Clear Cell and Histiocytic/Dendritic Cell Sarcomas: Clinical Outcomes, Molecular Features, and Diagnostic Pitfalls

TL;DR

This study examines rare sarcomas, showing poor treatment outcomes and the need for better diagnostic and therapeutic strategies.

Contribution

The study provides detailed clinical and molecular data from a larger cohort of rare sarcoma cases than previously reported.

Findings

Most patients with DHCS and CCS presented with advanced disease and had high progression rates during systemic therapy.

TP53 mutations and PD-L1 positivity were frequently observed in DHCS cases, suggesting potential biomarker relevance.

Mortality rates were 40% in DHCS and 60% in CCS, highlighting poor outcomes despite multimodal treatment.

Abstract

Dendritic and histiocytic cell sarcoma (DHCS) and clear cell sarcoma (CCS) are ultra-rare cancers that are difficult to diagnose and lack clear treatment guidelines, often leading to delayed recognition and inconsistent care. In this retrospective study of adults treated at a tertiary sarcoma center between 2010 and 2022, most patients presented with advanced disease and received multimodal management with surgery, radiation, and systemic therapies. This experience represents one of the larger single-institution DHCS series and a contemporaneous CCS cohort, with more granular line-level treatment and outcome data than many prior reports. However, over half of patients progressed under systemic therapy, and mortality remained high (40% in DHCS and 60% in CCS), highlighting poor outcomes observed with currently used approaches in this referral-based cohort. Molecular profiling of tumor protein p53 (TP53), programmed death-ligand 1 (PD-L1), and EWS RNA binding protein 1 (EWSR1) fusions provides biomarker-relevant data supporting the need for expert pathology review; systematic testing; and enrollment in collaborative, biomarker-driven clinical trials.

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.