{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:07:17Z","timestamp":1791234437252,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u20134) 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.<\/jats:p>","DOI":"10.3390\/ijms27114971","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:45:08Z","timestamp":1780404308000},"page":"4971","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrating Tumor Budding and the Invasive-Front Microenvironment in Colorectal Carcinoma: An Exploratory Histopathological Score-Based Association Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3478-9217","authenticated-orcid":false,"given":"Valeria","family":"Zuccal\u00e0","sequence":"first","affiliation":[{"name":"Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-1761","authenticated-orcid":false,"given":"Vincenzo","family":"Fiorentino","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"},{"name":"PhD Program in Translational Molecular Medicine and Surgery, Department of Biomedical Sciences, Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa Maria","family":"Martorana","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1349-0910","authenticated-orcid":false,"given":"Gabriele","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"PhD Program in Translational Molecular Medicine and Surgery, Department of Biomedical Sciences, Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy"},{"name":"Istituto Clinico Polispecialistico C.O.T. Cure Ortopediche Traumatologiche s.p.a., 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-3283","authenticated-orcid":false,"given":"Pietro","family":"Tralongo","sequence":"additional","affiliation":[{"name":"PhD Program in Translational Molecular Medicine and Surgery, Department of Biomedical Sciences, Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-3126","authenticated-orcid":false,"given":"Giuliana","family":"Ciappina","sequence":"additional","affiliation":[{"name":"Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Abbonante","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8043-6100","authenticated-orcid":false,"given":"Michele","family":"Ammendola","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-9148","authenticated-orcid":false,"given":"Massimiliano","family":"Berretta","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Fadda","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6260-6310","authenticated-orcid":false,"given":"Maurizio","family":"Martini","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2878-3572","authenticated-orcid":false,"given":"Antonio","family":"Ieni","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age \u201cGaetano Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e24585","DOI":"10.1002\/jcla.24585","article-title":"The role of the tumor microenvironment in colorectal cancer and the potential therapeutic approaches","volume":"36","author":"Zafari","year":"2022","journal-title":"J. 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