Pietro Tralongo

Background: Triple-negative breast carcinoma (TNBC) comprises several histological entities with different molecular alterations and clinical behaviour. Recognising these entities is important for accurate classification and for choosing appropriate immunohistochemical and molecular tests. Methods: We conducted a narrative review of English-language literature identified through PubMed/MEDLINE, Scopus, Web of Science Core Collection, citation searching and a Scopus publication list. Journal publications available through 24 August 2026 were eligible. Current reporting and regulatory guidance was obtained from official websites. Findings were synthesised qualitatively, without statistical pooling. Results: The review included 93 journal publications and two official documents. Secretory carcinoma, adenoid cystic carcinoma, tall cell carcinoma with reversed polarity and metaplastic carcinoma require a different diagnostic approach from conventional high-grade invasive breast carcinoma of no special type. Architectural, cytological and stromal findings guide the differential diagnosis and the selection of immunohistochemical stains and molecular assays. Limited sampling, tumour heterogeneity and treatment-related changes can affect tissue selection and interpretation. Conclusions: Pathology reports should specify the histological type and clearly state any remaining diagnostic uncertainty. Morphology should guide diagnostic testing, while validated predictive biomarkers and clinical criteria determine treatment eligibility.

Background/Objectives: We examined combinations of immune- and stromal-associated features in pretreatment triple-negative breast cancer (TNBC) biopsies and explored their clinical and germline associations. Methods: This retrospective study included 24 women with nonmetastatic TNBC from a clinically selected BRCA1/BRCA2-tested cohort. Two pathologists, blinded to clinical and germline data, jointly assessed stromal tumor-infiltrating lymphocytes (sTILs), programmed death-ligand 1 (PD-L1), CD68/CD163-positive macrophages, and CD117/tryptase-positive mast cells. Profiles were assigned before unblinding. A second blinded joint sTIL assessment provided continuous estimates for subsequent hierarchical clustering; profile assignments remained unchanged. Results: Profiles I–III comprised seven, 13, and four tumors, respectively. Profile I combined higher sTILs and PD-L1 with a CD68-high/CD163-low pattern and rare mast cells. Profile II showed lower sTILs and PD-L1, a CD68-low/CD163-high pattern, and dense mast-cell hotspots; Profile III had minimal sTILs, low macrophage counts, and no mast cells detected in evaluated fields. Clustering reproduced these assignments. All four patients with pathogenic/likely pathogenic germline BRCA1/BRCA2 variants were in Profile I (adjusted p = 0.030); omitting one positive case at a time increased the adjusted p value to 0.068. Seven of 16 neoadjuvant-treated patients achieved pathologic complete response. Five posttreatment recurrences and seven deaths were recorded; exploratory comparisons of pathologic complete response and overall survival were inconclusive. Conclusions: These profiles describe different combinations of lymphocytic infiltration, PD-L1 expression, macrophage counts, and mast-cell hotspots. The profiles and the exploratory BRCA1/BRCA2 finding require validation in larger, independent cohorts before clinical use.

Philadelphia‐negative myeloproliferative neoplasms (MPN), a spectrum of blood malignancies characterized by uncontrolled myeloid proliferation, persist as a key challenge in onco‐hematology due to their intricate molecular background, heterogeneous clinical phenotypes, and variable prognoses. Although generally accepted as indolent disorders, a considerable fraction of MPN patients exhibit progressive, and sometimes accelerated, bone marrow fibrosis, reflecting a critical shift toward a more debilitating condition marked by an increased symptom burden. As marrow scarring advances, hematopoietic capacity declines, severely compromising both patients' quality of life and survival. Increasing evidence highlights the crucial involvement of multiple players and mechanisms orchestrating marrow fibrotic transformation, thereby reflecting the multifaceted nature of this pathogenetic process. In this review, we untangle the pro‐fibrotic programs underlying fibrosis progression in MPN, critically analyzing the available scientific literature. We explore the potential impact of the mutational landscape on the fibrotic transformation risk and examine the role of dysfunctional megakaryocytes as principal catalysts of fibrotic remodeling. Additionally, we provide insight into the influence of the bone marrow microenvironment, examining the contribution of both soluble factors and direct cell‐cell communication in sustaining and exacerbating the fibrotic signature. The urgent need for earlier diagnoses, tailored prognoses, and more effective therapeutic strategies stresses the importance of investigating the pathological basis of fibrotic progression from a deeper perspective.

