{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:55:34Z","timestamp":1790034934459,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"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>Background: Gastric and gastroesophageal junction adenocarcinomas remain major causes of cancer- related mortality worldwide. Although perioperative chemotherapy, HER2-directed therapy, Claudin-18.2 (CLDN18.2)-targeted treatment, immune checkpoint inhibition, and anti-angiogenic therapy have improved outcomes in selected patients, clinically actionable targets are absent, heterogeneous, or lost in many high-grade, diffuse, poorly cohesive, signet-ring-cell micropapillary, hepatoid, and sarcomatoid carcinomas. Additional histopathology-assessable biomarkers that can support both molecular imaging and targeted therapy are of considerable clinical interest. Methods: Integrin \u03b1v\u03b26 is an epithelial-specific adhesion receptor that is minimally expressed in most normal adult tissues but becomes markedly upregulated during epithelial carcinogenesis, tissue remodeling, invasion, and activation of transforming growth factor-\u03b2 signaling. This retrospective histopathological and immunohistochemical study evaluated integrin \u03b1v\u03b26 expression by immunohistochemistry in 53 formalin-fixed paraffin-embedded diagnostic specimens of untreated primary gastric or gastroesophageal junction adenocarcinoma. Tumors were classified according to the WHO Classification of Tumors of the Digestive System, 5th edition. Membranous integrin \u03b1v\u03b26 staining intensity and the percentage of positive tumor cells were recorded, and an H-score was calculated. Expression patterns were compared descriptively with histological subtype, differentiation grade, HER2 status, and CLDN18.2 expression. Results: Integrin \u03b1v\u03b26 immunoreactivity was detected in 49 of 53 tumors (92.5%), the clinically more relevant moderate to strong expression (H-score &gt; 100) was present in 27 of 53 cases (50.9%), and strong expression was present in 13 of 53 cases (24.5%). Expression was not confined to conventional intestinal-type tumors; among carcinomas containing a signet-ring-cell component, 14 of 16 assessable cases (87.5%) showed integrin \u03b1v\u03b26 positivity, with 8 of 16 (50.0%) showing moderate to strong staining. By comparison, HER2 positivity was identified in 4 of 53 cases (7.5%; 4 of 52 assessable cases, 7.7%), and clinically relevant CLDN18.2 positivity, defined as moderate-to-strong membranous staining in at least 75% of tumor cells, was present in 7 of 38 assessable cases (18.4%). Conclusions: Integrin \u03b1v\u03b26 is frequently expressed in gastric and gastroesophageal junction adenocarcinoma, with moderate to strong expression in approximately half of all cases and in half of signet ring cell-containing tumors, including aggressive histological subtypes that often lack established therapeutic targets. The precise H-Score threshold for theranostic eligibility remains to be determined. The findings support integrin \u03b1v\u03b26 as a promising biomarker for histopathology-based screening, PET-based whole-body target assessment, and future targeted radionuclide therapy. Integration of immunohistochemistry and integrin \u03b1v\u03b26- targeted PET imaging will be essential to validate integrin \u03b1v\u03b26 as a candidate biomarker and to optimize radionuclide selection in gastric cancer, particularly with moderate to strong expression.<\/jats:p>","DOI":"10.3390\/cancers18142231","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:28:27Z","timestamp":1783927707000},"page":"2231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunohistochemical Evaluation of Integrin \u03b1v\u03b26 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma as a Histopathology-Driven Biomarker for Integrin \u03b1v\u03b26-Targeted Radiotheranostics"],"prefix":"10.3390","volume":"18","author":[{"given":"Muin","family":"Tuffaha","sequence":"first","affiliation":[{"name":"Institute of Pathology, Medical University Lausitz-Carl-Thiem, 03048 Cottbus, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2352-4435","authenticated-orcid":false,"given":"Wael","family":"Hananeh","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology and Public Health, Faculty of Veterinary Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8753-6347","authenticated-orcid":false,"given":"Michael","family":"Starke","sequence":"additional","affiliation":[{"name":"Nuclear Medicine, Medical University Lausitz-Carl-Thiem, 03048 Cottbus, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,11]]},"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. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1007\/s10120-014-0402-y","article-title":"HER2 screening data from ToGA: Targeting HER2 in gastric and gastroesophageal junction cancer","volume":"18","author":"Bang","year":"2015","journal-title":"Gastric Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/S0140-6736(23)00620-7","article-title":"Zolbetuximab plus mFOLFOX6 in patients with CLDN18. 