{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:36:22Z","timestamp":1791336982109,"version":"4.3.1"},"reference-count":41,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based on a quantitative, automated and repeatable evaluation of the spatial distribution of cells immunohistochemically positive for the proliferation marker Ki-67, performed on the entire extent of high-resolution whole slide images. Combining features from the fields of graph theory, fractality analysis, stochastic geometry and information theory, we describe the topology of replicating cells and predict prognosis in a histology-independent way. We demonstrate how our approach outperforms the well-recognised prognostic role of Ki-67 Labelling Index on a multi-centre dataset comprising the most controversial lung NENs. Moreover, we show that our system identifies arrangement patterns in the cells positive for Ki-67 that appear independently of tumour subtyping. Strikingly, the subset of these features whose presence is also independent of the value of the Labelling Index and the density of Ki-67-positive cells prove to be especially relevant in discerning prognostic classes. These findings disclose a possible path for the future of grading and classification of NENs.<\/jats:p>","DOI":"10.3390\/cancers13194875","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T08:27:44Z","timestamp":1632904064000},"page":"4875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6343-1735","authenticated-orcid":false,"given":"Matteo","family":"Bulloni","sequence":"first","affiliation":[{"name":"Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-3863","authenticated-orcid":false,"given":"Giada","family":"Sandrini","sequence":"additional","affiliation":[{"name":"Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9988-7606","authenticated-orcid":false,"given":"Irene","family":"Stacchiotti","sequence":"additional","affiliation":[{"name":"Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0943-4804","authenticated-orcid":false,"given":"Massimo","family":"Barberis","sequence":"additional","affiliation":[{"name":"Division of Pathology, IRCCS European Institute of Oncology, 20136 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorella","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, Medical School, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Anatomical Pathology Unit-Hospitais da Universidade de Coimbra\/Centro Hospitalar e Universit\u00e1rio de Coimbra-Portugal, Faculty of Medicine, University of Coimbra-Portugal, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Fontanini","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Medical, Molecular and Critical Area, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Al\u00ec","sequence":"additional","affiliation":[{"name":"Operative Unit of Anatomic Pathology, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8954-5888","authenticated-orcid":false,"given":"Francesco","family":"Fortarezza","sequence":"additional","affiliation":[{"name":"Operative Unit of Anatomic Pathology, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0431-9353","authenticated-orcid":false,"given":"Paul","family":"Hofman","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical and Experimental Pathology, FHU OncoAge, Louis Pasteur Hospital BB-0033-00025, IRCAN, Universit\u00e9 C\u00f4te d\u2019Azur, 06100 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Hofman","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical and Experimental Pathology, FHU OncoAge, Louis Pasteur Hospital BB-0033-00025, IRCAN, Universit\u00e9 C\u00f4te d\u2019Azur, 06100 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2418-5025","authenticated-orcid":false,"given":"Izidor","family":"Kern","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0472-5338","authenticated-orcid":false,"given":"Eugenio","family":"Maiorano","sequence":"additional","affiliation":[{"name":"Pathology Section, Department of Emergency and Organ Transplantation, University of Bari, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Maragliano","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8867-0938","authenticated-orcid":false,"given":"Deborah","family":"Marchiori","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9146-1747","authenticated-orcid":false,"given":"Jasna","family":"Metovic","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Turin, 10124 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Papotti","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Turin, 10124 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-3108","authenticated-orcid":false,"given":"Federica","family":"Pezzuto","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, Medical School, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Pisa","sequence":"additional","affiliation":[{"name":"Division of Pathology, IRCCS European Institute of Oncology, 20136 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Remmelink","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasme Hospital, Universit\u00e9 Libre de Bruxelles, 1050 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9021-4560","authenticated-orcid":false,"given":"Gabriella","family":"Serio","sequence":"additional","affiliation":[{"name":"Pathology Section, Department of Emergency and Organ Transplantation, University of Bari, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Marzullo","sequence":"additional","affiliation":[{"name":"Pathology Section, Department of Emergency and Organ Transplantation, University of Bari, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senia Maria Rosaria","family":"Trabucco","sequence":"additional","affiliation":[{"name":"Pathology Section, Department of Emergency and Organ Transplantation, University of Bari, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pennella","sequence":"additional","affiliation":[{"name":"Pathology Division, Department of Surgery, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3336-0021","authenticated-orcid":false,"given":"Angela","family":"De Palma","sequence":"additional","affiliation":[{"name":"Thoracic Surgery Section, Department of Surgery and Organ Transplantation, University of Bari, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Marulli","sequence":"additional","affiliation":[{"name":"Thoracic Surgery