Programmed death-ligand 1 (PD-L1) expression in Grade Group 1 (GG1) prostate carcinoma biopsies has not been established as a marker of pathological upgrading at radical prostatectomy (RP). This two-center retrospective case–control study included 172 men with GG1 carcinoma in the biopsy closest to RP: all 86 patients upgraded to GG2 and 86 randomly selected non-upgraded controls from 126 eligible GG1 patients. PD-L1 was assessed with the SP263 clone using the combined positive score (CPS), with CPS ≥ 1 predefined before outcome comparison. CPS ≥ 1 occurred in 36/86 upgraded cases (41.9%) and 18/86 controls (20.9%; unadjusted odds ratio [OR], 2.72; 95% confidence interval [CI], 1.39–5.33; p = 0.005). After adjustment for serum prostate-specific antigen, positive-core count, Prostate Imaging Reporting and Data System category, and center, CPS ≥ 1 remained associated with upgrading (adjusted OR, 2.91; 95% CI, 1.47–5.97; p = 0.003). A Firth bias-reduced sensitivity model including digital rectal examination yielded a similar CPS estimate. Biopsy CPS ≥ 1 was associated with biopsy–RP grade discordance, but the study does not establish an optimal cutoff, predictive performance, or clinical utility. Prospective multicenter validation, including active-surveillance outcomes, is required.

Mutations in isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) define a major subgroup of adult‐type diffuse gliomas and induce accumulation of D‐2‐hydroxyglutarate, resulting in extensive DNA and histone methylation changes. This epigenetic reprogramming underlies the glioma CpG island methylator phenotype (G‐CIMP) and contributes to tumour lineage, differentiation state and clinical behaviour. DNA methylation profiling has consequently evolved from a research tool into an important ancillary method for CNS tumour classification, molecular subclassification and copy‐number analysis. This narrative review examines the biological basis, analytical platforms and clinical applications of DNA methylation profiling in IDH‐mutant gliomas. Particular attention is given to the distinction between research‐defined G‐CIMP‐high and G‐CIMP‐low states and classifier‐defined lower‐grade and high‐grade methylation subclasses. High‐grade signatures, including A_IDH_HG and G‐CIMP‐low, are associated with adverse genomic features and outcome but should not be considered interchangeable or used in isolation to assign CNS WHO grade. Their interpretation requires integration with histology and established molecular criteria, including homozygous CDKN2A/B deletion. The review also discusses array‐based profiling, emerging Nanopore and long‐read approaches, computational quality control, and the integration of methylation data with genomic and transcriptomic alterations. Longitudinal studies indicate that a subset of IDH‐mutant astrocytomas undergoes methylation loss, copy‐number accumulation and altered cell‐state differentiation during progression, although these changes are not universal. The clinical relevance of MGMT promoter methylation is more context‐dependent than in IDH‐wildtype glioblastoma. Moreover, the INDIGO trial established the clinical activity of mutant IDH inhibition in selected Grade 2 gliomas but did not validate methylation class as a predictive biomarker or demonstrate complete epigenetic reversal. Emerging applications, including single‐cell and spatial epigenomics, tumour microenvironment deconvolution and CSF methylation profiling, remain investigational. Overall, DNA methylation profiling is most valuable when used as integrated diagnostic and risk‐stratification evidence within the complete histological, genomic and clinical context.

