Adele Busico1, Patrick Maisonneuve2, Natalie Prinzi3, Sara Pusceddu3, Giovanni Centonze1, Giovanna Garzone1, Alessio Pellegrinelli4, Luca Giacomelli5,6, Alessandro Mangogna7, Cinzia Paolino1,8, Antonino Belfiore1, Ketevani Kankava9, Federica Perrone1, Elena Tamborini1, Giancarlo Pruneri10,11, Nicola Fazio12, Massimo Milione13. 1. 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy. 2. Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy. 3. Medical Oncology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy. 4. Department of Pathology, ASST Franciacorta, Mellino Mellini Hospital, Chiari, Brescia, Italy. 5. Department of Surgical Sciences and Integrated Diagnostics, School of Medicine, University of Genoa, Genoa, Italy. 6. Polistudium SRL, Milan, Italy. 7. Pathology Unit, Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Ospedale di Cattinara, Trieste, Italy. 8. Department of Research, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy. 9. Teaching, Scientific and Diagnostic Pathology Laboratory, Tbilisi State Medical University, Tbilisi, Georgia. 10. School of Medicine, University of Milan, Milan, Italy. 11. 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy. 12. Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. 13. 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, Massimo.milione@istitutotumori.mi.it.
Abstract
BACKGROUND: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1. METHODS: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS). RESULTS: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2-89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9-169, p = 0.0007). CONCLUSIONS: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.
BACKGROUND: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1. METHODS: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS). RESULTS: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2-89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9-169, p = 0.0007). CONCLUSIONS: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.
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