2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): A multicentre, randomised, double-blind, phase 3 trial","volume":"401","author":"Shitara","year":"2023","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1038\/s41591-023-02465-7","article-title":"Zolbetuximab plus CAPOX in CLDN18. 2-positive gastric or gastroesophageal junction adenocarcinoma: The randomized, phase 3 GLOW trial","volume":"29","author":"Shah","year":"2023","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.annonc.2021.02.005","article-title":"FAST: A randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18. 2-positive gastric and gastro-oesophageal adenocarcinoma","volume":"32","author":"Sahin","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ungureanu, B.S., Lungulescu, C.-V., Pirici, D., Turcu-Stiolica, A., Gheonea, D.I., Sacerdotianu, V.M., Liliac, I.M., Moraru, E., Bende, F., and Saftoiu, A. (2021). Clinicopathologic relevance of Claudin 18.2 expression in gastric cancer: A meta-analysis. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.643872"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"155628","DOI":"10.1016\/j.prp.2024.155628","article-title":"Expression of claudin 18.2 in poorly cohesive carcinoma and its association with clinicopathologic parameters in East Asian patients","volume":"263","author":"Kim","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1007\/s00428-025-04247-7","article-title":"CLDN18. 2 expression in gastroesophageal adenocarcinoma: Prevalence, heterogeneity, and prognostic implications in Spanish patients","volume":"487","author":"Ortega","year":"2025","journal-title":"Virchows Arch."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0092-8674(02)00971-6","article-title":"Integrins: Bidirectional, allosteric signaling machines","volume":"110","author":"Hynes","year":"2002","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.biocel.2018.04.013","article-title":"Integrin \u03b1v\u03b26: Structure, function and role in health and disease","volume":"99","author":"Koivisto","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_12","first-page":"1","article-title":"Latent transforming growth factor beta-binding protein 1 (LTBP1): Roles as a multifunctional extracellular matrix regulator in human disease. From molecular mechanisms to clinical translation prospects","volume":"64","author":"Liu","year":"2026","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Brzozowska, E., and Deshmukh, S. (2022). Integrin alpha v beta 6 (\u03b1v\u03b26) and its implications in cancer treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012346"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tuffaha, M., Hananeh, W., Bangemann, N., Tuffaha, A., and Starke, M. (2026). Immunohistochemical Evaluation of Integrin \u03b26 Expression in Triple-Negative Breast Cancer as a Predictive Biomarker for Therapeutic and Diagnostic Radionuclides. Biomolecules, 16.","DOI":"10.3390\/biom16050706"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Golovina, E.L., Kochubey, V.V., Shabanova, M.A., Chekhvalova, D.M., Serebryakova, V.A., Skurikhin, E.G., Vaizova, O.E., Morozov, S.G., Kubatiev, A.A., and Dygai, A.M. (2025). Therapeutic prospects of \u03b1v integrins inhibition in fibrotic lung diseases and carcinogenesis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136202"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yu, J., Jia, W., Liu, Q., Yuan, A., Jia, Z., Sun, Y., Li, Z., and Cao, S. (2024). The association and clinicopathological significance of Integrin alphavbeta6 and Rac1 expression in gastric carcinoma. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1347270"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hou, S., Wang, J., Li, W., Hao, X., and Hang, Q. (2021). Roles of Integrins in Gastrointestinal Cancer Metastasis. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.708779"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1021\/acs.bioconjchem.5c00202","article-title":"Preclinical Evaluation of an Integrin \u03b1(v)\u03b2(6)-Targeted Photodynamic Therapy","volume":"36","author":"Zhang","year":"2025","journal-title":"Bioconjug. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1007\/s00259-021-05559-x","article-title":"PET\/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the \u201cCancer Integrin\u201d \u03b1v\u03b26 with Ga-68-Trivehexin","volume":"49","author":"Quigley","year":"2022","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rehm, J., Winzer, R., Pretze, M., M\u00fcller, J., Notni, J., Hempel, S., Distler, M., Folprecht, G., and Kotzerke, J. (2024). \u03b1v\u03b26-integrin targeted PET\/CT imaging in pancreatic cancer patients using 68Ga-Trivehexin. Front. Nucl. Med., 4.","DOI":"10.3389\/fnume.2024.1487602"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Urso, L., Napolitano, R., Speltri, G., Tuncel, M., Badrane, I., Uccelli, L., Porto, F., Martini, P., Niorettini, A., and Cittanti, C. (2025). 