{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T16:35:16Z","timestamp":1770395716519,"version":"3.49.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["\u7f16\u53f782460597"],"award-info":[{"award-number":["\u7f16\u53f782460597"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Histiocytic sarcoma (HS), reclassified in the WHO fifth edition as a Histiocytic\/dendritic cell neoplasms, represents a rare hematopoietic malignancy with extranodal predominance and aggressive clinical behavior. This study reports the case of a 53-year-old female diagnosed with primary pulmonary HS, who presented with a 60-mm mass in the right middle lobe and later developed fatal brain metastases. Using a combination of pathology, whole-exome sequencing, and fusion gene analysis, we identified key molecular drivers of tumor development and spread. Major findings include the concurrent activation of the RAS\/MAPK and PI3K\/mTOR pathway activation (118 combined gene variants), TP53 biallelic inactivation, HLA locus alterations, and persistent LOC285045 fusions. Drug sensitivity profiling suggested potential responses to sunitinib and MEK inhibitors. By comparing this case with nine other reported cases of lung HS, we found that lung HS has a significantly worse survival (p=0.03) than HS at other sites. A high cell growth rate (Ki-67 &amp;gt;30%) and large tumor size (&amp;gt;50 mm) were identified as critical indicators of poor prognosis.<\/jats:p>","DOI":"10.3389\/fonc.2026.1636634","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T05:22:14Z","timestamp":1770355334000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Primary pulmonary histiocytic sarcoma with CNS metastasis: a case report and molecular profiling insights"],"prefix":"10.3389","volume":"16","author":[{"given":"Kai","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Affiliated Hospital of Shihezi University, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruotong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingxian","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaige","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenghua","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lian","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weixia","family":"Nong","sequence":"additional","affiliation":[{"name":"Department of Hematology, The First Affiliated Hospital of Shihezi University, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianming","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology and National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central High Asia Diseases Incidence, Shihezi University School of Medicine\/The First Affiliated Hospital, Shihezi University","place":["Xinjiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.cbi.2009.10.009","article-title":"The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues: an overview with emphasis on the myeloid neoplasms","volume":"184","author":"Vardiman","year":"2010","journal-title":"Chem Biol Interact"},{"key":"B2","article-title":"Histiocytic sarcoma","volume":"22","author":"Tocut","year":"2020","journal-title":"Isr Med Assoc J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2018-0349-RS","article-title":"Histiocytic sarcoma","volume":"144","author":"Hung","year":"2020","journal-title":"Arch Pathol Lab Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3960\/jslrt.53.1","article-title":"Histiocytic sarcoma: an updated literature review based on the 2008 WHO classification","volume":"53","author":"Takahashi","year":"2013","journal-title":"J Clin Exp Hematop"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-10-812495","article-title":"Histiocytic sarcoma: a population-based analysis of incidence, demographic disparities, and long-term outcomes","volume":"131","author":"Kommalapati","year":"2018","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/01.pas.0000131541.95394.23","article-title":"Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid Malignancy","volume":"28","author":"Hornick","year":"2004","journal-title":"Am J Surg Pathol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2005-0026","article-title":"Histiocytic sarcoma in a 3-year-old male: a case report","volume":"116","author":"Buonocore","year":"2005","journal-title":"Pediatrics"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-009-0801-3","article-title":"Pulmonary histiocytic sarcoma mimicking pulmonary Langerhans cell histiocytosis in a young adult presenting with spontaneous pneumothorax: a potential diagnostic pitfall","volume":"455","author":"Stacher","year":"2009","journal-title":"Virchows Arch"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3960\/jslrt.55.45","article-title":"Histiocytic sarcoma originating in the lung in a 16-year-old male","volume":"55","author":"Tomita","year":"2015","journal-title":"J Clin Exp Hematop"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/dc.23285","article-title":"Fine needle aspiration cytology of histiocytic sarcoma with dendritic cell differentiation: a case of transdifferentiation from low-grade follicular lymphoma","volume":"43","author":"Mehrotra","year":"2015","journal-title":"Diagn Cytopathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/RLU.0000000000001908","article-title":"Simultaneous brain and lung histiocytic sarcoma revealed on 18F-FDG