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This narrative review synthesizes current diagnostic and treatment strategies, including imaging, HPV/EBV biomarkers, minimally invasive approaches, and transoral robotic surgery. A multidisciplinary management strategy remains central, while personalization and ongoing trials such as UK FIND suggest targeted surgery to tailor radiotherapy fields and improve outcomes.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/carcinoma-of-unknown-primary-cup-of-the-head-and-neck-state-of-the-art-and-future-perspectives/353025/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/carcinoma-of-unknown-primary-cup-of-the-head-and-neck-state-of-the-art-and-future-perspectives/353025.png","ImageObject",300,407,{"name":42,"@type":43},"eBook King","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-22","2026-09-22",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",13,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What defines carcinoma of unknown primary (CUP) in head and neck cancer?","Question",{"text":63,"@type":64},"CUP is defined when metastatic cancer is detected without an identifiable primary tumor. In the head and neck region, CUPs can represent up to 5% of diagnoses.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Which diagnostic approaches and biomarkers are discussed for head and neck CUP?",{"text":68,"@type":64},"The review covers imaging strategies, viral biomarkers including HPV and EBV, and minimally invasive procedures to support diagnosis when the primary site is not evident.",{"name":70,"@type":61,"acceptedAnswer":71},"How does transoral robotic surgery (TORS) fit into diagnosis and treatment?",{"text":72,"@type":64},"TORS has a dual role, contributing to both diagnostic assessment and treatment. For high-risk patients, a multidisciplinary approach combining neck dissection, radiotherapy, and chemotherapy remains foundational.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},353025,1790472709,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":116,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145},962088006270,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","TYPE Review  \nPUBLISHED 20 May 2026  \nDOI 10.3389/fonc.2026.1813394  \nOPEN ACCESS  \nEDITED BY  \nJan Baptist Vermorken,  \nUniversity of Antwerp, Belgium  \nREVIEWED BY  \nShachi Jenny Sharma,  \nUniversity Hospital of Cologne, Germany Maria Pouyiourou,  \nGerman Cancer Research Center (DKFZ), Germany  \n*CORRESPONDENCE  \nSara Farinatti  \n sara.farinatti@humanitas. it  \nRECEIVED 18 February 2026  \nREVISED 02 April 2026  \nACCEPTED 01 May 2026  \nPUBLISHED 20 May 2026  \nCITATION  \nFarinatti S, Paderno A, Giannitto C, Gurizzan C, Uccella S, Lorini L,  \nTeriaca MA, Ferreli F, Rodari M, Resteghini C, Di Bello A, Mercante G, Spriano G and Bossi P (2026) Carcinoma  \nof unknown primary (CUP) of the head and neck: state of the art and future perspectives.  \nFront. Oncol. 16:1813394 .  \ndoi: 10.3389/fonc.2026.1813394  \nCOPYRIGHT  \n© 2026 Farinatti, Paderno, Giannitto, Gurizzan, Uccella, Lorini, Teriaca, Ferreli, Rodari, Resteghini, Di Bello, Mercante, Spriano and Bossi. This is an open-access article distributed under the terms of the  \nCreative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nCarcinoma of unknown  \nprimary (CUP) of the head and neck: state of the art and future perspectives  \nSara Farinatti 1,2*, Alberto Paderno 2,3, Caterina Giannitto 4, Cristina Gurizzan 1, Silvia Uccella 2,5, Luigi Lorini 1,  \nMaria Ausilia Teriaca 6, Fabio Ferreli 2,3, Marcello Rodari 7, Carlo Resteghini 1,2, Armando Di Bello 8, Giuseppe Mercante 2,3, Giuseppe Spriano 2,3 and Paolo Bossi 1,2  \n1 Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy,  \n2 Department of Biomedical Sciences, Humanitas University, Milan, Italy, 3Otorhinolaryngology Head & Neck Surgery Unit, IRCCS Humanitas Research Hospital, Milan, Italy, 4 Radiology Division, IRCCS Humanitas Research Hospital, Milan, Italy, 5 Pathology Service IRCCS Humanitas Research Hospital, Milan, Italy, 6 Department of Radiotherapy and Radiosurgery, IRCCS Humanitas Research Hospital, Milan, Italy, 7 Department of Nuclear Medicine, IRCCS Humanitas Research Hospital, Milan, Italy,  \n8 Medical Oncology, Università Cattolica del Sacro Cuore, Comprehensive Cancer Center, Fondazione Policlinico Gemelli, IRCCS, Rome, Italy  \nDespite advances in molecular oncology, head and neck cancer diagnosis still relies on anatomical site and histopathology. In up to 5% of metastatic cases, noidentifiable primary tumor is found, defining carcinoma of unknown primary (CUP) and posing significant diagnostic and therapeutic challenges. We conducted a narrative review of the literature focusing on current diagnostic and treatment strategies for head and neck CUP, including imaging, viral biomarkers (HPV, EBV), minimally invasive procedures, and transoral robotic surgery (TORS) . While TORS plays a dual role in diagnosis and treatment, a multidisciplinary approach of neck dissection, radiotherapy, and chemotherapy in high-risk patients, remains the cornerstone of management. Personalization is increasingly crucial in this comprehensive context, mainly involving treatment tailoring and radiotherapy planning, where limited evidence on field definition is available. Ongoing trials, such as UK FIND study, highlight the potential of targeted surgery to tailor and possibly reduce radiotherapy fields for better patient outcomes and improved quality of life.  \nKEYWORDS  \ncarcinoma of unknown primary, head and neck cancer, personalization, squamous cell carcinomas, trans oral robotic surgery  \nIntroduction  \nWhile a personalized and molecular-based era of oncology is developing, we must come to terms with the idea that the cornerstone of oncological diagnosis still relies on two major factor","cbCaiiYjVEMkX7oe","https://ap.wps.com/l/cbCaiiYjVEMkX7oe","pdf",550891,"English","# Introduction\n## Carcinoma of unknown primary (CUP): definition and epidemiology\n## Diagnostic and histologic considerations\n## Treatment implications in the head and neck region\n# Diagnostic strategies and biomarkers\n# Minimally invasive procedures and transoral robotic surgery (TORS)\n# Multidisciplinary management and personalization\n# Future directions and ongoing clinical trials","[{\"question\":\"What defines carcinoma of unknown primary (CUP) in head and neck cancer?\",\"answer\":\"CUP is defined when metastatic cancer is detected without an identifiable primary tumor. In the head and neck region, CUPs can represent up to 5% of diagnoses.\"},{\"question\":\"Which diagnostic approaches and biomarkers are discussed for head and neck CUP?\",\"answer\":\"The review covers imaging strategies, viral biomarkers including HPV and EBV, and minimally invasive procedures to support diagnosis when the primary site is not evident.\"},{\"question\":\"How does transoral robotic surgery (TORS) fit into diagnosis and treatment?\",\"answer\":\"TORS has a dual role, contributing to both diagnostic assessment and treatment. For high-risk patients, a multidisciplinary approach combining neck dissection, radiotherapy, and chemotherapy remains foundational.\"}]","Carcinoma of unknown primary (CUP) of the head and neck - state of the art and future perspectives | PDF",1790102621,23]