Case reports

Vol. 117: Issue 5 - October 2025

Expanding the spectrum of AFF2 undifferentiated sarcoma associated to endometriosis: a novel ZDHHC9::AFF2 fusion sarcoma with high-grade features and poor prognosis

Authors

Damiano Arciuolo , Rita Alaggio , Antonio Travaglino , Giulia Scaglione , Angela Santoro , Isabella Giovannoni , Sabrina Barresi , Sara Patrizi , Evelina Miele , Luigi Pedone Anchora , Frediano Inzani , Gian Franco Zannoni

Key words: Sarcoma, undifferentiated gynecologic sarcoma, ZDHHC9::AFF2 sarcoma, cystic endometriosis
DOI: 10.32074/1591-951X-1221
Publication Date: 2025-12-16

Abstract

The AFF2 gene encodes a protein involved in transcriptional regulation and chromatin remodeling. While primarily associated with Fragile X syndrome, AFF2 fusions have recently been identified in certain malignancies, mostly sinonasal squamous cell carcinoma. Recently it has been implicated in an intra-abdominal sarcoma linked to endometriosis. We present the case of a 71-year-old woman with a 19 cm ovarian mass arising in cystic endometriosis. Histological examination revealed high-grade undifferentiated sarcoma with spindle to epithelioid morphology, high nuclear atypia, a high mitotic index, and extensive necrosis. Immunohistochemistry demonstrated positivity for Vimentin, ER, PR, CD10, focal WT1, Desmin, and NTRK, with aberrant p53 expression in 75% of tumor cells. RNA sequencing identified a novel ZDHHC9::AFF2 fusion. The patient underwent chemotherapy with epirubicin and ifosfamide but experienced recurrence with lymph node and peritoneal involvement and succumbed to the disease after 9 months.

In conclusion, this case expands the morphological spectrum of AFF2-related sarcomas, providing further evidence of their pathological heterogeneity. Moreover, it identifies a novel fusion, which may have implications for tumor classification and diagnostic refinement. The morphological findings also suggest a possible association with poor clinical outcomes. 

 In conclusion, this case expands the morphological spectrum of AFF2-related sarcomas, providing further evidence of their pathological heterogeneity. Moreover, it identifies a novel fusion, which may have implications for tumor classification and diagnostic refinement. The morphological findings also suggest a possible association with poor clinical outcomes.

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Authors

Damiano Arciuolo - Università Cattolica del Sacro Cuore

Rita Alaggio - 2 Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.

Antonio Travaglino - Unit of Pathology, Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy.

Giulia Scaglione - 4. Gynecopathology and Breast Pathology Unit, Department of Woman and Child’s Health and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Angela Santoro - 4. Gynecopathology and Breast Pathology Unit, Department of Woman and Child’s Health and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Isabella Giovannoni - 2 Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.

Sabrina Barresi - 2 Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.

Sara Patrizi - Hematology/Oncology, and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

Evelina Miele - Hematology/Oncology, and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

Luigi Pedone Anchora - Gynecologic Oncology Unit, Department of Woman and Child’s Health and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

Frediano Inzani - Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia.

Gian Franco Zannoni - Gynecopathology and Breast Pathology Unit, Department of Woman and Child’s Health and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

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Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

How to Cite
Arciuolo, D., Alaggio, R., Travaglino, A., Scaglione, G., Santoro, A., Giovannoni, I., Barresi, S., Patrizi, S., Miele, E., Pedone Anchora, L., Inzani, F., & Zannoni, G. F. (2025). Expanding the spectrum of AFF2 undifferentiated sarcoma associated to endometriosis: a novel ZDHHC9::AFF2 fusion sarcoma with high-grade features and poor prognosis. Pathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, 117(5). https://doi.org/10.32074/1591-951X-1221
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