Ida Rizzuto

Sequestosome 1 (SQSTM1/p62) links autophagy to cellular stress responses and can be assessed by immunohistochemistry. In triple-negative breast cancer (TNBC), however, its staining has no single biological interpretation. This selective narrative review examines human tissue studies alongside experimental evidence, focusing on the pathological assessment of mitochondrial stress. Human evidence remains limited—retrospective cohorts report inconsistent prognostic associations, and treatment-related changes are poorly characterized. Increased p62 can reflect enhanced synthesis or impaired degradation; mitochondrial clearance can also proceed without it. These observations explain why p62 staining alone cannot measure mitophagic flux. We propose assessing p62 distribution and abundance alongside mitochondrial content, oxidative damage and autophagy–lysosomal markers to describe exploratory tissue profiles. Each profile is linked to a proposed mechanism and to findings that would support or challenge that explanation. We consider baseline response associations separately from changes in residual disease, because complete responders lack residual invasive tumor for paired analysis. Mitochondrial turnover, respiratory function and genetic perturbation with rescue offer complementary ways to test the proposed dependencies. This framework provides a basis for investigating the relationship between mitochondrial damage, clearance, recovery and treatment persistence; its clinical relevance remains to be established.

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.

Pituitary neuroendocrine tumors (PitNETs) are usually indolent but may show invasive growth, recurrence, hormonal hypersecretion, and treatment resistance. Autophagy intersects with nutrient sensing, lysosomal homeostasis, mitochondrial quality control, and secretory-granule turnover, but its biological effects in PitNETs are context-dependent. This narrative review synthesizes PitNET-specific and mechanistically relevant evidence on macroautophagy, mitophagy, crinophagy, non-coding RNA and epigenetic regulation, treatment resistance, and pharmacological modulation, emphasizing the distinction between static autophagy markers and dynamic autophagic flux. Evidence is interpreted across human tissue, primary human cells, pituitary tumor cell lines, animal models, and clinical observations, while preserving clear separation between human observations and mechanistic evidence derived from experimental models. Across experimental systems, autophagy activation is associated with antitumor effects in selected settings, whereas completed basal flux may support stress adaptation and late-stage or selective-autophagy inhibition may enhance cytotoxicity. Biological outcome therefore depends on tumor lineage, treatment, the pathway stage affected, and whether flux is completed. Recent studies extend this framework to selective mitophagy, ncRNA/exosomal resistance networks, epitranscriptomic regulation, somatostatin-analogue resistance, and tumor-microenvironmental signaling. Clinical translation remains limited, and no autophagy-modulating strategy is validated for routine PitNET management. Future studies should integrate dynamic flux measurements, lineage-specific biomarkers, pharmacodynamic target engagement, and prospective clinical endpoints.

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.