Thermal ablation (TA) is an increasingly adopted minimally invasive treatment for benign thyroid nodules. However, TA induces marked histological alterations that may simulate thyroid malignancy, creating significant diagnostic pitfalls for pathologists. The present study expands our previous institutional series and further characterizes the morphologic, immunohistochemical, and molecular features of thermally ablated thyroid nodules in order to refine the differential diagnosis with thyroid carcinoma. Fourteen surgically excised thyroid nodules previously treated with laser thermal ablation were retrospectively analyzed. Histopathological evaluation focused on architectural changes, nuclear atypia, capsule alterations, degenerative phenomena, and evidence of invasion. Immunohistochemical analysis included galectin-3 (Gal-3), HBME-1, BRAF V600E, p53, and Ki-67. In addition, molecular profiling for the principal thyroid cancer-related alterations, including BRAF, RAS family genes, TERT promoter mutations, PIK3CA alterations, and RET rearrangements, was performed using targeted next-generation sequencing. All nodules showed treatment-related reactive and degenerative changes, including fibrosis/sclerosis, subcapsular hemorrhage, focal oncocytic metaplasia, and architectural distortion. No true capsular or vascular invasion was identified. Immunohistochemically, all cases were negative for Gal-3 and BRAF V600E, while HBME-1 expression was absent or only focally weak. Ki-67 proliferative activity remained consistently low (<3%) in all cases. Molecular analyses did not identify pathogenic alterations involving BRAF, RAS, TERT promoter, PIK3CA, or RET genes in any case. Thermal ablation induces reproducible reactive and degenerative histologic alterations that may closely mimic follicular or papillary thyroid neoplasms. The absence of malignancy-associated immunohistochemical and molecular alterations strongly supports the benign nature of these lesions and highlights the importance of an integrated morphologic, immunohistochemical, and molecular diagnostic approach in challenging post-ablation specimens. Thermally ablated thyroid nodules may display significant pseudo-neoplastic changes that can lead to overdiagnosis of carcinoma. Awareness of these treatment-related alterations, combined with immunohistochemical and molecular profiling, represents a reliable strategy to distinguish reactive post-ablation changes from true thyroid malignancy and to avoid inappropriate clinical management.

The invasive tumor front (ITF) of colorectal carcinoma (CRC) is a biologically active interface where epithelial dissociation, stromal activation, immune remodeling, and angiogenesis converge. This retrospective histopathological association study examined whether tumor budding combined with selected ITF microenvironmental markers could better characterize aggressive clinicopathological features of non-metastatic CRC. Fifty-two surgically resected primary CRCs were analyzed after exclusion of patients with distant metastatic disease at diagnosis or surgery. Tumor budding was scored according to ITBCC 2016 criteria. Immunohistochemistry evaluated stromal podoplanin (D2-40) expression, CD34-based microvessel density, the CD163/CD68 ratio, and CD117-positive mast cell density. An unweighted integrated ITF microenvironment score (0–4) was generated by summing high values for these four parameters. High histological grade, lymphovascular invasion, high tumor budding, and node-positive disease were significantly associated with multiple microenvironment-related alterations. The integrated ITF score was significantly higher in high-grade, lymphovascular invasion-positive, node-positive, and high-budding CRCs, suggesting cumulative stromal, immune, and vascular remodeling at the invasive front. These findings support the ITF as an integrated histopathological compartment in CRC progression. However, the score remains hypothesis-generating and requires validation in larger, independent, molecularly and outcome-annotated cohorts before prognostic or clinical use.

Programmed death-ligand 1 (PD-L1) has become a central biomarker and therapeutic target across multiple solid tumors, yet its clinical meaning in prostate cancer (PCa) remains unsettled. PCa is commonly described as an immunologically ‘cold’ malignancy, characterized by limited baseline cytotoxic T-cell infiltration and a tumor microenvironment (TME) shaped by myeloid-driven suppression and low neoantigen load in many cases. Against this background, PD-L1 expression in PCa is typically low in untreated primary tumors but can increase in aggressive variants, advanced stages, and metastatic castration-resistant disease, where therapy pressure and microenvironmental cues may select for immune-evasive phenotypes. The literature is further complicated by major analytic variability, including differences in antibody clones and platforms, scoring algorithms (tumor proportion score, combined positive score, immune-cell scoring), cut-offs, tissue sites and timing, and pre-analytical variables such as fixation and decalcification. Collectively, available studies suggest that higher PD-L1 expression tends to be associated with adverse clinicopathological features and may enrich for responses to immune checkpoint inhibitors in selected settings, but PD-L1 immunohistochemistry alone is insufficient as a stand-alone predictive tool in unselected patients. This review synthesizes the biological drivers of PD-L1 regulation in PCa, dissects key methodological sources of heterogeneity in PD-L1 assessment, summarizes clinicopathological and therapeutic correlations, and outlines emerging biomarkers and approaches (including mismatch repair deficiency/microsatellite instability, tumor mutational burden, gene-expression signatures, liquid biopsies, and neuro-immune interactions) that may enable more actionable patient stratification.