Massimo Milione1, Patrick Maisonneuve2, Federica Grillo3, Alessandro Mangogna4, Giovanni Centonze5,6, Natalie Prinzi7, Sara Pusceddu7, Giovanna Garzone5, Laura Cattaneo5, Adele Busico8, Paola Bossi9, Paola Spaggiari9, Alessio Pellegrinelli10, Alessandro Del Gobbo11, Stefano Ferrero11,12, Ketevani Kankava13, Giancarlo Pruneri8,14, Luigi Rolli15, Elisa Roca16, Luisa Bercich17, Andrea Tironi17, Mauro Roberto Benvenuti18, Maria Sole Gallazzi18, Rosalia Romano18, Alfredo Berruti16, Ugo Pastorino15, Carlo Capella19. 1. First Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy, Massimo.milione@istitutotumori.mi.it. 2. Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy. 3. Unit of Pathology, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy. 4. Unit of Pathology, Clinical Department of Medical, Surgical and Health Science, University of Trieste, Ospedale di Cattinara, Trieste, Italy. 5. First Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. 6. Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 7. Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. 8. 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. 9. Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy. 10. Department of Pathology, ASST Franciacorta, Mellino Mellini Hospital, Brescia, Italy. 11. Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 12. Department of Biomedical Surgical and Dental Sciences, University of Milan, Milan, Italy. 13. Teaching, Scientific and Diagnostic Pathology Laboratory, Tbilisi State Medical University, Tbilisi, Georgia. 14. School of Medicine, University of Milan, Milan, Italy. 15. Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 16. Medical Oncology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Brescia, Italy. 17. Department of Pathology, ASST Spedali Civili of Brescia, Brescia, Italy. 18. Thoracic Surgery Unit, Department of Medical and Surgical Specialties Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy. 19. Unit of Pathology, Department of Medicine and Surgery and Research Center for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy.
Abstract
BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.
BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.
Authors: Guido Rindi; Ozgur Mete; Silvia Uccella; Olca Basturk; Stefano La Rosa; Lodewijk A A Brosens; Shereen Ezzat; Wouter W de Herder; David S Klimstra; Mauro Papotti; Sylvia L Asa Journal: Endocr Pathol Date: 2022-03-16 Impact factor: 3.943
Authors: Fabrice Viol; Bence Sipos; Martina Fahl; Till S Clauditz; Tania Amin; Malte Kriegs; Maike Nieser; Jakob R Izbicki; Samuel Huber; Ansgar W Lohse; Jörg Schrader Journal: Cell Oncol (Dordr) Date: 2022-10-21 Impact factor: 7.051
Authors: Bregtje C M Hermans; Jules L Derks; Lisa M Hillen; Irene van der Baan; Esther C van den Broek; Jan H von der Thüsen; Robert-Jan van Suylen; Peggy N Atmodimedjo; T Dorine den Toom; Cecile Coumans-Stallinga; Wim Timens; Winand N M Dinjens; Hendrikus J Dubbink; Ernst-Jan M Speel; Anne-Marie C Dingemans Journal: Int J Cancer Date: 2021-11-10 Impact factor: 7.316