{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:11:46Z","timestamp":1784034706822,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Dendritic and histiocytic cell sarcoma (DHCS) and clear cell sarcoma (CCS) are ultra-rare soft-tissue sarcomas characterized by diagnostic ambiguity, limited treatment guidelines, and poor outcomes. Their rarity has restricted the development of evidence-based management strategies, leaving clinical decisions reliant on small case series and institutional experience. DHCS typically presents without a unifying molecular driver and is often misclassified without comprehensive immunophenotyping. CCS is defined by EWSR1-ATF1\/CREB1 fusions but exhibits low responsiveness to conventional chemotherapy. There remains a clear need to clarify natural history, therapeutic responses, and molecular characteristics in both. Methods: We conducted a retrospective cohort study of adult patients with histologically confirmed DHCS or CCS seen at The Ohio State University Comprehensive Cancer Center between 2010 and 2022. Demographics, treatment modalities, clinical outcomes, and molecular profiles were extracted and analyzed descriptively. Time to progression (TTP) and progression rates by treatment modality were recorded. A structured literature review was conducted to provide context for the findings. Results: Outcomes are descriptive and cohort-specific, reflecting institutional experience rather than generalizable estimates. A total of 10 patients with DHCS and 5 with CCS were evaluable. Most DHCS patients presented with metastatic disease. Among DHCS patients who received systemic therapies, 5 of 8 (62.5%) experienced progression during or shortly after treatment. Among CCS patients who received systemic therapies, 3 of 4 (75%) progressed during or shortly after treatment. Overall mortality occurred in 4 of 10 DHCS patients (40%) and 3 of 5 CCS patients (60%). TP53 mutations were identified in 4 of 7 next-generation sequencing (NGS)-tested DHCS cases, and PD-L1 positivity was detected in 5 of 7 tested DHCS cases and 1 of 5 tested CCS cases. Conclusions: Despite multimodal treatment, this referral-based cohort of patients with ultra-rare DHCS and CCS showed high rates of progression and mortality. Our findings underscore the urgent need for multi-institutional collaboration and biomarker-driven clinical trials to guide management of these ultra-rare sarcoma subtypes.<\/jats:p>","DOI":"10.3390\/cancers18040641","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T14:09:54Z","timestamp":1771250994000},"page":"641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clear Cell and Histiocytic\/Dendritic Cell Sarcomas: Clinical Outcomes, Molecular Features, and Diagnostic Pitfalls"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2565-6124","authenticated-orcid":false,"given":"Gabriel","family":"Tinoco","sequence":"first","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2649-1154","authenticated-orcid":false,"given":"Marium","family":"Husain","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7657-4137","authenticated-orcid":false,"given":"David","family":"Liebner","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4095-5202","authenticated-orcid":false,"given":"James L.","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati","family":"Satturwar","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Iwenofu","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8574-0715","authenticated-orcid":false,"given":"Valerie","family":"Grignol","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joal","family":"Beane","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-5240","authenticated-orcid":false,"given":"Scott","family":"Lenobel","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Konieczkowski","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Quinion","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Mayerson","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"ref_1","unstructured":"WHO Classification of Tumours Editorial Board (2020). Soft Tissue and Bone Tumours, International Agency for Research on Cancer."},{"key":"ref_2","first-page":"7","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA A Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"iv51","DOI":"10.1093\/annonc\/mdy096","article-title":"Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Casali","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_4","unstructured":"National Comprehensive Cancer Network (2024). Clinical Practice Guidelines in Oncology, National Comprehensive Cancer Network."},{"key":"ref_5","unstructured":"Fletcher, C.D.M., Bridge, J.A., Hogendoorn, P., and Mertens, F. (2013). WHO Classification of Tumours of Soft Tissue and Bone, International Agency for Research on Cancer."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2934","DOI":"10.1002\/cncr.33618","article-title":"Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities","volume":"127","author":"Stacchiotti","year":"2021","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1263","DOI":"10.1002\/onco.13801","article-title":"Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma","volume":"26","author":"Massoth","year":"2021","journal-title":"Oncologist"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100522","DOI":"10.1016\/j.esmoop.2022.100522","article-title":"Systemic treatment of advanced clear cell sarcoma: Results from a retrospective international series from the World Sarcoma Network","volume":"7","author":"Smrke","year":"2022","journal-title":"ESMO Open"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1016\/j.annonc.2021.07.006","article-title":"Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up \u2606","volume":"32","author":"Gronchi","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"854","DOI":"10.3324\/haematol.2019.246314","article-title":"Genomic profiling of histiocytic sarcoma: New insights into pathogenesis and subclassification","volume":"105","author":"Said","year":"2020","journal-title":"Haematologica"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"265","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":"ref_12","unstructured":"WHO Classification of Tumours Editorial Board (2024). Haematolymphoid Tumours, International Agency for Research on Cancer. [5th ed.]