{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:56:41Z","timestamp":1790035001458,"version":"4.0.1"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Integrins are heterodimeric transmembrane receptors that mediate bidirectional signaling and regulate cell\u2013cell and cell\u2013extracellular matrix interactions. Integrin \u03b1v\u03b26 is an epithelial-associated integrin that has emerged as a promising molecular target for PET\/CT imaging using integrin \u03b1v\u03b26-directed radiotracers such as 68Ga-Trivehexin, and, most recently, for antibody\u2013drug conjugate therapy in epithelial malignancies. Unexpected physiological and incidental uptake within the pituitary gland has been reported in integrin \u03b1v\u03b26-targeted PET studies, including uptake in morphologically normal pituitary glands and pituitary neuroendocrine tumors (PitNETs). However, the histological basis of integrin \u03b1v\u03b26 expression in the human pituitary gland remains poorly understood. The aim of this study is to characterize the immunohistochemical expression of integrin \u03b1v\u03b26 in normal human pituitary tissue and PitNETs and to evaluate its potential implications for integrin \u03b1v\u03b26-targeted imaging and theranostic applications. Five complete adult pituitary glands obtained at autopsy and 28 PitNETs were examined by immunohistochemistry for integrin \u03b1v\u03b26. Staining distribution, intensity, and cellular localization were assessed in the adenohypophysis, neurohypophysis, and Rathke\u2019s cleft remnants. PitNETs were classified according to transcription factor expression (PIT1, TPIT, and SF1). Among the 28 PitNETs, 17 were SF1-lineage (60.7%), three were PIT1-lineage (10.7), two were TPIT-lineage (7.1%), three lacked a dominant transcription factor (10.7%), and three showed plurilineage expression (10.7%). Integrin \u03b1v\u03b26 expression was evaluated semiquantitatively according to staining intensity and the percentage of positive tumor cells. In normal pituitary glands, integrin \u03b1v\u03b26 immunoreactivity was predominantly membranous and localized to larger adenohypophyseal cells irrespective of transcription factor lineage or hormone phenotype. Strong expression was also observed in the epithelial lining cells of Rathke\u2019s cleft remnants, whereas the neurohypophysis lacked detectable integrin \u03b1v\u03b26 expression. Among the 28 PitNETs, integrin \u03b1v\u03b26 expression was detected in 20 cases (71.4%). Positive tumors demonstrated variable staining intensity and extent, ranging from 20% to 100% positive tumor cells. By lineage, integrin \u03b1v\u03b26 expression was detected in 13 of 17 SF1-lineage tumors (76.5%), one of three PIT1-lineage tumors (33.3%), and zero of two TPIT-lineage tumors (0%). Additionally, all three tumors lacking a dominant transcription factor (100%) and all three plurilineage tumors (100%) demonstrated integrin \u03b1v\u03b26 expression. Eleven integrin \u03b1v\u03b26-positive tumors showed expression in \u226550% of tumor cells, and six exhibited strong or diffuse immunoreactivity. Integrin \u03b1v\u03b26 expression in adenohypophyseal cells and Rathke\u2019s cleft remnants provides a histological explanation for physiological pituitary uptake observed on \u03b1v\u03b26-targeted PET\/CT imaging. The high prevalence of integrin \u03b1v\u03b26 expression in PitNETs, particularly in a subset demonstrating strong and diffuse immunoreactivity, suggests potential applicability of integrin \u03b1v\u03b26-targeted molecular imaging and theranostic approaches, including both radioligand- and antibody-based strategies. However, these applications remain investigational and require further validation in preclinical and clinical studies. At the same time, physiological integrin \u03b1v\u03b26 expression in normal anterior pituitary tissue may limit imaging specificity and should be considered when developing integrin \u03b1v\u03b26-targeted radioligand therapies. Further clinicopathological and imaging correlation studies are warranted to define the diagnostic and therapeutic role of integrin \u03b1v\u03b26-targeted approaches in PitNETs.