PET\/CT","volume":"43","author":"Pan","year":"2018","journal-title":"Clin Nucl Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/dc.23963","article-title":"Primary mediastinal histiocytic sarcoma presenting as pleural effusion","volume":"46","author":"Jhuang","year":"2018","journal-title":"Diagn Cytopathol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.amsu.2021.102638","article-title":"Small bowel and lung histiocytic sarcoma revealed by acute peritonitis: A case report with review of literature","volume":"68","author":"Bellalah","year":"2021","journal-title":"Ann Med Surg (Lond)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e13741","DOI":"10.1111\/crj.13741","article-title":"Primary pulmonary histiocytic sarcoma with high PD-L1 expression benefited from immunotherapy: A case report and bioinformatic analysis","volume":"18","author":"Lin","year":"2024","journal-title":"Clin Respir J"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.230375","article-title":"Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups","volume":"105","author":"Egan","year":"2020","journal-title":"Haematologica"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3109\/10428191003699845","article-title":"Histiocytic sarcoma arising in indolent small B-cell lymphoma: report of two cases with molecular\/genetic evidence suggestive of a \u2018transdifferentiation\u2019 during the clonal evolution","volume":"51","author":"Wang","year":"2010","journal-title":"Leuk Lymphoma"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2011.102","article-title":"Clonally related histiocytic\/dendritic cell sarcoma and chronic lymphocytic leukemia\/small lymphocytic lymphoma: a study of seven cases","volume":"24","author":"Shao","year":"2011","journal-title":"Mod Pathol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2018.07.286","article-title":"Clinicopathologic features and clinical outcome differences in de novo versus secondary histiocytic sarcomas: A multi-institutional experience and review of the literature","volume":"18","author":"Broadwater","year":"2018","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.49.0078","article-title":"BRAF(V600E) mutation in a histiocytic sarcoma arising from hairy cell leukemia","volume":"32","author":"Michonneau","year":"2014","journal-title":"J Clin Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1590\/abd1806-4841.20132070","article-title":"Case report of cutaneous histiocytic sarcoma: diagnostic and therapeutic dilemmas","volume":"88","author":"Trevisan","year":"2013","journal-title":"Bras Dermatol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/modpathol.3800346","article-title":"Histiocytic sarcoma: a study of five cases including the histiocyte marker CD163","volume":"18","author":"Vos","year":"2005","journal-title":"Mod Pathol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2018-0220-RA","article-title":"Histiocytic sarcoma: review, discussion of transformation from B-cell lymphoma, and differential diagnosis","volume":"142","author":"Skala","year":"2018","journal-title":"Arch Pathol Lab Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2404491","article-title":"Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients","volume":"21","author":"Pileri","year":"2007","journal-title":"Leukemia"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-11-124792","article-title":"Clonally related follicular lymphomas and histiocytic\/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone","volume":"111","author":"Feldman","year":"2008","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s40257-018-0373-6","article-title":"Unusual clinical presentations of Malignant melanoma: A review of clinical and histologic features with special emphasis on dermatoscopic findings","volume":"19","author":"Cabrera","year":"2018","journal-title":"Am J Clin Dermatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.me.44.020193.002003","article-title":"Malignant melanoma","volume":"44","author":"Sanchez","year":"1993","journal-title":"Annu Rev Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-017-2176-1","article-title":"Histiocytic and dendritic cell neoplasms: what have we learnt by studying 67 cases","volume":"471","author":"Facchetti","year":"2017","journal-title":"Virchows Arch"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12458","article-title":"Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients","volume":"162","author":"Parikh","year":"2013","journal-title":"Br J Haematol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e31822b325b","article-title":"INI1-deficient tumors: diagnostic features and molecular genetics","volume":"35","author":"Hollmann","year":"2011","journal-title":"Am J Surg Pathol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/modpathol.3880357","article-title":"Pleomorphic rhabdomyosarcoma in adults: a clinicopathologic study of 38 cases with emphasis on morphologic variants and recent skeletal muscle-specific markers","volume":"14","author":"Furlong","year":"2001","journal-title":"Mod Pathol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3390\/ijms25137293","article-title":"Long-term remission with novel combined immune-targeted treatment for histiocytic sarcoma accompanied by follicular lymphoma: case report and literature review","volume":"25","author":"Zhang","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27263","article-title":"Clinical