Search Results (122)

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum–etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients. Full article

Neuroendocrine neoplasms (NENs) comprise a group of tumours that can develop in various internal organs, but in this review, we will describe only those arising in the lungs, thyroid, and thymus. Pulmonary neuroendocrine neoplasms (pulmonary NENs) account for approximately 25% of all lung cancers. They are classified into four groups of tumours: typical carcinoids (TCs), atypical carcinoids (ACs), small cell lung carcinoma, and large cell lung carcinoma. This review focuses on TC and AC. The treatment consists mainly of radiotherapy, chemotherapy, and surgical resection, but novel drugs like atezolizumab are also utilised. The most common neuroendocrine neoplasm of the thyroid gland is medullary thyroid carcinoma (MTC), which commonly possesses RET protooncogene mutations. MTC is treated by a total thyroidectomy. Recently, tyrosine kinase inhibitors (TKIs) have emerged as an effective treatment option for patients with advanced MTC. Neuroendocrine tumours of the thymus (NETTs) are also being treated with a radical surgery. Full article

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME—through inhibition of ECM components, MMPs, or integrin signaling—may enhance immune responses and improve clinical outcomes. Full article

Background/Objectives: Lung neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors requiring accurate differentiation from non-small cell lung cancer (NSCLC) for effective treatment. Conventional computed tomography (CT) lacks pathognomonic features to distinguish these subtypes. Radiomics, which extracts quantitative imaging features, offers a potential solution. Methods: This retrospective multicenter study included 301 patients with histologically confirmed lung cancer who underwent native CT scans. The dataset comprised 150 NSCLC cases (75 adenocarcinomas, 75 squamous cell carcinomas) and 151 NENs (75 SCLC, 60 carcinoids, 16 large cell neuroendocrine carcinomas). Tumors were manually segmented, and 107 radiomics features were extracted. Dimensionality reduction and feature selection were performed using Pearson correlation analysis and LASSO regression. Decision tree and random forest classifiers were trained and evaluated using a 70:30 training–testing split. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and F1-score. Results: The model differentiating NENs from NSCLC achieved an AUC of 0.988 on the test set, with an accuracy of 97.8%. The model distinguishing SCLC from other NENs attained an AUC of 0.860 and an accuracy of 82.6%. First-order and textural radiomics features were key discriminators. Conclusions: Radiomics-based machine learning models demonstrated high diagnostic accuracy in differentiating lung NENs from NSCLC and in subclassifying NENs. These findings highlight the potential of radiomics as a non-invasive, quantitative tool for lung cancer diagnosis, warranting further validation in larger multicenter studies. Full article

Due to the complex anatomy of the pelvis, various tumors may arise in this region. Some of these tumors are well known and have distinctive features that allow them to be identified by magnetic resonance imaging (MRI). These include sacrococcygeal teratoma (SCT), the most prevalent congenital tumor in children, often diagnosed prenatally and most frequently occurring in this anatomical location, and ovarian teratoma, which in its mature form is the most common ovarian neoplasm in children and adolescents. Additionally, rhabdomyosarcoma (RMS), commonly found in the bladder in both genders and in the prostate in males, and Ewing sarcoma (ES), affecting the flat bones of the pelvis, are relatively common tumors. In this study, selected atypical pelvic tumors in children are presented. Most of them are tumors of the reproductive system, such as cervical cancer, small cell neuroendocrine carcinoma of the ovary, ES/primitive neuroectodermal tumor (PNET) of the ovary, diffuse large B-cell lymphoma (DLBCL) of the ovaries and ovarian Sertoli–Leydig cell tumor (SLCT) with RMS due to DICER1 syndrome. Additionally, tumors originating from the nervous system, including neuroblastoma (NBL) and plexiform neurofibroma (pNF), associated and not associated with neurofibromatosis type 1 (NF1), are discussed. Furthermore, Rosai–Dorfman disease involving the pelvic and inguinal lymph nodes is presented. By reviewing the literature and presenting our cases, we tried to find radiological features of individual tumors that would bring the radiologist closer to the correct diagnosis, ensuring the implementation of appropriate treatment. However, the MR images cannot be considered in isolation. Additional patient data, such as the clinical picture, comorbidities/syndromes, and laboratory test results, are necessary. Full article

