{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:42:51Z","timestamp":1760240571568,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2019,7,15]],"date-time":"2019-07-15T00:00:00Z","timestamp":1563148800000},"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>Upregulation of carbonic anhydrase IX (CAIX) was found to be associated with unfavorable prognosis and resistance to treatment in a broad spectrum of malignancies, recently also in classical Hodgkin\u2019s lymphoma (cHL). As demonstrated, variable CAIX expression in a significant number of cHL cases was associated with poor treatment response. The current study focused on the quantification CAIX immunopositivity and its relative expression compared to the total CD30+ neoplastic pool using digital image analysis. One hundred and one lymph node samples featuring cHL histology were analyzed for both CD30 and CAIX by immunohistochemistry. Whole histological slides were scanned and immunopositivity was determined as the histoscore (H-score) using the DensitoQuant software module (3DHistech Kft., Budapest, Hungary). CAIX positivity was observed in the HRS-cells of 56\/101 cases (55.44%) and frequently observed in the proximity of necrotic foci. CAIX H-scores were highly variable (range: 2.16\u201390.36, mean 18.7 \u00b1 18.8). Individual CAIX values were independent of the much higher CD30 values (range 3.46\u2013151.3, mean 52.37 \u00b1 30.74). The CAIX\/CD30 index proved to be the highest in the aggressive lymphocyte-depleted (LD) subtype (CAIX\/CD30: 0.876). The CAIX expression and the CAIX\/CD30 relative index can be precisely determined by image analysis, and values reflect the extent of a tumor mass undergoing hypoxic-stress-related adaptation in the most aggressive forms of cHL.<\/jats:p>","DOI":"10.3390\/ijms20143463","type":"journal-article","created":{"date-parts":[[2019,7,15]],"date-time":"2019-07-15T04:55:27Z","timestamp":1563166527000},"page":"3463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Quantitative Analysis of Carbonic Anhydrase IX Uncovers Hypoxia-Related Functional Differences in Classical Hodgkin Lymphoma Subtypes"],"prefix":"10.3390","volume":"20","author":[{"given":"Orsolya","family":"Matolay","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00edvia","family":"Beke","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Gyurkovics","sequence":"additional","affiliation":[{"name":"Department of Pathology, J\u00f3sa Andr\u00e1s Teaching County Hospital, H-4400 Ny\u00edregyh\u00e1za, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nika","family":"Francz","sequence":"additional","affiliation":[{"name":"Department of Pathology, J\u00f3sa Andr\u00e1s Teaching County Hospital, H-4400 Ny\u00edregyh\u00e1za, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Varjasi","sequence":"additional","affiliation":[{"name":"Hematology Unit, J\u00f3sa Andr\u00e1s Teaching County Hospital, H-4400 Ny\u00edregyh\u00e1za, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e1szl\u00f3","family":"Rejt\u0151","sequence":"additional","affiliation":[{"name":"Hematology Unit, J\u00f3sa Andr\u00e1s Teaching County Hospital, H-4400 Ny\u00edregyh\u00e1za, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1rp\u00e1d","family":"Ill\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Bedekovics","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e1bor","family":"M\u00e9hes","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 revision of the World Health Organization classification of lymphoid neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"iv19","DOI":"10.1093\/annonc\/mdy080","article-title":"Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Eichenauer","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.anndiagpath.2019.02.001","article-title":"American Registry of Pathology Expert Opinions: Immunohistochemical evaluation of classic Hodgkin lymphoma","volume":"39","author":"Dogan","year":"2019","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/299065a0","article-title":"Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin\u2019s disease and a subset of normal lymphoid cells","volume":"299","author":"Schwab","year":"1982","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e603","DOI":"10.1038\/bcj.2017.85","article-title":"Understanding CD30 biology and therapeutic targeting: A historical perspective providing insight into future directions","volume":"7","author":"Pileri","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1006\/smim.1998.0156","article-title":"CD30: Expression and function in health and disease","volume":"10","author":"Horie","year":"1998","journal-title":"Semin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1016\/0092-8674(93)90361-S","article-title":"CD30 antigen, a marker for Hodgkin\u2019s lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF","volume":"73","author":"Smith","year":"1993","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1172\/JCI67230","article-title":"HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations","volume":"123","author":"Semenza","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.prp.2008.07.007","article-title":"Histological expression of angiogenic factors: VEGF, PDGFR\u03b1, and HIF-1\u03b1 in Hodgkin lymphoma","volume":"205","author":"Passam","year":"2009","journal-title":"Pathol. Res. