{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T06:00:53Z","timestamp":1772517653672,"version":"3.50.1"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Patients with carcinoma of unknown primary (CUP) generally have a poor prognosis due to the lack of effective treatment options resulting from unclear diagnosis. Determining the tumor type through tumor origin testing, followed by cancer-specific genetic testing and precision therapy, may potentially improve the prognosis of CUP patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      Case 1: A 44-year-old male patient presented to a local hospital with lower limb pain. A bone biopsy pathological report from our hospital indicated metastatic carcinoma in the bone lesion. The 90-gene expression analysis yielded a similarity score of 56.9, suggesting a high probability of lung cancer origin. Based on the genetic testing and combined with immunohistochemistry results, the diagnosis was metastatic adenocarcinoma. Subsequently, the bone biopsy tissue was tested for Epidermal growth factor receptor\/Anaplastic Lymphoma Kinase\/ROS proto-oncogene 1 (\n                      <jats:italic>EGFR\/ALK\/ROS1)<\/jats:italic>\n                      gene mutations, which revealed an\n                      <jats:italic>EGFR<\/jats:italic>\n                      exon 19 deletion (19Del) mutation. Based on the above results, the patient received chemotherapy with carboplatin and pemetrexed disodium combined with targeted therapy using the EGFR tyrosine kinase inhibitor (TKI) almonertinib mesylate tablets. Based on the molecular evidence provided by the tumor origin test results, a diagnosis was established for the patient by the clinician, and corresponding treatment plans were formulated accordingly. Unfortunately, after three cycles of treatment, the patient discontinued therapy due to other issues and was lost to follow-up. Case 2: A 59-year-old male patient sought medical attention in May 2021 due to dysphagia. He underwent radical esophagectomy for esophageal cancer at an external hospital, with postoperative pathological diagnosis of esophageal squamous cell carcinoma. In August 2024, he presented with cervical lymph node enlargement. A biopsy pathological diagnosis was metastatic poorly differentiated carcinoma, with current markers showing no definitive differentiation towards adenocarcinoma or non-keratinizing squamous cell carcinoma. The gene expression profile results indicated that the tumor sample was most likely derived from gastric and esophageal tissues, i.e., highly suggestive of gastric\/esophageal cancer, with a similarity score of 96.4. Based on the patient\u2019s medical history and immunohistochemistry results, the clinicians considered a diagnosis of esophageal squamous cell carcinoma (with lymph node metastasis). According to this diagnosis, the patient received six cycles of immunotherapy combined with chemotherapy. Regular follow-up examinations showed gradual shrinkage of the lymph nodes. A re-examination on August 12, 2025, indicated stable disease, with a progression-free survival (PFS) already reaching twelve months.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The two cases reported in this paper demonstrate that targeted and immune treatment plans based on the tissue of origin of the tumor can serve as a clinical option for patients with CUP. These findings may provide new information and references for clinical decision-making in the management of CUP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1741467","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T05:23:30Z","timestamp":1772515410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted and immunotherapy based on tissue of origin in carcinoma of unknown primary: a two-case report and literature review"],"prefix":"10.3389","volume":"16","author":[{"given":"Mei","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"DongYue","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingshan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065588","article-title":"From biology to diagnosis and treatment: the ariadne\u2019s thread in cancer of unknown primary","volume":"24","author":"Mathew","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2020.102882","article-title":"New rising entities in cancer of unknown primary: Is there a real therapeutic benefit","volume":"147","author":"Rassy","year":"2020","journal-title":"Crit Rev Oncol Hematol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61178-1","article-title":"Cancer of unknown primary site","volume":"379","author":"Pavlidis","year":"2012","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2022.06.017","article-title":"Chromosomal instability in cancers of unknown primary","volume":"172","author":"Chebly","year":"2022","journal-title":"Eur J Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2020.06.005","article-title":"Development and clinical validation of a 90\u2043Gene expression assay for identifying tumor tissue origin","volume":"22","author":"Ye","year":"2020","journal-title":"J Mol Diagn"},{"key":"B6","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1186\/s12967-019-2082-1","article-title":"90\u2043gene signature assay for tissue origin diagnosis of brain metastases","volume":"17","author":"Zheng","year":"2019","journal-title":"J Transl Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00354","article-title":"Gene expression profiling for diagnosis of triple\u2043Negative breast cancer: A multicenter, retrospective cohort study","volume":"9","author":"Wang","year":"2019","journal-title":"Front Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.725988","article-title":"Gene expression profiling for differential diagnosis of liver metastases: A multicenter, retro\u2043spective cohort study","volume":"11","author":"Wang","year":"2021","journal-title":"Front Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s12935-021-01748-8","article-title":"Gene expression profiling for the diagnosis of multiple primary Malignant tumors","volume":"21","author":"Zheng","year":"2021","journal-title":"Cancer Cell Int"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00313-9","article-title":"Site-specific therapy guided by a 90-gene expression assay versus empirical chemotherapy in patients with cancer of unknown primary (Fudan CUP-001): a randomised controlled trial. 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