Objectives: While the treatment of non-small-cell lung carcinoma has improved rapidly, the treatment of pulmonary large-cell neuroendocrine carcinoma (LCNEC) remains underdeveloped. The use of immunohistochemistry allows for accurate risk stratification. With our study, we investigated the outcome of patients with pulmonary LCNEC and analyzed whether CK7 correlates with long-term survival. Methods: We retrospectively collected the monocentric data of patients which underwent anatomical resection for lung cancer between January 2012 and December 2020. Patients that did not show pulmonary LCNEC or adenocarcinoma, had a positive resection margin, or underwent neoadjuvant therapy were excluded. The long-term survival rate of the LCNEC and adenocarcinoma groups were compared before and after propensity score matching. Furthermore, we performed survival analyses for a subgroup of LCNEC distinguished by CK7 expression, followed by Cox regression analyses. Results: A total of 466 patients were integrated for further analysis. The mean age was 65.3 ± 9.6 years. There were no significant differences between both groups regarding age, gender, or comorbidities. In terms of the UICC stage, the groups were equally distributed. Mean survival in the LCNEC group was significantly worse than in the adenocarcinoma group (LCENC: 36.4 ± 7.5 months; adenocarcinoma: 80.7 ± 8.1 months; p-value = 0.001). The mean survival rate was 19.23 ± 4.8 months in the CK7 expression group and 57.01 ± 8.5 months in the group without expression, which reached statistical significance (p-value = 0.019). Conclusions: Our study suggests that pulmonary LCNEC has a significantly worse prognosis than pulmonary adenocarcinoma. CK7 expression seems to be correlated with a worse outcome for the long-term survival rate of patients suffering from highly malignant pulmonary LCNEC. Full article

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, due in part to early invasion and metastasis, which in turn involves epithelial–mesenchymal transition (EMT) of the cancer cells. Prompted by the discovery that two PDAC cell lines of the quasi-mesenchymal subtype (PANC-1, MIA PaCa-2) exhibit neuroendocrine differentiation (NED), we asked whether NED is associated with EMT. Using real-time PCR and immunoblotting, we initially verified endogenous expressions of various NED markers, i.e., chromogranin A (CHGA), synaptophysin (SYP), somatostatin receptor 2 (SSTR2), and SSTR5 in PANC-1 and MIA PaCa-2 cells. By means of immunohistochemistry, the expressions of CHGA, SYP, SSTR2, and the EMT markers cytokeratin 7 (CK7) and vimentin could be allocated to the neoplastic ductal epithelial cells of pancreatic ducts in surgically resected tissues from patients with PDAC. In HPDE6c7 normal pancreatic duct epithelial cells and in epithelial subtype BxPC-3 PDAC cells, the expression of CHGA, SYP, and neuron-specific enolase 2 (NSE) was either undetectable or much lower than in PANC-1 and MIA PaCa-2 cells. Parental cultures of PANC-1 cells exhibit EM plasticity (EMP) and harbor clonal subpopulations with both M- and E-phenotypes. Of note, M-type clones were found to display more pronounced NED than E-type clones. Inducing EMT in parental cultures of PANC-1 cells by treatment with transforming growth factor-β1 (TGF-β1) repressed epithelial genes and co-induced mesenchymal and NED genes, except for SSTR5. Surprisingly, treatment with bone morphogenetic protein (BMP)-7 differentially affected gene expressions in PANC-1, MIA PaCa-2, BxPC-3, and HPDE cells. It synergized with TGF-β1 in the induction of vimentin, SNAIL, SSTR2, and NSE but antagonized it in the regulation of CHGA and SSTR5. Phospho-immunoblotting in M- and E-type PANC-1 clones revealed that both TGF-β1 and, surprisingly, also BMP-7 activated SMAD2 and SMAD3 and that in M- but not E-type clones BMP-7 was able to dramatically enhance the activation of SMAD3. From these data, we conclude that in EMT of PDAC cells mesenchymal and NED markers are co-regulated, and that mesenchymal–epithelial transition (MET) is associated with a loss of both the mesenchymal and NED phenotypes. Analyzing NED in another tumor type, small cell carcinoma of the ovary hypercalcemic type (SCCOHT), revealed that two model cell lines of this disease (SCCOHT-1, BIN-67) do express CDH1, SNAI1, VIM, CHGA, SYP, ENO2, and SSTR2, but that in contrast to BMP-7, none of these genes was transcriptionally regulated by TGF-β1. Likewise, in BIN-67 cells, BMP-7 was able to reduce proliferation, while in SCCOHT-1 cells this occurred only upon combined treatment with TGF-β and BMP-7. We conclude that in PDAC-derived tumor cells, NED is closely linked to EMT and TGF-β signaling, which may have implications for the therapeutic use of TGF-β inhibitors in PDAC management. Full article

