between January 2020 and December 2021. Tumour budding was classified as high-grade or low-grade based on density, which denotes the number of buds per x20 field. Clinicopathological data, including hormone receptor status, Ki-67 index, lymphovascular invasion (LVI), perineural invasion (PNI), and axillary lymph node involvement, were obtained. Statistical analyses were performed to identify a significant association between tumour budding and these factors. Univariate and multivariate logistic regression analyses were also done to demonstrate the significance of association.

Results: High-grade PTB showed significant associations with LVI (p = 0.046), PNI (p = 0.017), and axillary lymph node involvement (p = 0.021). In contrast, high-grade ITB was only significantly correlated with axillary lymph node involvement (p = 0.044). LVI (p-value = 0.240) and axillary lymph node involvement (p-value = 0.142) did not show any association with PTB on multivariate analysis and PNI (p-value = 0.074) near significant association with PTB). A significant inverse association was observed between PTB and Ki-67 (p = 0.012), which remained significant in univariate and multivariate analysis (p-value = 0.017). No significant associations were found between tumour budding and hormone receptor status or menopausal status.

Conclusion: Peripheral tumour budding (PTB) is significantly associated with several poor prognostic factors in IBC NST, while intra-tumoral budding (ITB) correlates primarily with axillary lymph node involvement. Tumor budding, particularly PTB, could serve as an important prognostic marker in breast cancer. Further research is needed to standardize tumour budding assessment in clinical practice.

Background: Angiogenesis is closely associated with tumor growth and metastasis, and microvascular density (MVD) is currently the clinical standard for evaluating tumor angiogenesis. Thus, the detection of intratumoral MVD is of great significance for understanding disease progression and predicting patient prognosis.

Methods: Tumor tissue sections of 238 patients with lung adenocarcinoma (LUAD) who underwent radical surgery were retrospectively analyzed. Immunohistochemical (IHC) staining was carried out using a CD34 polyclonal antibody to determine intratumoral MVD, and the relationship of CD34-MVD with the clinicopathological characteristics and survival time of LUAD patients was analyzed.

Results: CD34-MVD was associated with tumor size, lymph node metastasis, tumor recurrence, and patient survival status; patients with tumor size ≤3 cm (P = 0.015), negative for lymph node metastasis (P = 0.049), no tumor recurrence (P = 0.021), and survival (P = 0.042) had higher MVD. Survival analysis suggested that patients with high MVD had higher disease-free survival (log-rank P = 0.005) and overall survival (log-rank P = 0.004) compared to patients with low MVD. The Cox proportional hazards model showed that a high MVD (P = 0.022) reduced the risk of postoperative tumor recurrence in patients with LUAD.

Conclusion: Decreased intratumoral CD34 positive microvessels were associated with tumor development in patients with LUAD. CD34-MVD is an independent risk factor affecting postoperative tumor recurrence in patients with LUAD and can be used as a prognostic indicator for this group of patients.

Background and objectives: This study aims to evaluate the correlation between Tumor-Infiltrating Lymphocyte (TIL) levels and Fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) metabolic parameters, including spleen and bone marrow FDG uptake and tumor heterogeneity in non-luminal breast cancers (NLBC), and to elucidate their association with survival outcomes.

Methods: We retrospectively analyzed data from 100 females with stage 2-4 NLBC who underwent pretreatment ¹⁸F-FDG Positron emission tomography-computed tomography (PET/CT). TIL was scored based on Hematoxylin-Eosin-stained specimens and ¹⁸F-FDG PET metabolic parameters, including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), liver, spleen, and bone marrow FDG uptake were calculated. Heterogeneity Index (HI)1, HI2, and HI3 indices were analyzed with FDG metabolic parameters. The association between these factors and overall survival was analyzed using multivariate Cox regression models.

Results: TIL showed weak negative correlations with tumor size, tumor (T), and metastasis (M) stages. No significant correlation was found between TIL levels and overall SUV values. However, in stage 4, TIL correlated positively with liver, spleen, and bone marrow SUV values and negatively with heterogeneity indices (HI2, HI3). Higher tumor size, HI values, and Bone marrow-to-liver ratio (BLR) SUVmean were associated with increased mortality. A TIL cut-off value of <5 was linked to significantly worse survival.

Conclusion: Our study demonstrates a strong connection between TIL, FDG metabolic parameters, and tumor heterogeneity, particularly in advanced NLBC. Although TIL is not generally associated with SUV values, its association with certain metabolic and heterogeneity indices suggests that it is important in influencing survival. Further research involving larger cohorts and diverse breast cancer subtypes is needed to validate these results.

The neurotrophic tyrosine kinase receptor (NTRK) gene family is of rising importance as their fusions are oncogenic, and specific target drugs are available to inhibit the chimera proteins. Pan-TRK antibody, which shows the overexpression of the NTRK1-2-3 genes, is a useful tool to detect tumors with or without NTRK gene alterations, due to high negative predictive value. Though it is well known that pan-TRK immunopositivity is usually not connected to NTRK fusion, the role of other possible genetic alterations is under-researched. In our previous work, we found 3 NTRK1 amplified cases out of 6 cases with recurrent NTRK1 tyrosine kinase domain mutation pair, so we extended our investigation to a larger series to estimate amplification frequency. Pan-TRK immunopositivity was seen in 76 of the 132 dedifferentiated liposarcomas cases, followed by NTRK1-2-3 break-apart FISH tests in 76 pan-TRK positive cases to detect oncogenic fusions or other copy number alterations of these genes. None of the pan-TRK immunopositive dedifferentiated liposarcomas showed absolutely certain sign of fusion, however, 18 (28%) cases showed amplification of one of the genes, 13 had polysomy, 34 were normal, 11 were not evaluable. The extent of pan-TRK immunoreaction showed a positive correlation (p = 0.002) with the NTRK status found by FISH. Analyzing publicly available data from large series of 265 liposarcoma samples consisting of both well-differentiated and dedifferentiated liposarcoma case, 23 (8.6%) cases showed a mutual exclusive amplification of the NTRK genomic loci in a non-preselected, independent patient population indicating that our findings are presented in other cohorts. Our results underline the so far not revealed frequent occurrence of NTRK amplifications which might be important in the TRK inhibition therapy.