characteristics, molecular aberrations, treatments, and outcomes of Malignant histiocytosis","volume":"99","author":"Ruan","year":"2024","journal-title":"Am J Hematol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1177\/01455613221097200","article-title":"A case of primary histiocytic sarcoma arising from a neck lymph node. Article","volume":"104","author":"Kubota","year":"2025","journal-title":"ENT-Ear Nose Throat J"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2015-213871","article-title":"Disseminated histiocytic sarcoma in a child: a clinicopathological dichotomy with 8 years survival","volume":"2016","author":"Sharma","year":"2016","journal-title":"BMJ Case Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.9738\/intsurg-d-14-00023.1","article-title":"A case of G-CSF-producing histiocytic sarcoma of the stomach. Article","volume":"100","author":"Hanaoka","year":"2015","journal-title":"Int Surg"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt395","article-title":"OncodriveCLUST: exploiting the positional clustering of somatic mutations to identify cancer genes","volume":"29","author":"Tamborero","year":"2013","journal-title":"Bioinf"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.21920","article-title":"Prognostic factors for histiocytic and dendritic cell neoplasms","volume":"8","author":"Shimono","year":"2017","journal-title":"Oncotarget"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e1496","DOI":"10.1002\/cnr2.1496","article-title":"Primary splenic histiocytic sarcoma associated with hemophagocytic lymphohistiocytosis: A case report and review of literature of next-generation sequencing involving FLT3, NOTCH2, and KMT2A mutations","volume":"5","author":"Montalvo","year":"2022","journal-title":"Cancer Rep (Hoboken)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-00673-x","article-title":"The mutational landscape of histiocytic sarcoma associated with lymphoid Malignancy. Article","volume":"34","author":"Egan","year":"2021","journal-title":"Mod Pathol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.230375","article-title":"Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups. Article","volume":"105","author":"Egan","year":"2020","journal-title":"Haematologica"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00634-7","article-title":"HLA class I loss in colorectal cancer: implications for immune escape and immunotherapy. Review","volume":"18","author":"Anderson","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1996.662","article-title":"MYCL genotypes and loss of heterozygosity in non-small-cell lung cancer. Article","volume":"74","author":"Fong","year":"1996","journal-title":"Br J Cancer"},{"key":"B43","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1002\/cjp2.298","article-title":"The prognostic marker elastin correlates with epithelial-mesenchymal transition and vimentin-positive fibroblasts in gastric cancer","volume":"9","author":"Fang","year":"2023","journal-title":"J Pathol Clin Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800234200","article-title":"The hominoid-specific oncogene TBC1D3 activates ras and modulates epidermal growth factor receptor signaling and trafficking. Article","volume":"283","author":"Wainszelbaum","year":"2008","journal-title":"J Biol Chem"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0437015100","article-title":"The Tre2 (USP6) oncogene is a hominoid-specific gene. Article","volume":"100","author":"Paulding","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1511490","article-title":"Trametinib in histiocytic sarcoma with an activating MAP2K1 (MEK1) mutation","volume":"378","author":"Gounder","year":"2018","journal-title":"N Engl J Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1186\/s12887-025-05539-2","article-title":"An 8-year-old girl with secondary histiocytic sarcoma with BRAF(V600) mutation following T-cell acute lymphoblastic leukemia demonstrating stable disease for 3 years on dabrafenib and trametinib - a case report and literature review","volume":"25","author":"Tan","year":"2025","journal-title":"BMC Pediatr"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.282207","article-title":"Sirolimus as frontline therapy for PTEN-mutated histiocytic sarcoma","volume":"108","author":"Chohan","year":"2023","journal-title":"Haematologica"},{"key":"B49","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/ejh.12755","article-title":"Histiocytic sarcoma as a secondary Malignancy: pathobiology, diagnosis, and treatment","volume":"97","author":"Ansari","year":"2016","journal-title":"Eur J Haematol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2015.06.109","article-title":"Impact of surgery, radiation and systemic therapy on the outcomes of patients with dendritic cell and histiocytic sarcomas","volume":"51","author":"Gounder","year":"2015","journal-title":"Eur J Cancer"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1636634\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T05:22:16Z","timestamp":1770355336000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1636634\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,6]]},"references-count":50,"alternative-id":["10.3389\/fonc.2026.1636634"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1636634","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,6]]},"article-number":"1636634"}}