The Clinicopathologic Features of YWHAE-FAM22 Endometrial Stromal Sarcomas: A Histologically High-grade and Clinically Aggressive Tumor Cheng-Han Lee, MD, PhD,*w Adrian Marin ˜o-Enriquez, MD,* Wenbin Ou, PhD,* Meijun Zhu, PhD,* Rola H. Ali, MD,w Sarah Chiang, MD,z Fre´de´ric Amant, MD,y C. Blake Gilks, MD,w Matt van de Rijn, MD, PhD,8 Esther Oliva, MD,z Maria Debiec-Rychter, MD,z Paola Dal Cin, PhD,* Jonathan A. Fletcher, MD,* and Marisa R. Nucci, MD* Abstract: Endometrial stromal sarcoma (ESS) is a genetically heterogenous group of uterine sarcomas, of which almost half are associated with JAZF1 rearrangement. We recently identi- fied a novel genetic fusion between YWHAE and FAM22A/B in ESS harboring t(10;17)(q22;p13) and herein describe the clin- icopathologic features of 13 YWHAE-FAM22 ESS cases (11 primary and 3 metastatic) and compare them with 20 ESS cases with JAZF1 rearrangement. Ten of 11 primary uterine tumors contained morphologically high-grade areas composed of round cells arranged in nests with a delicate stromal capillary network. The tumor cells showed large nuclei with irregular nuclear contours and significant mitotic activity (> 10 mitoses/10 HPF) in addition to focal tumor necrosis, in contrast to JAZF1 ESS, which lacked a nested growth pattern, were composed of cells with small round/oval nuclei, and typically had < 5 MF/ 10 HPF. In 7 of the 11 uterine tumors, there was an additional cytologically bland and mitotically weakly active spindle cell component with a fibrous/fibromyxoid stroma (ESS, fibromyx- oid variant). Two metastatic tumors (pulmonary) also contained round cell and spindle cell components, whereas 1 metastasis (vaginal) was composed solely of the spindle cell component. In both primary and metastatic tumors, the spindle cells were dif- fusely positive for estrogen and progesterone receptors and CD10, in contrast to the round cell areas, which were negative. Clinically, 10 of 12 patients with YWHAE-FAM22 ESS pre- sented with FIGO stages II to III disease, in contrast to only 4 of 16 patients with JAZF1 ESS presenting with stages II to III disease (P < 0.05). Tumors with YWHAE-FAM22 rearrange- ments constitute a distinct group of ESS, which is associated with high-grade morphology and aggressive clinical behavior com- pared to JAZF1 ESS. Thus, their distinction from typical JAZF1 ESS is important for prognostic and therapeutic purposes. Key Words: endometrial stromal sarcoma, 14-3-3, YWHAE, FAM22, JAZF1 (Am J Surg Pathol 2012;36:641–653) E ndometrial stromal sarcoma (ESS) is the second most common malignant uterine mesenchymal tumor, and it affects women primarily in the perimenopausal age group. These tumors are composed of cells that mor- phologically resemble non-neoplastic proliferative-phase endometrial stroma and have been termed “low-grade ESS” according to the current WHO classification to re- flect their highly differentiated state. Classically, the tu- mor cells have bland nuclear features with monotonous oval to spindle cells concentrically proliferating around a rich vascular network of arterioles and capillaries; mitotic activity is typically low (<5 per 10HPF), and tumor necrosis is absent in most tumors. 8,9,31 The WHO also recognizes another category of malignant stromal neoplasia, termed undifferentiated endometrial sarcoma (UES). In contrast to low-grade ESS, UES by definition does not re- semble endometrial stroma; instead, it exhibits high-grade cytologic atypia with marked nuclear pleomorphism ac- companied in most instances by a high mitotic rate and the presence of tumor necrosis. Distinction between ESS and UES is crucial because of major differences in prognosis between these 2 tumor types (5 y survival approximately From the *Department of Pathology, Brigham and Women’s Hospital; zDepartment of Pathology, Massachusetts General Hospital, Boston, MA; wDepartment of Pathology, Vancouver General Hos- pital, Vancouver, BC, Canada; Departments of yOncology; zHuman Genetics, Catholic University Leuven and University Hospital, Leuven, Belgium; and 8Department of Pathology, Stanford Uni- versity Medical Center, Stanford, CA. Presented in a platform presentation at USCAP 2011 annual meeting (San Antonio, USA)—abstract 1081 published in Modern Pathology, 2011;24(S1):255A. Conflicts of Interest and Source of Funding: A.M.-E. is supported by a research grant from Fundacio´n Alfonso Martı´n Escudero, Madrid, Spain. For the remaining authors none were declared. Correspondence: Marisa R. Nucci, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Amory 3, Boston, MA 02115 (e-mail: mnucci@partners.org). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.ajsp.com. Copyright r 2012 by Lippincott Williams & Wilkins ORIGINAL ARTICLE Am J Surg Pathol  Volume 36, Number 5, May 2012 www.ajsp.com | 641