Although rare, Merkel cell carcinoma (MCC) is a highly aggressive and increasingly prevalent neuroendocrine cancer of the skin. While current interventions, including surgical resection, radiation, and immunotherapy have been employed in treating many patients, those who remain unresponsive to treatment are met with sparse alternatives and a grim prognosis. For this reason, it is of interest to expand the repertoire of available therapies for MCC patients who remain resistant to current primary interventions. Recently, our improved mechanistic understanding of aberrant cell signaling observed in both MCPyV-positive and -negative MCC has facilitated exploration into several small molecules and inhibitors, among them receptor tyrosine kinase inhibitors (TKIs) and somatostatin analogs (SSAs), both of which have positively improved response rates and reduced tumor volumes upon application to treatment of MCC. The introduction of such targeted therapies into treatment protocols holds promise for more personalized care tailored towards patients of diverse subtypes, thereby improving outcomes and mitigating tumor burden, especially for treatment-resistant individuals. In this review, we characterize recent findings surrounding targeted treatments that have been applied to MCC and provide an overview of emerging perspectives on translatable options that can be further developed to offer additional therapeutic avenues for patients with the disease. Full article

Background/Objectives: Pulmonary neuroendocrine neoplasms (NENs) account for 20% of malignant lung tumors. Their management is challenging due to their diverse clinical features and aggressive nature. Currently, metabolomics offers a range of potential cancer biomarkers for diagnosis, monitoring tumor progression, and assessing therapeutic response. However, a specific metabolomic profile for early diagnosis of lung NENs has yet to be identified. This study aims to identify specific metabolomic profiles that can serve as biomarkers for early diagnosis of lung NENs. Methods: We measured 153 metabolites using liquid chromatography combined with mass spectrometry (LC-MS) in the plasma of 120 NEN patients and compared them with those of 71 healthy individuals. Additionally, we compared these profiles with those of 466 patients with non-small-cell lung cancers (NSCLCs) to ensure clinical relevance. Results: We identified 21 metabolites with consistently altered plasma concentrations in NENs. Compared to healthy controls, 18 metabolites were specific to carcinoid tumors, 5 to small-cell lung carcinomas (SCLCs), and 10 to large-cell neuroendocrine carcinomas (LCNECs). These findings revealed alterations in various metabolic pathways, such as fatty acid biosynthesis and beta-oxidation, the Warburg effect, and the citric acid cycle. Conclusions: Our study identified biomarker metabolites in the plasma of patients with each subtype of lung NENs and demonstrated significant alterations in several metabolic pathways. These metabolomic profiles could potentially serve as biomarkers for early diagnosis and better management of lung NENs. Full article

