{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T16:56:40Z","timestamp":1764953800436,"version":"3.46.0"},"reference-count":42,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017638","name":"Ministry of Health of the Russian Federation","doi-asserted-by":"publisher","award":["056\u201303-2024\u2013046"],"award-info":[{"award-number":["056\u201303-2024\u2013046"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Cell-in-cell (CIC) structure is a histological picture of a whole cell inside another cell. Homotypic CIC structures formed by cancer cells are consistently demonstrated to be a factor of poor prognosis and resistance to chemo- and immunotherapy in colorectal cancer (CRC). However, the absence of a standardized counting method limits the use of this factor in the applied research. Objective: To propose an adapted method for quantifying CIC structures in CRC surgical specimens and to evaluate their correlation with established adverse prognostic factors. Methods: A total of 250 histological slides of surgical specimens from 58 patients with pT1-pT4 colorectal adenocarcinoma were studied. Identification of tumor cells and visualization of CIC structures were performed by immunohistochemistry (CK20). Quantitative assessment was performed on digital scans of H&amp;E stained slides. Quantitative assessment was performed on digital slide scans stained with H&amp;E. CIC structures were counted in 5 fields of view corresponding to a \u00d740 objective (0.975 mm2). A correlation analysis of CIC structures with CRC poor prognosis factors was performed. Results: Immunohistochemical study (CK20) confirmed the formation and prevalence of homotypic structures (95%) over heterotypic ones (5%) (p &lt; 0.001). This finding informed the evaluation of H&amp;E-stained slides and the formulation of criteria for CIC structure identification. A significant predominance of CIC structures in the invasive front was established compared to the tumor central zone (16.7 \u00b1 5.2 and 1.2 \u00b1 1.3 per 5 fields of view, respectively, p &lt; 0.0001). Correlation analysis revealed weak but statistically significant relationships with the tumor-stromal ratio, the tumor buds number and the density of tumor-infiltrating lymphocytes. No correlations were found with the right- or left-sided location, pTNM, grading, lymphovascular and perineural invasion. Conclusions: The paper presents the adapted CIC structures counting method for surgical specimens of CRC, defines the criteria of the CIC, and demonstrates a higher number of CIC structures in the tumor invasive front. Weak correlations between the CIC structures and established factors of CRC poor prognosis are obtained.<\/jats:p>","DOI":"10.3390\/jpm15120591","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T16:37:02Z","timestamp":1764952622000},"page":"591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-in-Cell Structures in Colorectal Cancer: A Proposed Assessment Method and Correlation with Established Poor Prognostic Factors"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4343-2500","authenticated-orcid":false,"given":"Arseniy","family":"Potapov","sequence":"first","affiliation":[{"name":"Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod 603082, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0088-0659","authenticated-orcid":false,"given":"Ruslan","family":"Spashchanskii","sequence":"additional","affiliation":[{"name":"Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod 603082, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksey","family":"Kazakov","sequence":"additional","affiliation":[{"name":"Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod 603082, Russia"},{"name":"Research Institute of Clinical Oncology \u201cNizhny Novgorod Regional Clinical Oncological Dispensary\u201d, Nizhny Novgorod 603093, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3713-1293","authenticated-orcid":false,"given":"Anastasiya","family":"Shepeleva","sequence":"additional","affiliation":[{"name":"Research Institute of Clinical Oncology \u201cNizhny Novgorod Regional Clinical Oncological Dispensary\u201d, Nizhny Novgorod 603093, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uliana","family":"Lisitsa","sequence":"additional","affiliation":[{"name":"Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod 603082, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Bugrova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod 603082, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0293-3069","authenticated-orcid":false,"given":"Irina","family":"Druzhkova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod 603082, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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