{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:13:42Z","timestamp":1760148822501,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero della Salute","award":["J53C2300300003"],"award-info":[{"award-number":["J53C2300300003"]}]},{"name":"Italian Ministry of Foreign Affairs and International Cooperation","award":["J53C2300300003"],"award-info":[{"award-number":["J53C2300300003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The majority of patients with Follicular Lymphoma (FL) experience subsequent phases of remission and relapse, making the disease \u201cvirtually\u201d incurable. To predict the outcome of FL patients at diagnosis, various clinical-based prognostic scores have been proposed; nonetheless, they continue to fail for a subset of patients. Gene expression profiling has highlighted the pivotal role of the tumor microenvironment (TME) in the FL prognosis; nevertheless, there is still a need to standardize the assessment of immune-infiltrating cells for the prognostic classification of patients with early or late progressing disease. We studied a retrospective cohort of 49 FL lymph node biopsies at the time of the initial diagnosis using pathologist-guided analysis on whole slide images, and we characterized the immune repertoire for both quantity and distribution (intrafollicular, IF and extrafollicular, EF) of cell subsets in relation to clinical outcome. We looked for the natural killer (CD56), T lymphocyte (CD8, CD4, PD1) and macrophage (CD68, CD163, MA4A4A)-associated markers. High CD163\/CD8 EF ratios and high CD56\/MS4A4A EF ratios, according to Kaplan\u2013Meier estimates were linked with shorter EFS (event-free survival), with the former being the only one associated with POD24. In contrast to IF CD68+ cells, which represent a more homogeneous population, higher in non-progressing patients, EF CD68+ macrophages did not stratify according to survival. We also identify distinctive MS4A4A+CD163-macrophage populations with different prognostic weights. Enlarging the macrophage characterization and combining it with a lymphoid marker in the rituximab era, in our opinion, may enable prognostic stratification for low-\/high-grade FL patients beyond POD24. These findings warrant validation across larger FL cohorts.<\/jats:p>","DOI":"10.3390\/ijms24129909","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T02:59:57Z","timestamp":1686279597000},"page":"9909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Follicular Lymphoma Microenvironment Traits Associated with Event-Free Survival"],"prefix":"10.3390","volume":"24","author":[{"given":"Maria Maddalena","family":"Tumedei","sequence":"first","affiliation":[{"name":"Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0371-7782","authenticated-orcid":false,"given":"Filippo","family":"Piccinini","sequence":"additional","affiliation":[{"name":"Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"},{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5808-7044","authenticated-orcid":false,"given":"Irene","family":"Azzali","sequence":"additional","affiliation":[{"name":"Biostatistics and Clinical Trials Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7629-2439","authenticated-orcid":false,"given":"Francesca","family":"Pirini","sequence":"additional","affiliation":[{"name":"Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0075-8538","authenticated-orcid":false,"given":"Sara","family":"Bravaccini","sequence":"additional","affiliation":[{"name":"Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"De Matteis","sequence":"additional","affiliation":[{"name":"Immunobiology of Transplants and Advanced Cellular Therapies Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Agostinelli","sequence":"additional","affiliation":[{"name":"Hematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4892-925X","authenticated-orcid":false,"given":"Gastone","family":"Castellani","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Zanoni","sequence":"additional","affiliation":[{"name":"Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6869-000X","authenticated-orcid":false,"given":"Michela","family":"Cortesi","sequence":"additional","affiliation":[{"name":"Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Vergani","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biagio Eugenio","family":"Leone","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Righi","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Gazzola","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4453-6064","authenticated-orcid":false,"given":"Beatrice","family":"Casadei","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Gentilini","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioral Sciences, Universit\u00e0 di Pavia, 27100 Pavia, Italy"},{"name":"Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4283-0988","authenticated-orcid":false,"given":"Luciano","family":"Calzari","sequence":"additional","affiliation":[{"name":"Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1367-3525","authenticated-orcid":false,"given":"Francesco","family":"Limarzi","sequence":"additional","affiliation":[{"name":"Pathology Unit, Morgagni-Pierantoni Hospital, AUSL Romagna, Via Carlo Forlanini, 34, 47121 Forl\u00ec, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4136-3591","authenticated-orcid":false,"given":"Elena","family":"Sabattini","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0379-9562","authenticated-orcid":false,"given":"Andrea","family":"Pession","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, 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