Section, Department of Surgery and Organ Transplantation, University of Bari, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambrogio","family":"Fassina","sequence":"additional","affiliation":[{"name":"Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padova, Via Aristide Gabelli, 61, 35121 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-3724","authenticated-orcid":false,"given":"Valeria","family":"Maffeis","sequence":"additional","affiliation":[{"name":"Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padova, Via Aristide Gabelli, 61, 35121 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2614-944X","authenticated-orcid":false,"given":"Gabriella","family":"Nesi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Naheed","sequence":"additional","affiliation":[{"name":"Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Rea","sequence":"additional","affiliation":[{"name":"Thoracic Surgery Unit, Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, Medical School, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3619-1657","authenticated-orcid":false,"given":"Christian H.","family":"Ottensmeier","sequence":"additional","affiliation":[{"name":"Liverpool Head and Neck Centre, Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L1 8JX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fausto","family":"Sessa","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5714-7295","authenticated-orcid":false,"given":"Silvia","family":"Uccella","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4725-4692","authenticated-orcid":false,"given":"Giuseppe","family":"Pelosi","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"},{"name":"Inter-Hospital Pathology Division, IRCCS MultiMedica, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Pattini","sequence":"additional","affiliation":[{"name":"Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","unstructured":"(2021, June 24). Surveillance, Epidemiology, and End Results (SEER) Program (Www.Seer.Cancer.Gov) SEER*Stat Database: Incidence\u2014SEER Research Limited-Field Data, 21 Registries, November 2019 Sub (2000\u20132017)\u2014Linked To County Attributes\u2014Time Dependent (1990\u20132017) Income\/Rurality, 1969\u20132018 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Released April 2020, Based on the November 2019 Submission, Available online: https:\/\/seer.cancer.gov\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1053\/j.seminoncol.2018.07.001","article-title":"Epidemiologic trends in neuroendocrine tumors: An examination of incidence rates and survival of specific patient subgroups over the past 20 years","volume":"45","author":"Sackstein","year":"2018","journal-title":"Semin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1097\/JTO.0000000000000630","article-title":"The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances since the 2004 Classification","volume":"10","author":"Travis","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_4","first-page":"223","article-title":"Grading lung neuroendocrine tumors: Controversies in search of a solution","volume":"32","author":"Pelosi","year":"2017","journal-title":"Histol. Histopathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1038\/s41467-019-11276-9","article-title":"Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids","volume":"10","author":"Alcala","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/s41467-018-03099-x","article-title":"Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors","volume":"9","author":"George","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1159\/000506292","article-title":"Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology","volume":"111","author":"Cros","year":"2020","journal-title":"Neuroendocrinology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1016\/j.jtho.2019.05.003","article-title":"Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations","volume":"14","author":"Simbolo","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1159\/000495806","article-title":"Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20","volume":"108","author":"Kasajima","year":"2019","journal-title":"Neuroendocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s00428-017-2177-0","article-title":"Distinctive pathological and clinical features of lung carcinoids with high proliferation index","volume":"471","author":"Gatti","year":"2017","journal-title":"Virchows Arch."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/PAS.0000000000000767","article-title":"High-Grade Neuroendocrine Carcinoma of the Lung with Carcinoid Morphology: A Study of 12 Cases","volume":"41","author":"Quinn","year":"2017","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/path.4853","article-title":"Lung neuroendocrine tumours: Deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D","volume":"241","author":"Simbolo","year":"2017","journal-title":"J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1158\/1078-0432.CCR-15-2946","article-title":"Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma\u2013like and Non\u2013Small Cell Carcinoma\u2013like Subsets","volume":"22","author":"Rekhtman","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1159\/000502776","article-title":"Classification and Prognostic Stratification of Bronchopulmonary Neuroendocrine Neoplasms","volume":"110","author":"Oka","year":"2020","journal-title":"Neuroendocrinology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/ERC-13-0246","article-title":"Grading the neuroendocrine tumors of the lung: An evidence-based proposal","volume":"21","author":"Rindi","year":"2014","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1038\/s41379-018-0110-y","article-title":"A common classification framework for neuroendocrine neoplasms: An International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal","volume":"31","author":"Rindi","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.pathol.2019.03.011","article-title":"Prognostic value of cyclin A2 and B1 expression in lung carcinoids","volume":"51","author":"Brcic","year":"2019","journal-title":"Pathology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1097\/JTO.0000000000000316","article-title":"The Oncofetal Protein IMP3: A Useful Marker to Predict Poor Clinical Outcome in Neuroendocrine Tumors of the Lung","volume":"9","author":"Vaira","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"41959","DOI":"10.18632\/oncotarget.9747","article-title":"Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects","volume":"7","author":"Neubauer","year":"2016","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s00428-019-02596-8","article-title":"Spread through air spaces (STAS) is a predictor of poor outcome in atypical carcinoids of the lung","volume":"475","author":"Altinay","year":"2019","journal-title":"Virchows Arch."