. Available online: https:\/\/publications.iarc.who.int\/637."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.critrevonc.2013.05.006","article-title":"Dendritic cell sarcoma: A pooled analysis including 462 cases with presentation of our case series","volume":"88","author":"Saygin","year":"2013","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_14","first-page":"1815","article-title":"Massive parallel sequencing unveils homologous recombination deficiency in follicular dendritic cell sarcoma","volume":"109","author":"Lorenzi","year":"2024","journal-title":"Haematologica"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"951","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":"ref_16","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1038\/s41379-018-0200-x","article-title":"Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma","volume":"32","author":"Shanmugam","year":"2019","journal-title":"Mod. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/s41586-019-1012-y","article-title":"Efficacy of MEK inhibition in patients with histiocytic neoplasms","volume":"567","author":"Diamond","year":"2019","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.3390\/cancers6042275","article-title":"Clinicopathologic characteristics and outcomes of histiocytic and dendritic cell neoplasms: The moffitt cancer center experience over the last twenty five years","volume":"6","author":"Dalia","year":"2014","journal-title":"Cancers"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"467","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":"ref_20","first-page":"e85606","article-title":"Clear Cell Sarcoma Incidence and Survival: A Surveillance, Epidemiology, and End Results (SEER) Database Analysis","volume":"17","author":"Wang","year":"2025","journal-title":"Cureus"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.ejso.2014.01.016","article-title":"Clear cell sarcoma of soft tissue: A retrospective review and analysis of 31 cases treated at Istituto Ortopedico Rizzoli","volume":"40","author":"Bianchi","year":"2014","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Cazzato, G., Piscazzi, F., Filosa, A., Colagrande, A., Del Fiore, P., Ambrogio, F., Battilotti, C., Danese, A., Federico, S., and Cassalia, F. (2025). Clear Cell Sarcoma (CCS) of the Soft Tissue: An Update Narrative Review with Emphasis on the Utility of PRAME in Differential Diagnosis. J. Clin. Med., 14.","DOI":"10.3390\/jcm14041233"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1093\/annonc\/mdp611","article-title":"Tumor response to sunitinib malate observed in clear-cell sarcoma","volume":"21","author":"Stacchiotti","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sidlik Muskatel, R., Pillar, N., Godefroy, J., Lotem, M., and Goldstein, G. (2022). Case report: Robust response of metastatic clear cell sarcoma treated with cabozantinib and immunotherapy. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.940927"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S1033","DOI":"10.1016\/j.annonc.2024.08.1817","article-title":"1725MO IMMUNOSARC II master trial (phase II of sunitinib and nivolumab): Results from the clear cell sarcoma (CCS) cohort: A GEIS, ISG, and UCL study","volume":"35","author":"Palmerini","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"98723","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":"ref_27","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1159\/000546447","article-title":"PDL1 Expression and Outcomes in Histiocytic Neoplasms","volume":"18","author":"Moon","year":"2025","journal-title":"Case Rep. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1080\/14737140.2016.1197122","article-title":"Biology and management of clear cell sarcoma: State of the art and future perspectives","volume":"16","author":"Cornillie","year":"2016","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ejca.2021.04.034","article-title":"Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis","volume":"152","author":"Saerens","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1702","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":"ref_31","doi-asserted-by":"crossref","first-page":"e29166","DOI":"10.1002\/pbc.29166","article-title":"Secondary histiocytic sarcoma with BRAF(V600E) mutation responsive to MAPK-targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR-targeted therapy","volume":"68","author":"Venkataraman","year":"2021","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Feng, Z., Du, Z., Liang, Y., and Zhou, J. (2024). Apatinib manifests an unexpectedly favorable outcome in the management of axillary lymph node follicular dendritic cell sarcoma: A case report. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1388982"},{"key":"ref_33","doi-asserted-by":"crossref","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":"ref_34","doi-asserted-by":"crossref","first-page":"100023","DOI":"10.1016\/j.bneo.2024.100023","article-title":"Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium","volume":"1","author":"Kemps","year":"2024","journal-title":"Blood Neoplasia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1212\/WNL.0000000000000880","article-title":"Dramatic response of a BRAF V600E-mutated primary CNS histiocytic sarcoma to vemurafenib","volume":"83","author":"Idbaih","year":"2014","journal-title":"Neurology"}],"updated-by":[{"DOI":"10.3390\/cancers18142245","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000}}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:45:46Z","timestamp":1783997146000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,16]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cancers18040641"],"URL":"https:\/\/doi.org\/10.3390\/cancers18040641","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,16]]}}}