Biomedical subjects

Paola Spaggiari

Publications and source records attributed to Paola Spaggiari.

3 recordsLinked to original sources

PubMed2026

Comprehensive Clinicopathologic, Immunohistochemical, and Genomic Profiling of Sporadic Ampullary Somatostatin-producing D-cell Neuroendocrine Tumors Identifies Recurrent HRAS Hotspot Mutations.

Ampullary somatostatin-producing D-cell neuroendocrine tumors are rare neoplasms that may be associated with type 1 neurofibromatosis. The molecular features of sporadic ampullary somatostatin-producing D-cell neuroendocrine tumors (SAMSOM-NETs) remain poorly characterized. We performed an integrated morphological, immunohistochemical, and genomic analysis of a multicenter series of SAMSOM-NETs. Eleven cases were included (73% male; median age: 63 years). All six patients who underwent lymphadenectomy were staged as pN1, and liver metastases were found in three cases; however, no tumor-related deaths occurred (median follow-up: 104 months). Common histologic features that can pose diagnostic challenges in the differential diagnosis with adenocarcinoma included a tubulo-glandular architecture (100%), periodic Acid-Schiff (PAS)-positive intraluminal mucin (73%), MUC1 expression (100%), and carcinoembryonic antigen (45%) expression. All tumors exhibited dot-like cytoplasmic reactivity for cytokeratins (CK) CAM5.2 or CK AE1/AE3, and 82% were CK7-positive. ISL1 and PDX1 were diffusely expressed in all cases, while CDX2 was positive in 54% and ARX showed only focal expression in four tumors. Genomic profiling revealed microsatellite stability and low tumor mutational burden. Alterations in the RAS pathway, including HRAS mutations (4 cases, 36%), a KRAS mutation (1 case), and NF1 alterations (one case), were identified in 54% of cases and in all tumors with liver metastases. Additional molecular findings included a CDK12 splice-site alteration and an NTRK3::PRDM4 fusion. Potentially actionable alterations affecting kinase-related pathways were detected in 64% of tumors. Our findings support SAMSOM-NET as a peculiar neuroendocrine tumor subtype showing distinctive histologic and molecular characteristics with potential diagnostic and therapeutic implications.

Humans↗

PubMed2026

Multinucleated Giant Cells in Human Pancreatic Cancer Are a Distinct Macrophage Population Undergoing a DNA Damage Response and Associated with an Aggressive Tumor Microenvironment.

Macrophages (Mϕ) constitute a dominant and functionally diverse immune population within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), yet how Mϕ heterogeneity contributes to the tumor remains poorly defined. In an institutional cohort of 145 PDAC specimens, we identified a population of multinucleated giant cells (MGC) of Mϕ origin, an entity previously described in chronic inflammation but rarely in cancer. CD68+ MGCs were present in 28% of tumors, enriched in squamous, nonglandular regions, and more frequent after neoadjuvant chemotherapy. By integrating spatial transcriptomics and quantitative imaging, we defined the features of these cells, which, compared with MGCs in nonneoplastic inflammatory lesions, lacked canonical polarization markers (HLA-DR and CD163) and displayed a distinctive transcriptional program characterized by upregulation of the POLR2K, TUBA8, COX5B, and VDAC1 genes, which encode proteins involved in DNA repair, oxidative stress, and MYC signaling. Spatial analyses revealed activation of hypoxia and extracellular matrix-remodeling pathways in MGC-associated niches, and experimental hypoxia promoted MGC formation in vitro. Consistent with these data, we found that in the The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset a Mϕ MGC gene signature was enriched in the squamous PDAC subtype and correlated with poorer overall survival (P = 0.018). Morphometric and immunofluorescence analyses further showed increased 53BP1+Ki67+ nuclei and nuclear atypia in MGCs, indicating ongoing proliferation despite DNA damage. Together, these data identify MGCs of Mϕ origin as an immune cell state shaped by hypoxia and stress signaling, associated with aggressive tumor phenotypes, and potentially exploitable as an immune classifier in PDAC.

Humans↗

PubMed2025

Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.

Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.

Humans↗