{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:45:27Z","timestamp":1793371527142,"version":"4.5.0"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Primary hepatic small cell carcinoma (PHSCC) is an extraordinarily rare and aggressive malignancy with a dismal prognosis. No standard treatment exists, and the role of immunotherapy in this tumor type, especially in programmed cell death ligand 1 (PD-L1) negative cases, remains unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      A 55-year-old woman presented with a large, unresectable liver mass. Biopsy confirmed a neuroendocrine carcinoma, small cell type, with a PD-L1 Combined Positive Score (CPS) of 0. She received neoadjuvant therapy with cisplatin\/carboplatin, etoposide, and serplulimab; after the first cycle, cisplatin was switched to carboplatin due to renal impairment. After 4 cycles, imaging showed a partial response, allowing for successful surgical resection. Pathological examination of the resected specimen revealed a complete pathological response (pCR) with no viable tumor cells. Multiplex immunofluorescence (mIF) analysis of the tumor microenvironment post-resection revealed an immune-rich stroma, characterized by a high density of CD38+ cells (800 cells\/mm\n                      <jats:sup>2<\/jats:sup>\n                      ) and PD-L1+ macrophages, alongside a prominent intratumoral CD8+ T-cell infiltrate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This case demonstrates that neoadjuvant chemoimmunotherapy can achieve pCR and facilitate surgical resection in initially unresectable PHSCC, even with a negative PD-L1 status. The response may be mediated by a chemotherapy-synergized, PD-1 inhibitor-driven immune activation within a receptive tumor microenvironment, particularly the stromal compartment. The presence of an immune-rich stroma may serve as a critical determinant for immunotherapy efficacy, highlighting the limitations of relying solely on tumor cell PD-L1 expression as a biomarker in this rare malignancy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1901608","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:32:55Z","timestamp":1789101175000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Complete pathological response after neoadjuvant chemoimmunotherapy in PD-L1-negative unresectable primary hepatic small cell carcinoma: a case report and tumor microenvironment analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yupeng","family":"Hong","sequence":"first","affiliation":[{"name":"Cancer Center, Department of Medical Oncology, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital, Hangzhou Medical College, Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sifu","family":"Yang","sequence":"additional","affiliation":[{"name":"Cancer Center, Department of Medical Oncology, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital, Hangzhou Medical College, Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Cancer Center, Department of Medical Oncology, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital, Hangzhou Medical College, Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital, Hangzhou Medical College, Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[{"name":"Cancer Center, Department of Medical Oncology, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital, Hangzhou Medical College, Hangzhou","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radcr.2025.01.074","article-title":"Extrapulmonary small cell carcinoma of the liver treated with chemotherapy and durvalumab","volume":"20","author":"Golemba","year":"2025","journal-title":"Radiol Case Rep"},{"key":"B2","article-title":"Primary hepatic small cell carcinoma: Two case reports, molecular characterization and pooled analysis of known clinical data","volume":"36","author":"Shastri","year":"2016","journal-title":"Anticancer Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1080\/02841860601071893","article-title":"Extrapulmonary small cell carcinoma: Single center experience with 61 patients","volume":"46","author":"Lee","year":"2007","journal-title":"Acta Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2007.48.6.1066","article-title":"Extrapulmonary small cell carcinoma of the liver: Clinicopathological and immunohistochemical findings","volume":"48","author":"Choi","year":"2007","journal-title":"Yonsei Med J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1159\/000514520","article-title":"Extrapulmonary small cell cancer: A new insight into a rare disease","volume":"99","author":"Brazg Ferro","year":"2021","journal-title":"Oncology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2012.04247.x","article-title":"Extrapulmonary small cell carcinoma: A clinicopathological study with identification of potential diagnostic mimics","volume":"61","author":"Quinn","year":"2012","journal-title":"Histopathology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejso.2020.04.017","article-title":"Extrapulmonary small cell carcinoma: Prognostic factors, patterns of care, and overall survival","volume":"46","author":"Mandish","year":"2020","journal-title":"Eur J Surg Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-7563.2010.01284.x","article-title":"Retrospective review of extra-pulmonary small cell carcinoma at King Chulalongkorn memorial hospital cases during 1998-2005","volume":"6","author":"Chalermchai","year":"2010","journal-title":"Asia Pac J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2009.07.1039","article-title":"Should extrapulmonary small cell cancer be managed like small cell lung cancer","volume":"116","author":"Brennan","year":"2010","journal-title":"Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2004.09.075","article-title":"Small-cell carcinomas of the gastrointestinal tract: A review","volume":"22","author":"Brenner","year":"2004","journal-title":"J Clin Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.01881","article-title":"Extensive-stage small-cell lung cancer: First-line and second-line treatment options","volume":"40","author":"Zugazagoitia","year":"2022","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-23-1689","article-title":"Durvalumab \u00b1 Tremelimumab + platinum-etoposide in extensive-stage small cell lung cancer (CASPIAN): Outcomes by PD-L1 expression and tissue tumor mutational burden","volume":"30","author":"Paz-Ares","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s40425-019-0540-1","article-title":"Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung cancer (SCLC)","volume":"7","author":"Carvajal-Hausdorf","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.71","article-title":"Unravelling the biology of SCLC: Implications for therapy","volume":"14","author":"Sabari","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s12943-024-02014-x","article-title":"Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: Analyses of the CASPIAN phase 3 study","volume":"23","author":"Xie","year":"2024","journal-title":"Mol Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.16464","article-title":"Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer: The ASTRUM-005 randomized clinical trial","volume":"328","author":"Cheng","year":"2022","journal-title":"Jama"},{"key":"B17","doi-asserted-by":"publisher","first-page":"3969","DOI":"10.1038\/s41467-021-24112-w","article-title":"Molecular determinants of response to PD-L1 blockade across tumor types","volume":"12","author":"Banchereau","year":"2021","journal-title":"Nat Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-025-04218-z","article-title":"Divergent outcomes of neoadjuvant therapy for locally advanced small-cell lung cancer: Two cases report and literature review","volume":"17","author":"Qiao","year":"2025","journal-title":"Discov Oncol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1080\/17425247.2021.1825376","article-title":"Platinum-based chemotherapy in combination with PD-1\/PD-L1 inhibitors: Preclinical and clinical studies and mechanism of action","volume":"18","author":"Xue","year":"2021","journal-title":"Expert Opin Drug Delivery"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1146791","article-title":"CD38: An ecto-enzyme with functional diversity in T cells","volume":"14","author":"Ghosh","year":"2023","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s12943-023-01725-x","article-title":"Roles of tumor-associated macrophages in anti-PD-1\/PD-L1 immunotherapy for solid cancers","volume":"22","author":"Zhang","year":"2023","journal-title":"Mol Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00689-z","article-title":"Clinical implications of T cell exhaustion for cancer immunotherapy","volume":"19","author":"Chow","year":"2022","journal-title":"Nat Rev Clin Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1901608\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:33:07Z","timestamp":1789101187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1901608\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":22,"alternative-id":["10.3389\/fimmu.2026.1901608"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1901608","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]},"article-number":"1901608"}}