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.jtho.2019.05.009","article-title":"Spread Through Air Spaces (STAS) Is Prognostic in Atypical Carcinoid, Large Cell Neuroendocrine Carcinoma, and Small Cell Carcinoma of the Lung","volume":"14","author":"Aly","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8","DOI":"10.4103\/jpi.jpi_76_18","article-title":"Ki67 quantitative interpretation: Insights using image analysis","volume":"10","author":"Asa","year":"2019","journal-title":"J. Pathol. Inform."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"513","DOI":"10.21037\/tlcr.2017.09.04","article-title":"Classification of pulmonary neuroendocrine tumors: New insights","volume":"6","author":"Pelosi","year":"2017","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s00428-013-1408-2","article-title":"Interobserver Agreement of Proliferation Index (Ki-67) Outperforms Mitotic Count in Pulmonary Carcinoids","volume":"462","author":"Warth","year":"2013","journal-title":"Virchows Arch."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kwon, A.-Y., Park, H.Y., Hyeon, J., Nam, S.J., Kim, S.W., Lee, J.E., Yu, J.-H., Lee, S.K., Cho, S.Y., and Cho, E.Y. (2019). Practical approaches to automated digital image analysis of Ki-67 labeling index in 997 breast carcinomas and causes of discordance with visual assessment. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212309"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1097\/PAS.0b013e31821a0696","article-title":"Effect of Tumor Heterogeneity on the Assessment of Ki67 Labeling Index in Well-differentiated Neuroendocrine Tumors Metastatic to the Liver: Implications for Prognostic Stratification","volume":"35","author":"Yang","year":"2011","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"982","DOI":"10.5858\/arpa.2019-0374-OA","article-title":"Ki-67 Labeling Index in Pulmonary Carcinoid Tumors: Comparison Between Small Biopsy and Resection Using Tumor Tracing and Hot Spot Methods","volume":"144","author":"Boland","year":"2020","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1177\/1066896919889148","article-title":"Correlation Between Digital and Manual Determinations of Ki-67\/MIB-1 Proliferative Indices in Human Meningiomas","volume":"28","author":"Pham","year":"2020","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"226","DOI":"10.3389\/fbioe.2019.00226","article-title":"IHC Color Histograms for Unsupervised Ki67 Proliferation Index Calculation","volume":"7","author":"Geread","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.pathol.2019.08.004","article-title":"Invasive lobular carcinoma of the breast: Assessment of proliferative activity using automated Ki-67 immunostaining","volume":"51","author":"Dessauvagie","year":"2019","journal-title":"Pathology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/his.14140","article-title":"Automated assessment of Ki-67 in breast cancer: The utility of digital image analysis using virtual triple staining and whole slide imaging","volume":"77","author":"Hida","year":"2020","journal-title":"Histopathology"},{"key":"ref_32","unstructured":"(2020, August 04). NDP.View2 Viewing Software. Available online: https:\/\/nanozoomer.hamamatsu.com\/eu\/en\/product\/search\/U12388-01\/index.html."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s00428-015-1843-3","article-title":"Interlaboratory variability of MIB1 staining in well-differentiated pancreatic neuroendocrine tumors","volume":"467","author":"Blank","year":"2015","journal-title":"Virchows Arch."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1097\/PAI.0000000000000799","article-title":"Impact of Primary Antibody Clone, Format, and Stainer Platform on Ki67 Proliferation Indices in Breast Carcinomas","volume":"27","author":"Nielsen","year":"2019","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00428-016-2062-2","article-title":"Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied","volume":"470","author":"Fabbri","year":"2017","journal-title":"Virchows Arch."},{"key":"ref_36","first-page":"1796","article-title":"Ripley\u2019s K Function","volume":"3","author":"Dixon","year":"2001","journal-title":"Encycl. Env."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Napolitano, A., Ungania, S., and Cannat, V. (2012). Fractal Dimension Estimation Methods for Biomedical Images. MATLAB\u2014A Fundamental Tool for Scientific Computing and Engineering Applications\u2014Volume 3, InTech.","DOI":"10.5772\/48760"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ahammer, H. (2011). Higuchi Dimension of Digital Images. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024796"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"162","DOI":"10.4304\/jcp.7.1.161-168","article-title":"Neighborhood Component Feature Selection for High-Dimensional Data","volume":"7","author":"Yang","year":"2012","journal-title":"J. Comput."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1090\/S0025-5718-1980-0572855-7","article-title":"Updating Quasi-Newton Matrices with Limited Storage","volume":"35","author":"Nocedal","year":"1980","journal-title":"Math. Comput."},{"key":"ref_41","first-page":"255","article-title":"Iterative Single Data Algorithm for Training Kernel Machines from Huge Data Sets: Theory and Performance","volume":"177","author":"Kecman","year":"2005","journal-title":"Integr. Fuzzy Logic. Chaos Theory"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/19\/4875\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:07:02Z","timestamp":1760166422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/19\/4875"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":41,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["cancers13194875"],"URL":"https:\/\/doi.org\/10.3390\/cancers13194875","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]}}}