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3389\/fphys.2013.00400","article-title":"Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors","volume":"4","author":"Sedlakova","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1158\/0008-5472.CAN-08-2470","article-title":"Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH","volume":"69","author":"Chiche","year":"2009","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/sj.bjc.6604844","article-title":"The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy","volume":"100","author":"Tan","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s11307-015-0885-x","article-title":"Evaluation of CAIX and CAXII Expression in Breast Cancer at Varied O2 Levels: CAIX is the Superior Surrogate Imaging Biomarker of Tumor Hypoxia","volume":"18","author":"Tafreshi","year":"2016","journal-title":"Mol. Imaging Biol."},{"key":"ref_14","first-page":"69","article-title":"Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis","volume":"6","author":"Yaromina","year":"2016","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/his.13808","article-title":"Hypoxia related carbonic anhydrase IX expression is associated with unfavourable response to first-line therapy in classical Hodgkin\u2019s lymphoma","volume":"74","author":"Matolay","year":"2019","journal-title":"Histopathology"},{"key":"ref_16","first-page":"23","article-title":"Whole slide imaging in pathology: Advantages, limitations, and emerging perspectives","volume":"7","author":"Farahani","year":"2015","journal-title":"Pathol. Lab. Med. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.5858\/arpa.2013-0093-CP","article-title":"Validating Whole Slide Imaging for Diagnostic Purposes in Pathology: Guideline from the College of American Pathologists Pathology and Laboratory Quality Center","volume":"137","author":"Pantanowitz","year":"2013","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.compbiolchem.2013.04.003","article-title":"Image database analysis of Hodgkin lymphoma","volume":"46","author":"Schmitz","year":"2013","journal-title":"Comput. Biol. Chem."},{"key":"ref_19","unstructured":"Schmitz, A., Sch\u00e4fer, T., Sch\u00e4fer, H., D\u00f6ring, C., Ackermann, J., Dichter, N., Hartmann, S., Hansmann, M.-L., and Koch, I. (2019, January 18). Automated Image Analysis of Hodgkin lymphoma. Available online: http:\/\/arxiv.org\/abs\/1209.3189."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1093\/bioinformatics\/btv542","article-title":"CD30 cell graphs of Hodgkin lymphoma are not scale-free\u2014An image analysis approach","volume":"32","author":"Ackermann","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1634\/theoncologist.9-90005-4","article-title":"Tumor Hypoxia: Causative Factors, Compensatory Mechanisms, and Cellular Response","volume":"9","author":"Vaupel","year":"2004","journal-title":"Oncologist"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fimmu.2018.00040","article-title":"Hypoxia Pathway Proteins As Central Mediators of Metabolism in the Tumor Cells and Their Microenvironment","volume":"9","author":"Sormendi","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1053\/j.semnuclmed.2014.11.002","article-title":"The clinical significance of hypoxia in human cancers","volume":"45","author":"Dhani","year":"2015","journal-title":"Semin. Nucl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1365-2559.2012.04185.x","article-title":"Tissue microarray and digital image analysis: A methodological study with special reference to the microenvironment in Hodgkin lymphoma: Tissue microarray and digital imaging","volume":"61","author":"Glimelius","year":"2012","journal-title":"Histopathology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/14\/3463\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:05:37Z","timestamp":1760187937000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/14\/3463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,15]]},"references-count":24,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["ijms20143463"],"URL":"https:\/\/doi.org\/10.3390\/ijms20143463","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2019,7,15]]}}}