<\/jats:p>","DOI":"10.3390\/biom16081182","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:31:09Z","timestamp":1786613469000},"page":"1182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrin \u03b1v\u03b26 Expression in the Human Pituitary Gland and Pituitary Neuroendocrine Tumors: Immunohistochemical Characterization with Potential Relevance to \u03b1v\u03b26 PET\/CT Pituitary Uptake and Theranostic Implications"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0300-929X","authenticated-orcid":false,"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"}]},{"given":"Ehab","family":"Shiban","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University Lausitz-Carl-Thiem, 03048 Cottbus, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8753-6347","authenticated-orcid":false,"given":"Michael","family":"Starke","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Medical University Lausitz-Carl-Thiem, 03048 Cottbus, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1242\/jcs.108.6.2241","article-title":"Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling","volume":"108","author":"Breuss","year":"1995","journal-title":"J. Cell Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15330338231189399","DOI":"10.1177\/15330338231189399","article-title":"Review and Application of Integrin Alpha v Beta 6 in the Diagnosis and Treatment of Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma","volume":"22","author":"Lian","year":"2023","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0092-8674(00)80545-0","article-title":"The integrin alpha v beta 6 binds and activates latent TGF beta 1: A mechanism for regulating pulmonary inflammation and fibrosis","volume":"96","author":"Munger","year":"1999","journal-title":"Cell"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1038\/s41467-019-11863-w","article-title":"Evaluation of integrin \u03b1v\u03b2(6) cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis","volume":"10","author":"Kimura","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1158\/1078-0432.CCR-18-2665","article-title":"Preclinical development and first-in-human imaging of the integrin \u03b1v\u03b26 with [18F] \u03b1v\u03b26-binding peptide in metastatic carcinoma","volume":"25","author":"Hausner","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4107","DOI":"10.1007\/s00259-021-05443-8","article-title":"PET\/CT imaging of pancreatic carcinoma targeting the \u201ccancer integrin\u201d \u03b1v\u03b26","volume":"48","author":"Quigley","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1097\/RLU.0000000000005278","article-title":"Potential Efficacy of 68Ga-Trivehexin PET\/CT and Immunohistochemical Validation of \u03b1v\u03b26 Integrin Expression in Patients with Head and Neck Squamous Cell Carcinoma and Pancreatic Ductal Adenocarcinoma","volume":"49","author":"Das","year":"2024","journal-title":"Clin. Nucl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e175","DOI":"10.1097\/RLU.0000000000005585","article-title":"Superiority of 68Ga-Trivehexin PET\/CT over 18F-FDG PET\/CT in the Evaluation of Lymph Nodes in Patients with Breast Cancer","volume":"50","author":"Kaplan","year":"2025","journal-title":"Clin. Nucl. Med."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1007\/s00259-024-06846-z","article-title":"68Ga-Trivehexin PET\/CT: A promising novel tracer for primary hyperparathyroidism","volume":"51","author":"Kuyumcu","year":"2024","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1200\/JCO-25-02016","article-title":"First-in-Human, Phase I Study of Sigvotatug Vedotin, an Integrin Beta-6-Directed Antibody-Drug Conjugate: Results from Dose Expansion in Advanced Non-Small Cell Lung Cancer","volume":"44","author":"Peters","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103128","DOI":"10.1016\/j.ctrv.2026.103128","article-title":"Integrin beta-6: Its emerging role as a therapeutic target in solid tumors","volume":"146","author":"Sanborn","year":"2026","journal-title":"Cancer Treat. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1007\/s00259-021-05595-7","article-title":"Pilot-phase PET\/CT study targeting integrin \u03b1v\u03b26 in pancreatic cancer patients using the cystine-knot peptide-based 18F-FP-R01-MG-F2","volume":"50","author":"Nakamoto","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e726","DOI":"10.1097\/RLU.0000000000006266","article-title":"Focal 68Ga-Trivehexin Uptake in a Normal Pituitary Gland: Expanding the Spectrum of \u03b1v\u03b26-integrin PET Findings","volume":"51","author":"Arca","year":"2026","journal-title":"Clin. Nucl. Med."