68Ga-Trivehexin: Current status of \u03b1v\u03b26-integrin imaging and perspectives. Cancers, 17.","DOI":"10.3390\/cancers17091504"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1021\/acsomega.8b00035","article-title":"Therapeutic radiopharmaceuticals targeting integrin \u03b1v\u03b26","volume":"3","author":"Wurzer","year":"2018","journal-title":"ACS Omega"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4311","DOI":"10.1007\/s00259-026-07826-1","article-title":"First \u03b1v\u03b26-integrin targeted radioligand therapy of breast cancer using Lu-177-Therahexin","volume":"53","author":"Kreissl","year":"2026","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.7150\/thno.92775","article-title":"Terbium radionuclides for theranostic applications in nuclear medicine: From atom to bedside","volume":"14","author":"Koole","year":"2024","journal-title":"Theranostics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"108998","DOI":"10.1016\/j.nucmedbio.2025.108998","article-title":"Terbium-161 in nuclear medicine: Preclinical and clinical progress in comparison with lutetium-177","volume":"144","author":"Trejtnar","year":"2025","journal-title":"Nucl. Med. Biol."},{"key":"ref_26","first-page":"200","article-title":"Expression of integrin alphavbeta6 in the intestinal epithelial cells of patients with inflammatory bowel disease","volume":"1","author":"Feng","year":"2009","journal-title":"N. Am. J. Med. Sci."},{"key":"ref_27","unstructured":"WHO Classification of Tumours Editorial Board (2019). Digestive System Tumours: WHO Classification of Tumours, International Agency for Research on Cancer. [5th ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/his.13975","article-title":"The 2019 WHO classification of tumours of the digestive system","volume":"76","author":"Nagtegaal","year":"2019","journal-title":"Histopathology"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Rounds, L., Nagle, R.B., Muranyi, A., Jandova, J., Gill, S., Vela, E., and Wondrak, G.T. (2021). Glyoxalase 1 Expression as a Novel Diagnostic Marker of High-Grade Prostatic Intraepithelial Neoplasia in Prostate Cancer. Cancers, 13.","DOI":"10.3390\/cancers13143608"},{"key":"ref_30","first-page":"577","article-title":"Claudin-18.2 as a Precision Oncology Target in Gastric and Gastro-Oesophageal Junction Cancer: Systematic Review of Zolbetuximab and Emerging Therapeutic Platforms","volume":"5","author":"Sarkar","year":"2026","journal-title":"Ann. Med. Med. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Scurtu, A.G., Sala, D.T., Jung, I., Bara, T., Neagoe, R.M., F\u00fcl\u00f6p, Z.Z., and Gurzu, S. (2026). HER2-Low Gastric and Gastroesophageal Junction Adenocarcinoma: From Assessment to Treatment Strategies. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27114673"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"147121","DOI":"10.1016\/j.ijbiomac.2025.147121","article-title":"Activation of transforming growth factor beta 1 through integrin alpha V beta 6 and its molecular insights into cancer progression, and future directions","volume":"324","author":"Deb","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Arca, B., Isik, E.G., Denizmen Zorba, D., Barburoglu, M., and Sanli, Y. (Clin. Nucl. Med., 2025). Focal 68Ga-Trivehexin Uptake in a Normal Pituitary Gland: Expanding the Spectrum of \u03b1v\u03b26-integrin PET Findings, Clin. Nucl. Med., in press.","DOI":"10.1097\/RLU.0000000000006266"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s12105-017-0800-7","article-title":"Intestinal-type adenocarcinoma: Classification, immunophenotype, molecular features and differential diagnosis","volume":"11","author":"Leivo","year":"2017","journal-title":"Head Neck Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e70043","DOI":"10.1002\/cai2.70043","article-title":"Potential Targets and Biomarkers of Radionuclide Therapy in Breast Cancer","volume":"5","author":"Tan","year":"2026","journal-title":"Cancer Innov."},{"key":"ref_36","first-page":"262024","article-title":"Gallium 68 Trivehexin PET-CT for \u03b1v\u03b26-Integrin Imaging in Pancreatic Cancer: A Head-to-Head Comparison with 18F-Fluorodeoxyglucose PET\/CT","volume":"67","author":"Simon","year":"2026","journal-title":"J. Nucl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e717","DOI":"10.1097\/RLU.0000000000005950","article-title":"\u03b1v\u03b26 Imaging With 68Ga-Trivehexin PET\/CT in Pituitary Macroadenoma","volume":"50","author":"Sadeq","year":"2025","journal-title":"Clin. Nucl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/s00411-022-01000-5","article-title":"Heterogeneity of dose distribution in normal tissues in case of radiopharmaceutical therapy with alpha-emitting radionuclides","volume":"61","author":"Li","year":"2022","journal-title":"Radiat. Environ. Biophys."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ar\u00e7ay \u00d6zt\u00fcrk, A., Sa\u00fade-Conde, R., Gebruers, J., and Flamen, P. (2026). FAP-Targeted Radionuclide Therapy: Mechanisms, Clinical Applications, and Combination Strategies. Biomedicines, 14.","DOI":"10.3390\/biomedicines14071479"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2231\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:10:47Z","timestamp":1784164247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,11]]},"references-count":39,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18142231"],"URL":"https:\/\/doi.org\/10.3390\/cancers18142231","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,11]]}}}