The large T antigen (LT) of the Merkel cell polyomavirus (MCPyV) is crucial for Merkel cell carcinoma (MCC), a rare but very aggressive form of neuroendocrine skin cancer. The clonal integration of MCPyV DNA into the host genome is a signature event of this malignancy. The resulting expression of oncogenes, including the small T (sT) antigen and a truncated form of the LT (truncLT), directly contribute to carcinogenesis. The truncation of the C-terminus of LT prevents the virus from replicating due to the loss of the origin binding domain (OBD) and the helicase domain. This precludes cytopathic effects that would lead to DNA damage and ultimately cell death. At the same time, the LxCxE motif in the N-terminus is retained, allowing truncLT to bind the retinoblastoma protein (pRb), a cellular tumor suppressor. The continuously inactivated pRb promotes cell proliferation and tumor development. truncLT exerts several classical functions of an oncogene: altering the host cell cycle, suppressing innate immune responses to viral DNA, causing immune escape, and shifting metabolism in favor of cancer cells. Given its central role in MCC, the LT is a major target for therapeutic interventions with novel approaches, such as immune checkpoint inhibition, T cell-based immunotherapy, and cancer vaccines. Full article

Background: This retrospective study aims to examine the patient demographics, survival rates, and treatment methods for small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC) of prostate origin while also identifying the main differences between common types of prostate cancer with comparative analysis for survival. Methods: Our analysis utilized the Surveillance, Epidemiology, and End Results database (SEER), and data was collected from 2000–2020. Cox proportional hazards and chi-squared analysis were used for statistical analysis. Results: A total of 718 cases of prostate small and large neuroendocrine carcinoma were identified. The median age was 71.5 years, and the median follow-up was 11.0 years (95% confidence interval (95% CI) = 9.2–12.8). Most patients were over the age of 80 years (33.8%) and Caucasian (74.4%). The overall 5-year survival was 8.0% (95% CI = 6.8–9.2). The 5-year OS for Caucasians was 7.3% (95% C.I. 6.0–8.3). For Black Americans, the 5-year OS was 11.9% (95% C.I. 7.3–16.5). For Hispanics, the 5-year OS was 12.2% (95% C.I. 7.7–16.7). The 5-year cause-specific survival (CSS) was 16.2% (95% CI = 14.3–18.1). For treatment modality, the five-year survival for each were as follows: chemotherapy, 3.5% (95% CI = 2.1–4.9); surgery, 18.2% (95% CI = 13.6–22.8); multimodality therapy (surgery and chemotherapy), 4.8% (95% CI = 1.7–7.9); and combination (chemoradiation with surgery), 5.0% (95% CI = 1.0–9.0). The prognostic nomogram created to predict patient survivability matched the findings from the statistical analysis with a statistical difference found in race, income, housing, stage, and nodal status. The nomogram also indicated a slight increase in mortality with tumors of greater size. This analysis showed a slight increase in mortality for patients of Asian race. In addition, there was a significant increase in death for patients with stage 3 tumors, as well as patients who underwent surgery and radiation. Furthermore, we performed propensity score matching for survival differences, and no survival difference was found between SCNEC and LCNEC. Conclusions: Asian patients, larger tumor size, and distant disease were associated with worse long-term clinical outcomes. By leveraging insights from registry-based studies, clinicians can better strategize treatment options, improving patient outcomes in this challenging oncology arena. Full article