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/(SICI)1097-0215(19960703)67:1<45::AID-IJC10>3.0.CO;2-B","article-title":"Adenomatous transformation of the human anterior pituitary is associated with alterations in integrin expression","volume":"67","author":"Farnoud","year":"1996","journal-title":"Int. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ilie, M.D., Vasiljevic, A., Raverot, G., and Bertolino, P. (2019). The Microenvironment of Pituitary Tumors-Biological and Therapeutic Implications. Cancers, 11.","DOI":"10.3390\/cancers11101605"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pandit, N., Wehbeh, Y., Itani, O., and Kanakis, D. (2026). Transcription Factor-Based Classification of Pituitary Neuroendocrine Tumors: Practical Immunohistochemical Algorithms, Molecular Correlates, and Diagnostic Challenges in the 5th WHO Era. Int. J. Mol. Sci., 27.","DOI":"10.20944\/preprints202601.1233.v1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.3346\/jkms.2025.40.e56","article-title":"Comprehensive Classification of Surgically Resected Pituitary Neuroendocrine Tumors: Updates from a Single-Institution Experience Based on the WHO 5th Edition","volume":"40","author":"Kim","year":"2025","journal-title":"J. Korean Med. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Krzentowska, A., Czepko, R., Adamek, D., Filipowicz, M., Broniatowska, E., and Go\u0142kowski, F. (2025). Radiological and Immunohistochemical Characteristics of PitNETs in 79 Patients Undergoing Neurosurgery. Cancers, 17.","DOI":"10.20944\/preprints202501.0072.v1"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.2967\/jnumed.122.264749","article-title":"Preclinical Evaluation of 68Ga- and 177Lu-Labeled Integrin \u03b1v\u03b26-Targeting Radiotheranostic Peptides","volume":"64","author":"Ganguly","year":"2023","journal-title":"J. Nucl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sachindra, S., Hellberg, T., Exner, S., Prasad, S., Beindorff, N., Rogalla, S., Kimura, R., Gambhir, S.S., Wiedenmann, B., and Gr\u00f6tzinger, C. (2021). SPECT\/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin \u03b1v\u03b26 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.684713"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.7150\/thno.96403","article-title":"Actinium-225 targeted alpha particle therapy for prostate cancer","volume":"14","author":"Bidkar","year":"2024","journal-title":"Theranostics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e08225","DOI":"10.1002\/advs.202508225","article-title":"Integrin \u03b1v\u03b26-Targeted PET\/CT Imaging of Non-Small Cell Lung Cancer with [68Ga]Ga-Trivehexin: Improved Preoperative Lymph Node Staging and Association with Immunohistochemistry","volume":"12","author":"Wu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Marques, P. (2023). The Effects of Peptide Receptor Radionuclide Therapy on the Neoplastic and Normal Pituitary. Cancers, 15.","DOI":"10.3390\/cancers15102710"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e250073","DOI":"10.1530\/EO-25-0073","article-title":"Success of 177Lu-DOTATATE therapy in a metastatic pituitary neuroendocrine tumor","volume":"5","author":"Wolf","year":"2025","journal-title":"Endocr. Oncol."},{"key":"ref_30","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_31","doi-asserted-by":"crossref","unstructured":"Tuffaha, M., Hananeh, W., and Starke, M. (2026). Immunohistochemical Evaluation of Integrin \u03b1v\u03b26 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma as a Histopathology-Driven Biomarker for Integrin \u03b1v\u03b26-Targeted Radiotheranostics. Cancers, 18.","DOI":"10.3390\/cancers18142231"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8405","DOI":"10.1002\/cam4.4345","article-title":"Pituitary function following peptide receptor radionuclide therapy for neuroendocrine tumours","volume":"10","author":"Elston","year":"2021","journal-title":"Cancer Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1182\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:49:12Z","timestamp":1786614552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["biom16081182"],"URL":"https:\/\/doi.org\/10.3390\/biom16081182","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}