Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas

Fernández-Pérez J, Pommepuy I, Michal M, Michal M, Cleven AH, Bouvier C, Gomez-Brouchet A, Weingertner N, Papke DJ, Jo VY, Garcia J, Agaimy A, Azmani R, Bourdon A, Hostein I, Soubeyran I, Alame M, Velasco V, Coindre JM, Le Loarer F, Perret RE (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Modern Pathology Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 38

Article Number: 100810

Journal Issue: 10

DOI: 10.1016/j.modpat.2025.100810

Abstract

Pseudoendocrine sarcoma (PS) is a recently described neoplasm of uncertain differentiation, characterized by recurrent CTNNB1 mutations, frequent paravertebral location, and a neuroendocrine-like histomorphology. In this study, we report the clinicopathologic, immunohistochemical, transcriptomic, and epigenetic findings of 12 PS cases. The tumors affected 7 men and 5 women with a median age of 66 years and were located in the paraspinal/paravertebral region (n = 11) and the thigh (n = 1). Median tumor size was 82 mm (range, 32-170 mm). Histologically, the tumors comprised sheets and nests of epithelioid-to-ovoid cells with uniform nuclei and speckled chromatin, frequently associated with extracellular hyaline globules and fibrovascular cords/septa. Uncommon findings included microcalcifications, myxoid stroma, pseudopapillary, pseudoglandular, microcystic or corded architecture, and lumen and rosette-like structures. Necrosis was absent, and mitotic activity was low. On immunohistochemistry, the tumors showed aberrant nuclear staining for beta-catenin (8/8) and expression of CD56 (7/7), S100 (8/8), desmin (2/6), and androgen receptor (1/4). Pankeratin (AE1/AE3), progesterone receptor, synaptophysin, chromogranin, and INSM1 were negative. All tested cases harbored CTNNB1 mutations. Using a customized cohort, methylation profiling revealed that PS formed a common cluster with solid pseudopapillary neoplasm of the pancreas (SPNP), distinct from all methylation classes from the Heidelberg sarcoma classifier and a subset of paragangliomas. Transcriptomic analysis showed that PS formed an independent cluster from a control group of tumors (including SPNP). Differential gene expression analysis showed enrichment in genes of the Wnt signaling pathway (HALLMARK gene sets) and biological processes related to sensory perception, among others (gene ontology - biological process [GO-BP]). Additionally, upregulated genes were related to various fetal cell types from the cell type signature data set (MSigDB), particularly of neuronal and epithelial lineage. Immunohistochemical assessment of potential markers identified through gene expression analysis revealed focal-to-diffuse expression of GLUT1 (6/6) and focal/multifocal expression of Brachyury (4/9) and HuD (3/7). Follow-up information, available for 10 cases (median duration of 18 months; range, 7-69 months), showed local recurrences and metastatic spread in 2 patients each. Evidence of response to radiotherapy was documented in one tumor. Altogether, this study expands knowledge on PS and suggests biological links with SPNP, including a potential shared cell of origin.

Authors with CRIS profile

Abbas Agaimy Institute of Pathology

Involved external institutions

Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ) Centre Hospitalier Universitaire (CHU) de Toulouse FR France (FR) Institut Bergonié FR France (FR) Centre Hospitalier Universitaire de Bordeaux / CHU Bordeaux FR France (FR) Hospital Center University De Limoges Dupuytren FR France (FR) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen NL Netherlands (NL) Hôpital de la Timone FR France (FR) Harvard University US United States (USA) (US) Hôpitaux universitaires de Strasbourg (HUS) / University Hospital Strasbourg FR France (FR)

How to cite

APA:

Fernández-Pérez, J., Pommepuy, I., Michal, M., Michal, M., Cleven, A.H., Bouvier, C.,... Perret, R.E. (2025). Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas. Modern Pathology, 38(10). https://doi.org/10.1016/j.modpat.2025.100810

MLA:

Fernández-Pérez, Juan, et al. "Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas." Modern Pathology 38.10 (2025).

BibTeX: Download