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs. Full article

(1) Objective: Lung cancer is one of the leading causes of cancer death among men and women across the globe. The accurate and timely diagnosis of lung lesions is of paramount importance for prognosis. This single-center study is the first to assess the diagnostic yield and complication rate of a computed tomography (CT)-guided needle biopsy of pulmonary parenchymal and pleural nodules in an academic training center in the United States. (2) Methods: This is a retrospective study approved by IRB. Patients who underwent CT-guided needle biopsy between 2016 and 2020 were reviewed. A CT-guided needle biopsy involving mediastinal lesions was excluded, focusing only on lung parenchymal and pleural lesions. A CT-guided needle biopsy aborted at any point during the procedure was also excluded from this study. (3) Results: 1063 patients were included in this study; 532 were males, and 531 were females. Lesion size ranged from 0.26 cm to 9.2 cm. 1040 patients received diagnoses, among which 772 had a specific diagnosis, and 268 had nonspecific inflammatory or non-malignant diagnoses. Twenty-three cases were non-diagnostic. Among the patients with specific diagnoses, 691 were malignant, 5 were hamartomas, 30 were fungal infections, 6 were acid-fast-positive organisms, and 40 were unspecified atypical cells. Of the patients that had a malignant diagnosis, 317 were adenocarcinoma, 197 were squamous cell carcinoma, 26 were a neuroendocrine tumor, 45 were non-small cell carcinoma (undifferentiated), 17 were small cell carcinoma, and 89 were other metastatic malignancies to the lung. Various common complications, including pneumothorax (337), hemorrhage (128), and hemoptysis (17), were observed, and 42 of the cases required chest tube intervention; others were treated with observation. Other rare complications observed included hemothorax (4) and oxygen desaturation (2), and there was no death in this series. (4) Conclusions: CT-guided needle biopsy is a reliable diagnostic modality for patients with lung parenchymal and pleural nodules, and it can effectively distinguish between benign and cancerous lesions before invasive procedures such as video-assisted thoracoscopy (VATs) or thoracotomy are planned. Our study showed a higher rate of pneumothorax and pulmonary hemorrhage compared to the rates established in guidelines, attributable to the varying experience level in a busy training academic center. Full article

Background and Objectives: High-grade malignant neuroendocrine tumors (G3 NETs) and neuroendocrine carcinomas (NECs) are characterized by rapid proliferation, high metastatic capacity, and strong expression of somatostatin receptors (SSTRs). We aimed to analyze the presence of SSTRs in NET G3 and NEC, and to correlate their expression with the use of octreotide and pasireotide. Materials and Methods: For this purpose, we first performed a retrospective study of G3 NET and NEC patients, which included the determination of SSTR expression and response to octreotide treatment. Second, we selected the H69 small cell lung cancer cell line to determine the effect of octreotide and pasireotide. Results: Our results showed the traditional somatostatin analog (SSA) octreotide was ineffective in patients with NET G3 and NEC. On the other hand, RT-qPCR showed a high expression of SSTR2 and SSTR5 in H69 cells. Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. Conclusions: In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment. Full article

An elevated serum β2-microglobulin (β2M) level is indicative of impaired glomerular filtration and prerenal diseases, such as malignant tumors, autoimmune disorders, and liver diseases. An elevated serum β2M level has been shown to promote metastasis via the induction of epithelial–mesenchymal transition (EMT) in cancer cells. However, the therapeutic potential of targeting β2M remains unclear. Here, we aimed to investigate the efficacy of Filtor, a small polymethyl methacrylate fiber-based β2M removal column, in reducing the β2M level and suppressing cancer cell-induced EMT and metastasis. We assessed the effects of Filtor on the changes in metastasis based on the number of circulating tumor cells (CTCs), which reflects the post-EMT cancer cell population. We performed therapeutic apheresis using Filtor on a male patient with sinonasal neuroendocrine carcinoma, a female patient with a history of colorectal cancer, and another female patient with a history of pancreatic ductal adenocarcinoma. Significantly low serum β2M levels and CTC counts were observed immediately and 4 weeks after treatment compared with those in the pretreatment phase. Moreover, the CTC count immediately after therapeutic intervention was markedly reduced, likely because Filtor had trapped CTCs directly. These findings suggest that therapeutic apheresis with Filtor can prevent cancer metastasis and recurrence by directly removing CTCs. Full article